CN112062860A - 与p53-MHC I类复合物结合的T细胞受体样抗体 - Google Patents
与p53-MHC I类复合物结合的T细胞受体样抗体 Download PDFInfo
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Abstract
本文描述了与肽‑MHC复合物结合的抗体及其片段。具体地,要求保护与肽‑MHC复合物结合的抗体,所述肽‑MHC复合物包含p53肽以及包含由HLA‑A*24等位基因编码α链的MHC I类分子。还公开了包含此类抗体和片段的组合物,以及使用其治疗、预防和诊断癌症的用途和方法。
Description
本申请是申请日为2018年3月1日、申请号为201880023533.8、发明名称为“与p53-MHC I类复合物结合的T细胞受体样抗体”的发明专利申请的分案申请。
本申请要求于2017年3月8日提交的SG申请No.10201701883R的优先权,出于各种目的引用其内容和组成并入本文。
技术领域
本发明涉及与肽-MHC复合物结合的抗体,具体地所述肽-MHC复合物包含p53肽和MHC I类分子。
背景技术
肿瘤抑制基因p53是恶性肿瘤中最常见的突变基因之一。p53转录因子通过调节参与凋亡、衰老、细胞周期停滞和基因组稳定性的基因在肿瘤抑制中起重要作用。p53的突变因而导致功能丧失增加了对肿瘤发生的易感性。
在抗肿瘤免疫反应中,免疫系统的关键组成部分是CD8+T细胞反应对肿瘤细胞的细胞毒性。细胞毒性CD8+T细胞通过识别来自细胞内加工的肽来区分肿瘤细胞和正常健康细胞,所述肽通过MHC I类分子,如HLA*A24,呈递至细胞表面。
然而,为了使CD8+T细胞进行有效免疫应答,肽-MHC复合物必须是外来的或“非自身的”才能破坏耐受性。p53的突变可能潜在地导致这种与正常健康细胞不同的肽的产生,因此可被T细胞识别以引发强大的抗肿瘤免疫应答。此外,p53突变体在肿瘤细胞中的积累可导致p53降解反应的改变,这反过来导致区分肿瘤细胞和正常细胞的不同的抗原肽库的生成。
尽管已经证明治疗性单克隆抗体在癌症治疗领域是成功的,但其受限于癌细胞表面上靶分子的有效性。经典抗体途径无法接触到细胞内蛋白如p53。源自细胞内蛋白的抗原表位呈递为表达于细胞表面的肽-MHC复合物的过程,提供了用单克隆抗体靶向此类抗原的机会。
不同的小组已经开发了靶向癌症期间MHC I类分子异常表达的细胞内靶标的抗体。然而,这些抗体主要集中于HLA*A02,其是高加索人种中的主要等位基因,例如在欧洲的14种最常见的HLA*A类型中,HLA*A02代表其中约30%。亚洲的HLA-A分布更分散,HLA*A24和HLA*A11也是常见的等位基因。
发明概述
在一个方面,本发明提供一种任选分离的抗体或抗原结合片段,其能够与细胞内蛋白肽和MHC I类分子的复合物结合。在一些实施方案中,所述的细胞内蛋白是p53。
另一方面,本发明提供一种任选分离的抗体或抗原结合片段,其能够与包含p53肽和MHC I类分子的肽-MHC复合物结合。
在根据本发明的各个方面的一些实施方案中,所述的MHC I类分子包含由HLA-A*24等位基因编码的MHC I类α链。在一些实施方案中,所述的p53肽包含以下氨基酸序列或由以下氨基酸序列组成:SEQ ID NO:75所示氨基酸序列或在该氨基酸序列中具有一个或两个或三个氨基酸取代的其变体。在一些实施方案中,所述的抗体或抗原结合片段包含氨基酸序列i)至vi):
i)LC-CDR1:X1GSX2SNIGX3X4YX5X6X7(SEQ ID NO:46);
TGTSSDVGGYNYVS(SEQ ID NO:29);或者
RASQSIGTDLA(SEQ ID NO:21);
ii)LC-CDR2:GNX8NRPS(SEQ ID NO:47);
DASNRAT(SEQ ID NO:22);或者
DVSSRPS(SEQ ID NO:30);
iii)LC-CDR3:QSYDSX9LSX10X11WV(SEQ ID NO:48);
QQRSNWPPT(SEQ ID NO:23);或者
SSYTVFSTLV(SEQ ID NO:31);
iv)HC-CDR1:SGGYYWX12(SEQ ID NO:49);或者
X13YYX14H(SEQ ID NO:50);
v)HC-CDR2:YIYYSGX15TYYNPSLKS(SEQ ID NO:51);或者
WX16X17PX18SX19X20TX2`YAQKFQG(SEQ ID NO:52);
vi)HC-CDR3:ENFGX22X23DX24(SEQ ID NO:53);
EGADGIYYFDY(SEQ ID NO:39);或者
DTYGHDY(SEQ ID NO:45);
或其变体,所述变体在序列i)至vi)的一个或多个序列中有一个或两个或三个氨基酸被另一氨基酸取代;
其中X1=T或A,X2=S或Y,X3=A或D,X4=G或D,X5=D或E,X6=V或T,X7=H或N,X8=N或T,X9=N或S,X10=不存在或D,X11=A或T,X12=S或A,X13=G或D,X14=M或I,X15=S或T,X16=I或M,X17=N或S,X18=N或D,X19=A或G,X20=G或A,X21=N或Y,X22=A或S,X23=F或Y,X24=H或Y。
在一些实施方案中,LC-CDR1是TGSSSNIGADYETH(SEQ ID NO:17),AGSYSNIGDDYETH(SEQ ID NO:20),TGSSSNIGAGYDVH(SEQ ID NO:24),TGSSSNIGAGYDVN(SEQ ID NO:27),TGTSSDVGGYNYVS(SEQ ID No:29)或RASQSIGTDLA(SEQ ID NO:21)之一。在一些实施方案中,LC-CDR2是GNTNRPS(SEQ ID NO:18),GNNNRPS(SEQ ID NO:25),DASNRAT(SEQ ID No:22)或DVSSRPS(SEQ ID NO:30)之一。在一些实施方案中,LC-CDR3是QSYDSNLSAWV(SEQ ID NO:19),QSYDSNLSDTWV(SEQ ID NO:26),QSYDSSLSAWV(SEQ ID NO:28),QQRSNWPPT(SEQ ID No:23)或SSYTVFSTLV(SEQ ID NO:31)之一。在一些实施方案中,HC-CDR1是SGGYYWS(SEQ IDNO:32),SGGYYWA(SEQ ID NO:35),SGGYYWS(SEQ ID NO:40),GYYMH(SEQ ID No:37)或DYYIH(SEQ ID NO:43)之一。在一些实施方案中,HC-CDR2是YIYYSGSTYYNPSLKS(SEQ ID NO:33),YIYYSGTTYYNPSLKS(SEQ ID NO:41),WINPNSAGTNYAQKFQG(SEQ ID No:38)或WMSPDSGATYYAQKFQG(SEQ ID NO:44)之一。在一些实施方案中,HC-CDR3是ENFGAFDH(SEQ IDNO:34),ENFGSYDY(SEQ ID NO:36),EGADGIYYFDY(SEQ ID No:39)或DTYGHDY(SEQ ID NO:45)之一。
在一些实施方案中,所述的抗体或抗原结合片段具有至少一个包含以下CDR的轻链可变区:
LC-CDR1:TGSSSNIGADYETH(SEQ ID NO:17)
LC-CDR2:GNTNRPS(SEQ ID NO:18)
LC-CDR3:QSYDSNLSAWV(SEQ ID NO:19);
或者
LC-CDR1:AGSYSNIGDDYETH(SEQ ID NO:20)
LC-CDR2:GNTNRPS(SEQ ID NO:18)
LC-CDR3:QSYDSNLSAWV(SEQ ID NO:19);
或者
LC-CDR1:RASQSIGTDLA(SEQ ID NO:21)
LC-CDR2:DASNRAT(SEQ ID NO:22)
LC-CDR3:QQRSNWPPT(SEQ ID NO:23);
或者
LC-CDR1:TGSSSNIGAGYDVH(SEQ ID NO:24)
LC-CDR2:GNNNRPS(SEQ ID NO:25)
LC-CDR3:QSYDSNLSDTWV(SEQ ID NO:26);
或者
LC-CDR1:TGSSSNIGAGYDVN(SEQ ID NO:27)
LC-CDR2:GNNNRPS(SEQ ID NO:25)
LC-CDR3:QSYDSSLSAWV(SEQ ID NO:28);
或者
LC-CDR1:TGTSSDVGGYNYVS(SEQ ID NO:29)
LC-CDR2:DVSSRPS(SEQ ID NO:30)
LC-CDR3:SSYTVFSTLV(SEQ ID NO:31)。
在一些实施方案中,所述的抗体或抗原结合片段具有至少一个包含以下CDR的重链可变区:
HC-CDR1:SGGYYWS(SEQ ID NO:32)
HC-CDR2:YIYYSGSTYYNPSLKS(SEQ ID NO:33)
HC-CDR3:ENFGAFDH(SEQ ID NO:34);
或者
HC-CDR1:SGGYYWA(SEQ ID NO:35)
HC-CDR2:YIYYSGSTYYNPSLKS(SEQ ID NO:33)
HC-CDR3:ENFGAFDH(SEQ ID NO:34);
或者
HC-CDR1:SGGYYWS(SEQ ID NO:32)
HC-CDR2:YIYYSGSTYYNPSLKS(SEQ ID NO:33)
HC-CDR3:ENFGSYDY(SEQ ID NO:36);
或者
HC-CDR1:SGGYYWA(SEQ ID NO:35)
HC-CDR2:YIYYSGSTYYNPSLKS(SEQ ID NO:33)
HC-CDR3:ENFGSYDY(SEQ ID NO:36);
或者
HC-CDR1:GYYMH(SEQ ID NO:37)
HC-CDR2:WINPNSAGTNYAQKFQG(SEQ ID NO:38)
HC-CDR3:EGADGIYYFDY(SEQ ID NO:39);
或者
HC-CDR1:SGGYYWS(SEQ ID NO:40)
HC-CDR2:YIYYSGTTYYNPSLKS(SEQ ID NO:41)
HC-CDR3:ENFGAFDY(SEQ ID NO:42);
或者
HC-CDR1:DYYIH(SEQ ID NO:43)
HC-CDR2:WMSPDSGATYYAQKFQG(SEQ ID NO:44)
HC-CDR3:DTYGHDY(SEQ ID NO:45)。
另一方面,本发明提供一种任选分离的抗体或抗原结合片段,其能够与包含p53肽和MHC I类分子的肽-MHC复合物结合,包含轻链和重链可变区序列,其中:
轻链包含LC-CDR1,LC-CDR2,LC-CDR3,其与以下LC-CDR1具有至少85%的总体序列同一性:X1GSX2SNIGX3X4YX5X6X7(SEQ ID NO:46),TGTSSDVGGYNYVS(SEQ ID NO:29)或RASQSIGTDLA(SEQ ID NO:21)之一;LC-CDR2:GNX8NRPS(SEQ ID NO:47),DASNRAT(SEQ IDNO:22)或DVSSRPS(SEQ ID NO:30)之一;LC-CDR3:QSYDSX9LSX10X11WV(SEQ ID NO:48),QQRSNWPPT(SEQ ID NO:23)或SSYTVFSTLV(SEQ ID NO:31)之一;和
重链包含HC-CDR1,HC-CDR2,HC-CDR3,其与以下HC-CDR1具有至少85%的总体序列同一性:SGGYYWX12(SEQ ID NO:49)或X13YYX14H(SEQ ID NO:50)之一;HC-CDR2:YIYYSGX15TYYNPSLKS(SEQ ID NO:51)或WX16X17PX18SX19X20TX21YAQKFQG(SEQ ID NO:52)之一;HC-CDR2:ENFGX22X23DX24(SEQ ID NO:53),EGADGIYYFDY(SEQ ID NO:39)或DTYGHDY(SEQ IDNO:45)之一;
其中X1=T或A,X2=S或Y,X3=A或D,X4=G或D,X5=D或E,X6=V或T,X7=H或N,X8=N或T,X9=N或S,X10=不存在或D,X11=A或T,X12=S或A,X13=G或D,X14=M或I,X15=S或T,X16=I或M,X17=N或S,X18=N或D,X19=A或G,X20=G或A,X21=N或Y,X22=A或S,X23=F或Y,X24=H或Y。
另一方面,本发明提供一种任选分离的抗体或抗原结合片段,其能够与包含p53肽和MHC I类分子的肽-MHC复合物结合,包含轻链和重链可变区序列,
其中:
轻链序列与SEQ ID NO:1至7之一的轻链序列具有至少85%的序列同一性;且
重链序列与SEQ ID NO:8-16之一的重链序列具有至少85%的序列同一性。
在本发明各方面的一些实施方案中,所述的抗体或抗原结合片段对包含或表达肽-MHC复合物的细胞表现出抗体依赖性细胞介导的细胞毒性(ADCC),所述肽-MHC复合物包含p53肽和MHC I类分子。在一些实施方案中,所述的抗体或抗原结合片段被包含或表达含p53肽和MHC I类分子的肽-MHC复合物的细胞内化。在一些实施方案中,所述的抗体或抗原结合片段是全人抗体或全人抗体片段。在一些实施方案中,所述的抗体或抗原结合片段与药物部分或可检测部分偶联。
在本发明各方面的一些实施方案中,所述的抗体或抗原结合片段还包含对肽-MHC复合物以外的靶标具有特异性的抗体或抗原结合片段。在一些实施方案中,对肽-MHC复合物以外的靶标具有特异性的抗体或抗原结合片段是能够结合免疫细胞表面分子的抗体或抗原结合片段,即除肽-MHC复合物之外的靶标是免疫细胞表面分子。
另一方面,本发明提供了一种嵌合抗原受体(CAR),其包含本发明所述的抗原结合片段。
另一方面,本发明提供一种任选分离的体外复合物,其包含与包含p53肽和MHC I类分子的肽-MHC复合物结合的本发明所述的抗体、抗原结合片段或CAR。
另一方面,本发明提供了一种组合物,其包含本发明所述的抗体、抗原结合片段或CAR,和至少一种药学上可接受的载体。
另一方面,本发明提供了一种编码本发明所述的抗体、抗原结合片段或CAR的分离的核酸。
另一方面,本发明提供了一种包含本发明所述的核酸的载体。
另一方面,本发明提供了一种细胞,其包含本发明所述的核酸或本发明所述的载体。
另一方面,本发明提供了本发明所述的抗体、抗原结合片段或CAR的制备方法,包括在适于表达抗体或抗原结合片段或CAR的条件下培养本发明所述的细胞。
另一方面,本发明提供了本发明所述的抗体、抗原结合片段、CAR、组合物、核酸、载体或细胞,用于治疗或医学治疗方法。
另一方面,本发明提供了本发明所述的抗体、抗原结合片段、CAR、组合物、核酸、载体或细胞,用于治疗或预防癌症。
另一方面,本发明提供了本发明所述的抗体、抗原结合片段、CAR、组合物、核酸、载体或细胞的用途,其用于制备用于治疗或预防癌症的药物。
另一方面,本发明提供一种治疗或预防癌症的方法,包括给予受试者治疗或预防有效量的本发明所述的抗体、抗原结合片段、CAR、组合物、核酸、载体或细胞。
另一方面,本发明提供一种治疗或预防受试者癌症的方法,包括:
(a)从受试者中分离至少一个细胞;
(b)修饰该至少一个细胞以表达或包含本发明所述的抗体、抗原结合片段、CAR、核酸或载体;
(c)将修饰的该至少一个细胞给予受试者。
另一方面,本发明提供一种治疗或预防受试者癌症的方法,包括:
(a)从受试者中分离至少一个细胞;
(b)将本发明所述的核酸或本发明所述的载体引入该至少一个细胞中,从而修饰该至少一个细胞;
(c)将修饰的该至少一个细胞给予受试者。
另一方面,本发明提供了一种试剂盒,其包含预定量的本发明所述的抗体、抗原结合片段、CAR、组合物、核酸、载体或细胞。
另一方面,本发明提供一种诊断受试者的疾病或病症的方法,该方法包括使含有或怀疑含有肽-MHC复合物的样品与权利要求1至21任一向所述的抗体或抗原结合片段接触,并检测抗体或抗原结合片段与肽-MHC复合物的复合物的形成。
描述
本发明涉及与肽-MHC复合物结合的抗体和抗原结合片段,特别是能够结合肽-MHC复合物的抗体,所述肽-MHC复合物包含与MHC I类分子结合(即由其呈递)的p53肽。
模拟TCR对肿瘤相关肽-MHC复合物,如p53/HLA*A24的特异性的抗体/片段,可用作肿瘤特异性靶向剂。此类物质本身有效作为治疗剂、或作为用于特异性递送有效载荷(例如药物和毒素)的靶向工具、以及作为诊断工具。
肽-MHC复合物
T细胞受体(TCR)识别由MHC分子呈递的抗原肽。
抗原通过抗原呈递细胞(APC)的分子机器加工成肽,然后与MHC分子结合并呈递为位于细胞表面的肽-MHC复合物。不同的TCR对不同的肽-MHC复合物显示出不同的结合能力,因此具有不同的反应性。MHC上的抗原加工、加载和呈递详细描述于例如Immunobiology,第5版。Janeway CA Jr,Travers P,Walport M,等人.纽约:Garland Science(2001),第5章,通过引用整体并入本文。
本发明具体地涉及TCR样抗体,其能够特异性结合肽-MHC复合物。具体地,本发明涉及能够结合肽-MHC复合物的抗体,所述肽-MHC复合物包含由MHC I类分子呈递的细胞内蛋白的肽。
“细胞内蛋白”可以是在表达该蛋白的细胞表面上不显著表达的蛋白。细胞内蛋白的亚细胞定位可以主要是表达该蛋白的细胞的细胞质或细胞核,或者是表达该蛋白的细胞的细胞器如内质网、高尔基体等。
在一些实施方案中,本发明所述的抗体能够结合含细胞内蛋白肽的肽-MHC复合物,在疾病如癌症时,所述细胞内蛋白的通过MHC I类呈递上调。在一些实施方案中,本发明所述的抗体能够结合含癌相关肽的肽-MHC复合物。
在一些实施方案中,本发明所述的抗体能够结合含p53肽的肽-MHC复合物。
p53肿瘤抑制因子是由TP53基因在人体内编码的蛋白。p53在细胞对DNA损伤和其他基因组畸变的反应中起着至关重要的作用。TP53的激活导致细胞周期停滞、DNA修复或凋亡。
在本说明书中,“p53”是指来自任何物种的p53,并且包括来自任何物种的p53的同种型、片段、变体或同源物。在一些实施方案中,p53是人p53、灵长类动物p53、非人灵长类动物p53、啮齿动物p53、鼠p53或哺乳动物p53。
在一些实施方案中,p53可包含UniProtKB-P04637(p53_人源)的氨基酸序列或由其组成:
MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDP
GPDEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHS
GTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVR
RCPHHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIH
YNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKK
GEPHHELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELK
DAQAGKEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD(SEQ ID NO:70)
在一些实施方案中,p53可包含与SEQ ID NO:70的氨基酸序列具有至少60%序列同一性的氨基酸序列或由其组成,如至少65%,70%,75%,80%,85%,90%,91%,92%,93%,94%,95%,96%,97%,98%或99%中的一种。
编码p53的基因的突变涉及多种癌症的发展和进展(Muller和Vousden,CancerCell(2014)25:304-317)。如Sakakura等人(2007年,Clin Immunol.125(1):43-51)所解释的,p53功能丧失是人类癌症中最常见的异常,超过80%的肿瘤表现出p53缺陷,这些变化通过肿瘤细胞上的HLA I类分子导致野生型p53表位(衍生自p53蛋白的非突变肽序列)的呈递增加,因而由HLA I类限制性T细胞识别。
已经鉴定了识别呈递不同p53表位的MHC I类的CD8+T细胞。这些包括HLA-A*02(HLA-A2)限制性表位p5365-73、p53149-157、p53264-272和p53217-225,以及HLA-A*24(HLA-A24)限制性表位p53125-134、p53161-169和p53204-212(参见,例如Chikamatsu等,Oral Oncol.2008 44(9):870-877)。这些p53肽的氨基酸序列如下所示。
p5365-73:RMPEAAPPV(SEQ ID NO:71)
p53149-157:STPPPGTRV(SEQ ID NO:72)
p53264-272:LLGRNSFEV(SEQ ID NO:73)
p53217-225:VVPYEPPEV(SEQ ID NO:74)
p53125-134:TYSPALNKMF(SEQ ID NO:75)
p53161-169:AIYKQSQHM(SEQ ID NO:76)
p53204-212:EYLDDRNTF(SEQ ID NO:77)
如本文所用,“肽”是指通过肽键连接的两个或更多个氨基酸单体的链。在一些实施方案中,肽的长度可以是50个氨基酸或更少。如本文所用的“多肽”是指通过肽键连接的两个或更多个肽的链。
在一些实施方案中,p53肽可包含5-20、5-18、5-15、5-14、5-13、5-12、5-11或5-10个氨基酸的连续序列,或由其组成。在一些实施方案中,肽可以是长度为5、6、7、8、9、10、11、12、13、14或15个氨基酸。
在一些实施方案中,p53肽包含SEQ ID NO:71至77之一的序列,或其氨基酸序列中具有一个或两个或三个氨基酸取代的变体,或由其组成。在一些实施方案中,肽在氨基酸序列的一端或两端另外包含1、2、3、4、5个氨基酸。在一些实施方案中,肽在氨基酸序列的一端或两端另外包含1-2、1-3、1-4或1-5个氨基酸。
在一些实施方案中,p53肽不由SEQ ID NO:73组成。
在一些实施方案中,p53肽包含SEQ ID NO:75的序列,或其氨基酸序列中具有一个或两个或三个氨基酸取代的变体,或由其组成。
该肽由MHC分子(如,MHC I类分子)呈递。MHC I类分子是α链和β2-微球蛋白的异二聚体。α链具有三个结构域,分别为α1、α2和α3。α1和α2结构域一起形成凹槽结构,凹槽与MHCI类分子呈递的肽结合,以形成肽-MHC复合物。MHC I类α链是多态的,并且不同的α链能够结合并呈递不同的肽。在人类中,MHC I类α链由人白细胞抗原(HLA)基因编码。
在本说明书中,MHC I类α/HLA可以来自任何物种,并且包括来自任何物种的同种型、片段、变体或同源物。在一些实施方案中,MHC I类a/HLA类是人、灵长类动物、非人灵长类动物、啮齿动物、鼠或哺乳动物。
在一些实施方案中,MHC I类分子包含在HLA-A基因座编码的α链。在一些实施方案中,α链由HLA-A等位基因编码,所述HLA-A等位基因是等位基因群(allele group)HLA-A2或HLA-A24的成员。在一些实施方案中,α链由HLA-A等位基因编码,所述HLA-A等位基因是等位基因群HLA-A24的成员(例如HLA-A2402或HLA-A2403)。在一些实施方案中,α链由HLA-A2402编码。
在一些实施方案中,MHC I类分子包含不由HLA-A201编码的α链。在一些实施方案中,MHC I类分子包含不由等位基因群HLA-A2的成员编码的α链。
在具体的实施方案中,本发明涉及能够结合肽:MHC复合物的抗体或抗原结合片段,所述肽:MHC复合物包含肽和MHC I类分子,所述肽含有SEQ ID NO:75的氨基酸序列或由其组成,所述MHC I类分子包含由HLA-A*24等位基因编码的MHC I类α链。
抗体/抗原结合片段
本发明所述的抗体和抗原结合片段与肽-MHC复合物结合,所述复合物为p53肽和MHC I类分子的肽-MHC复合物。
“抗体”包括其片段和衍生物,或合成抗体或合成抗体片段。如本文所用,抗体是能够与相关靶分子(即抗体对其具有特异性的抗原)特异性结合的多肽。本发明所述的抗体可以是分离的形式。
考虑到与单克隆抗体技术相关的现有技术,可以针对大多数抗原制备抗体。抗原结合部分可以是抗体的一部分(如Fab片段)或合成的抗体片段(如单链Fv片段[ScFv])。所选抗原的合适单克隆抗体可以通过已知技术制备,例如在下文中公开的那些“单克隆抗体:技术手册”,H Zola(CRC出版社,1988年)和“单克隆杂交瘤抗体:技术与应用”,J G RHurrell(CRC出版社,1982年)。Neuberger等人(1988,第8届国际生物技术研讨会第2部分,792-799)讨论了嵌合抗体。
单克隆抗体(mAb)可用于本发明所述的方法,并且是特异性靶向抗原上的单个表位的同源抗体群。
抗体的抗原结合片段(如Fab和Fab2片段)也可以作为/是基因工程化的抗体和抗体片段。抗体的可变重链(VH)和可变轻链(VL)结构域参与抗原识别,这是早期蛋白酶消化实验首先认识到的事实。通过啮齿动物抗体的“人源化”进一步确认。啮齿动物来源的可变结构域可以与人源恒定结构域融合,使得所得抗体保留啮齿动物亲本抗体的抗原特异性(Morrison等(1984)Proc.Natl.Acad.Sci.USA 81,6851-6855)。
在一些实施方案中,抗体/片段是全人抗体/片段。全人抗体/片段由人源核酸序列编码。全人抗体/片段缺乏非人氨基酸序列。
用于产生全人抗体的两种最常用的技术是(i)噬菌体展示,其中人抗体基因在噬菌体展示文库中表达,以及(ii)在转基因小鼠中产生抗体,所述转基因小鼠工程化以具有人抗体基因(Park和Smolen描述于蛋白化学进展Advances in Protein Chemistry(2001)56:369-421)。简而言之,在人抗体基因-噬菌体展示技术中,编码VH和VL链的基因通过PCR扩增、从“天然”人淋巴细胞克隆产生,并组装成文库,从所述文库中可以表达为二硫键连接的Fab片段或作为单链Fv(scFv)片段。编码Fab或scFv的基因与丝状噬菌体的表面外壳蛋白融合,然后可以通过用抗原筛选文库来确定能够结合目标靶的Fab或scFv。可以使用分子进化或亲和力成熟操作来增强Fab/scFv片段的亲和力。在转基因小鼠技术中,体内鼠内源性Ig基因座被其人同源物同源重组取代的小鼠用抗原免疫,并通过常规杂交瘤技术制备单克隆抗体,以产生全人单克隆抗体。
从涉及抗体片段的细菌表达的实验中得知,该抗原特异性由可变结构域赋予并且与恒定结构域无关,所述抗体片段均含有一个或多个可变结构域。这些分子包括Fab样分子(Better等(1988)Science 240,1041);Fv分子(Skerra等(1988)Science 240,1038);单链Fv(ScFv)分子,其中VH和VL伴侣结构域通过柔性寡肽连接(Bird等(1988)Science 242,423;Huston等(1988)Proc.Natl.Acad.Sci.USA85,5879)和包含单独的V结构域的单结构域抗体(dAb)(Ward等(1989)Nature341,544)。保留其特异性结合位点的抗体片段合成中涉及的技术的综述可见Winter&Milstein(1991)Nature 349,293-299。
“ScFv分子”是指其中VH和VL伴侣结构域共价连接(如,通过柔性寡肽)的分子。
Fab、Fv、ScFv和dAb抗体片段都可以在大肠杆菌中表达和分泌,因此可以容易地产生大量的所述片段。
全抗体和F(ab')2片段是“二价的”。“二价”是指所述抗体和F(ab')2片段具有两个抗原结合位点。相反,Fab、Fv、ScFv和dAb片段是单价的,仅具有一个抗原结合位点。
本发明所述的抗原结合片段可以是能够结合靶抗原的多肽的任何片段。
在一些实施方案中,抗原结合片段包含至少三个轻链CDR(即LC-CDR1、LC-CDR2和LC-CDR3;本文也称为LC-CDR1-3)和三个重链CDR(即HC-CDR1、HC-CDR2和HC-CDR3;在本文中也称为HC-CDR1-3),它们一起限定抗体或抗原结合片段的抗原结合区。在一些实施方案中,抗原结合片段可包含抗体或抗原结合片段的轻链可变结构域和重链可变结构域。在一些实施方案中,抗原结合片段可包含抗体或抗原结合片段的轻链多肽和重链多肽。
本发明还提供了一种嵌合抗原受体(CAR),其包含一种或多种本发明所述的抗原结合片段或多肽。
嵌合抗原受体(CAR)是同时提供抗原结合和T细胞活化功能的重组受体。例如,在Dotti等,Immunol Rev(2014)257(1)中综述了CAR结构和工程化,该文献通过引用整体并入本文。CAR通常包含与细胞膜锚定区(如跨膜区)连接的细胞外抗原结合区和信号传导区。任选的铰链或间隔区可以是抗原结合区和细胞膜锚定区之间的分隔,并且可以充当柔性接头。
本文提供了本发明所述的抗原结合片段或多肽,作为嵌合抗原受体(CAR)的抗原结合结构域。在一些实施方案中,CAR包含本文所述的抗体、抗原结合片段或多肽的任何实施方案的VL结构域和VH结构域。可以采用任何合适的形式,例如,scFv、scFab等提供本发明所述的CAR的抗原结合区。
细胞膜锚定区或跨膜区,位于CAR的抗原结合区和信号传导区之间,并用于将CAR锚定到表达CAR的细胞的细胞膜,其中抗原结合区在细胞外空间,而信号传导区在细胞内。在一些实施方案中,CAR包含细胞膜锚定区,其包含一段氨基酸序列或由其组成,所述氨基酸序列包含、由其组成或源自CD3ζ、CD4、CD8或CD28之一的跨膜区氨基酸序列。如本文所用,“源自”参比氨基酸序列的区域所包含的氨基酸序列与参比序列的序列同一性至少为60%,例如,至少65%,70%,75%,80%,85%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%之一。
细胞膜锚定区或跨膜区可以是跨细胞膜的疏水性α螺旋。通常使用与信号传导区域相关的跨膜区,或者可通过氨基酸取代选择或修饰跨膜区,以避免这些结构域与相同或不同表面膜蛋白的跨膜结构域结合,从而最大程度降低与受体复合物的其他成员间的相互作用。
CAR可与共刺激配体、嵌合共刺激受体或细胞因子组合,以进一步增强T细胞效力、特异性和安全性(Sadelain等,嵌合抗原受体(CAR)设计的基本原理。Cancer Discov.2013年4月;3(4):388-398.DOI:10.1158/2159-8290.CD-12-0548,具体地通过引用并入本文。
还提供了一种包含本发明所述的CAR的细胞。本发明所述的CAR可用于产生表达CAR的免疫细胞,如T细胞。这些细胞可以靶向癌细胞(如肿瘤细胞),所述癌细胞表达CAR的特异性抗原。将CAR工程改造入T细胞可以在为转导和扩增的体外培养期间进行,例如发生在用于过继性T细胞疗法的T细胞扩增期间。
本发明还提供了双特异性抗体和双特异性抗原结合片段,其中包含本发明所述的抗体或抗原结合片段。双特异性抗体或双特异性抗原结合片段可包含(i)本发明所述的抗体或抗原结合片段,和(ii)肽-MHC复合物以外的靶标的特异性抗体或抗原结合片段。
在一些实施方案中,双特异性抗体和双特异性抗原结合片段包含本发明所述的抗原或抗原结合片段,以及能够结合免疫细胞表面分子的抗体或抗原结合片段。本文中,免疫细胞表面分子是在免疫细胞的细胞表面表达的分子,并且可以是任何肽/多肽、糖蛋白、脂蛋白、聚糖、糖脂、脂质、或其片段。
免疫细胞表面分子可以表达于任何免疫细胞的细胞表面。在一些实施方案中,免疫细胞可以是造血来源的细胞,例如,中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、树突细胞、淋巴细胞或单核细胞。淋巴细胞可以是例如T细胞、B细胞、自然杀伤(NK)细胞、NKT细胞或先天淋巴细胞(ILC)、或其前体(如,胸腺细胞或前B细胞)。细胞可表达一种或多种CD3多肽(例如CD3ε、CD3γ、CD3δ、CD3ζ和/或CD3η)、TCR多肽(TCRα、TCRβ、TCRγ和/或TCRδ)、CD27、CD28、CD4、CD8、CD16、CCR5、CCR7、CD2、CD7、PD-1、和/或CTLA4。
在一些实施方案中,所述的免疫细胞是T细胞。在一些实施方案中,所述的T细胞是CD3+T细胞。在一些实施方案中,所述的T细胞是CD3+,CD8+T细胞。在一些实施方案中,所述的T细胞是CD3+,CD4+T细胞。在一些实施方案中,所述的T细胞是细胞毒性T细胞(如细胞毒性T淋巴细胞(CTL))、T辅助细胞(例如Th1、Th2、Th9、Th17、Th22或Tfh细胞)、调节性T细胞(Treg)、中枢记忆细胞(Tcm)、或效应记忆细胞(Tem)。
在一些实施方案中,所述的免疫细胞是NK细胞。在一些实施方案中,所述的T细胞是CD16+NK细胞。
在一些实施方案中,所述的免疫细胞表面分子选自一种或多种CD3多肽(例如CD3ε、CD3γ、CD3δ、CD3ζ或CD3η)、TCR多肽(TCRα、TCRβ、TCRγ和TCRδ)、CD27、CD28、CD4、CD8、CCR5、CCR7、CD2、CD7、PD-1和CTLA4。
CD3是在T淋巴细胞的细胞表面表达的多肽的复合物。在哺乳动物中,CD3复合物含有一条CD3γ链、一条CD3δ链和两条CD3ε链。这些链与TCR多肽(TCRα和TCRβ)和CD3ζ/CD3η链结合形成CD3-TCR复合物,其在T淋巴细胞中产生激活信号。
在一些实施方案中,所述的免疫细胞表面分子是在T细胞的细胞表面表达的分子。在一些实施方案中,所述的免疫细胞表面分子是CD3-TCR复合物的多肽。在一些实施方案中,所述的免疫细胞表面分子是CD3多肽(例如CD3ε、CD3γ、CD3δ、CD3ζ或CD3η)、含有CD3多肽的复合物、TCR多肽(TCRα、TCRβ、TCRγ或TCRδ)或含有TCR多肽的复合物。
在一些实施方案中,所述的双特异性抗体和双特异性抗原结合片段包含本发明所述的抗体或抗原结合片段和CD3结合结构域。在一些实施方案中,所述的双特异性抗体和双特异性抗原结合片段包含本发明所述的抗体或抗原结合片段和CD3-TCR复合多肽结合结构域。在一些实施方案中,所述的CD3-TCR复合多肽结合结构域是CD3多肽结合结构域。在一些实施方案中,所述的CD3-TCR复合多肽结合结构域是CD3ε结合结构域。
双特异性抗体/片段可以是任何合适的形式,例如Kontermann MAbs 2012,4(2):182-197中描述的那些形式特此通过引用整体并入。例如,双特异性抗体或双特异性抗原结合片段可以是双特异性抗体偶联物(例如IgG2、F(ab’)2或CovX体),双特异性IgG或IgG样分子(例如IgG、scFv4-Ig、IgG-scFv、scFv-IgG、DVD-Ig、IgG-sVD、sVD-IgG、2合1-IgG、mAb2或Tandemab通用LC),不对称双特异性IgG或IgG样分子(例如kih IgG、kih IgG通用LC、CrossMab、kih IgG-scFab、mAb-Fv、电子对或SEED体),小的双特异性抗体分子(例如双体(Diabody,Db)、dsDb、DART、scDb、tandAbs、串联scFv(taFv)、串联dAb/VHH、三体、三头、Fab-scFv、或F(ab')2-scFv2),双特异性Fc和CH3融合蛋白(例如taFv-Fc、Di-diabody、scDb-CH3、scFv-Fc-scFv、HCAb-VHH、scFv-kih-Fc、或scFv-kih-CH3),或双特异性融合蛋白(例如scFv2-白蛋白、scDb-白蛋白、taFv-毒素、DNL-Fab3、DNL-Fab4-lgG、DNL-Fab4-IgG-细胞因子2)。具体参见Kontermann MAbs 2012,4(2):182-19的图2。所述的双特异性抗体或抗原结合片段可以是双特异性T细胞接合物(BiTE)。
在一些实施方案中,所述的肽-MHC复合物以外的靶标的特异性抗体或抗原结合片段位于本文所述的双特异性抗体或双特异性抗原结合片段的片段可结晶区(Fc区)上。在一些实施方案中,所述的双特异性抗体或双特异性抗原结合片段的Fab区包含肽-MHC复合物以外的靶标的特异性抗体或抗原结合片段。在一些实施方案中,所述的肽-MHC复合物以外的靶标的特异性抗体或抗原结合片段取代本文所述的双特异性抗体或双特异性抗原结合片段的Fab区。
产生双特异性抗体的方法包括抗体或抗体片段的化学交联,如利用还原性二硫化物或非还原性硫醚键,例如Segal和Bast,2001.双特异性抗体的生产。《最新免疫学方法》(Current Protocols in Immunology).14:IV:2.13:2.13.1-2.13.16中所述,其全部内容通过引用并入本文。例如,可利用N-琥珀酰亚胺基-3-(-2-吡啶基二硫代)-丙酸酯(SPDP)通过,例如铰链区SH-基团化学交联Fab片段,以产生二硫键连接的双特异性F(ab)2异二聚体。其他方法包括融合产生抗体的杂交瘤,如用聚乙二醇来制备能够分泌双特异性抗体的四倍体细胞,例如D.M.和Bast,B.J.2001.双特异性抗体的生产。《最新免疫学方法》.14:IV:2.13:2.13.1-2.13.16。双特异性抗体和双特异性抗原结合片段也可以通过表达如编码抗原结合分子多肽的核酸构建体而重组产生,例如在《抗体工程:方法和流程》,第二版(Humana出版社,2012年),第40章:生产双特异性抗体:二体和串联scFv(Hornig和-Schwarz),或French,如何制备双特异性抗体,Methods Mol.Med.2000;40:333-339中所述,两者的全部内容在此引入作为参考。
抗体可以通过亲和力成熟过程产生,与未修饰的亲本抗体相比,亲和力成熟过程产生对抗原的亲和力有所改善的经修饰抗体。亲和力成熟的抗体可以通过本领域已知的方法产生,例如Marks等,Rio/Technology 10:779-783(1992);巴尔巴斯等人.ProcNat.Acad.Sci.USA 91:3809-3813(1994);Schier等人.Gene169:147-155(1995);耶尔顿等人.J.Immunol.155:1994-2004(1995);Jackson等人,J.Immunol.154(7):331 0-15 9(1995);和霍金斯等人,J.Mol.Biol.226:889-896(1992)。
本发明提供了进一步经历了链改组过程(如,轻链改组和/或重链改组)的本文所述抗体。用于改善抗体亲和力的链改组在Marks,通过链改组的抗体亲和力成熟、抗体工程化方法和流程,Humana出版社(2004)第248卷,第327-343页,特别是在其3.1和3.2节中详细描述了轻链改组,通过引用整体并入本文。在轻链改组中,抗体的重链可变区与轻链可变区伴侣库联合,以形成对目标靶蛋白具有高亲和力的新VL/VH组合。以此方式优化抗体/片段得到非常高的结合亲和力。
在一些方面,本发明所述的抗体/片段包含本文所述抗体克隆的VH和/或VL结构域的CDR(即CDR1-3)、或其变体。在一些实施方案中,本发明所述的抗体/片段包含本文所述的抗体克隆的HC-CDR1-3、或其变体。在一些实施方案中,本发明所述的抗体/片段包含本文所述的抗体克隆的LC-CDR1-3、或其变体。
本公开的抗体克隆的HC-CDR1-3和LC-CDR1-3根据Kabat定义(Kabat等人,NIH出版社,91-3242(1991)确定,所述内容在此全文引入作为参考。
如本文所用,CDR的变体可在CDR的氨基酸序列中包含,例如1或2或3个取代。如本文所用,VL或VH结构域的变体可在该结构域的氨基酸序列中包含,例如1、2、3、4、5、6、7、8、9或10个取代。
在一些实施方案中,本发明所述的抗体/片段包含本文所述的抗体克隆的HC-CDR1-3、或其变体,和本文所述的抗体克隆的LC-CDR1-3、或其变体。
在一些方面,本发明所述的抗体/片段包含本文所述的抗体克隆的VH和/或VL结构域的CDR、或其变体。在一些方面,本发明所述的抗体/片段包含本文所述的抗体克隆的VH和/或VL结构域、或其变体。
在一些方面,本发明所述的抗体/片段包含一克隆的VH和/或VL结构域的CDR、或其变体,所述克隆选自P1C1、P1C1_g1、P1C1_dm、P1C1_tm、1G7、2E3、1E11、P1H4、P1B11、P1A8或P2B4。
在一些方面,本发明所述的抗体/片段包含一克隆的VH和/或VL结构域、或其变体,所述克隆选自P1C1、P1C1_g1、P1C1_dm、P1C1_tm、1G7、2E3、1E11、P1H4、P1B11、P1A8或P2B4。
在一些方面,本发明所述的抗体/片段包含本文所述的抗体克隆的VH结构域的HC-CDR1-3、或其变体。在一些方面,本发明所述的抗体/片段包含一克隆的VH结构域、或其变体。
在一些方面,本发明所述的抗体/片段包含本文所述的抗体克隆的VL结构域的LC-CDR1-3、或其变体。在一些方面,本发明所述的抗体/片段包含一克隆的VL结构域或其变体。
在一些实施方案中,本发明所述的抗体/片段包含抗体克隆的VH结构域或VH结构域的HC-CDR1-3,所述的抗体克隆选自P1C1、P1C1_g1、P1C1_dm、P1C1_tm、1G7、2E3、1E11、P1H4、P1B11、P1A8或P2B4。
在一些实施方案中,本发明所述的抗体/片段包含抗体克隆的VL结构域或VL结构域的LC-CDR1-3,所述的抗体克隆选自P1C1、P1C1_g1、P1C1_dm、P1C1_tm、1G7、2E3、1E11、P1H4、P1B11、P1A8或P2B4。
抗体克隆P1C1、P1C1_g1、P1C1_dm、P1C1_tm、1G7、2E3、1E11、P1H4、P1B11、P1A8或P2B4的VL结构域的氨基酸序列如图1所示,根据Kabat系统(Kabat等,NIH出版社,91-3242(1991))定义的LC-CDR1-3也是如此。P1C1、P1C1_g1、P1C1_dm、P1C1_tm、1G7、2E3、1E11、P1H4、P1B11、P1A8或P2B4的VH结构域的氨基酸序列如图2所示,根据Kabat系统定义的HC-CDR1-3也是如此。
本发明所述的抗体/片段可包含VL和/或VH链,所述VL和/或VH链包含与本文所述的一个或多个VL和/或VH氨基酸序列具有高百分比序列同一性的氨基酸序列。例如,本发明所述的抗体包括有VL链的抗体,所述VL链包含与SEQ ID NO:1至7之一所示的VL链氨基酸序列具有至少70%,更优选至少75%,80%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%之一的序列同一性的氨基酸序列。本发明所述的抗体/片段包括具有VH链的抗体,所述VH链包含与SEQ ID NO:8至16之一所示的VH链氨基酸序列具有至少70%,更优选至少75%,80%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%之一的序列同一性的氨基酸序列。
本发明所述的抗体/片段可包含由核酸序列编码的VL和/或VH链,所述核酸序列与本文所述的一种或多种VL和/或VH核酸序列具有高百分比序列同一性,或由于密码子简并性编码相同的氨基酸序列。例如,本发明所述的抗体包括具有VL链的抗体,所述VL链由与SEQ ID NO:54至60之一的核酸序列具有至少70%,更优选至少75%,80%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%之一的序列同一性的核酸序列编码,或由因密码子简并性而编码与SEQ ID NO:54至60之一(编码)的相同氨基酸序列的核酸序列编码。
本发明所述的抗体/片段包括具有VH链的抗体,所述VL链由与SEQ ID NO:61至69之一的核酸序列具有至少70%,更优选至少75%,80%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%之一的序列同一性的核酸序列编码,或由因密码子简并性而编码与SEQ ID NO:61至69之一(编码)的相同氨基酸序列的核酸序列编码。
本文公开的轻链和重链CDR与许多不同的框架区结合也可能特别有用。因此,含LC-CDR1-3或HC-CDR1-3的轻链和/或重链可具有替代的框架区。
合适的框架区是本领域熟知的,并且描述于例如M.Lefranc和G.Lefranc(2001)《免疫球蛋白概况》,学术出版社,通过引用并入本文。
本发明所述的抗体/片段可以被可检测地标记,或至少能够被检测。例如,所述的抗体可以用放射性原子、或有色分子、或荧光分子、或可以任何其他容易地检测的分子标记。合适的可检测分子包括荧光蛋白、荧光素酶、酶底物、放射性标记和结合部分。标记可以与抗体/片段偶联。抗原结合分子可以用可检测标记直接标记、或者可以间接标记。在一些实施方案中,所述的标记可以选自:放射性核苷酸、正电子发射放射性核素(如用于正电子发射断层扫描(PET))、MRI造影剂或荧光标记。
本发明所述的抗体和抗原结合片段可以与效应部分偶联,例如,药物部分如细胞毒性小分子。通过效应部分的靶向递送,这种偶联物可用于靶向杀死表达靶标的细胞,所述靶标为抗体/抗原结合片段特异性的靶标。
或者,在一些实施方案中,本发明所述的抗体和抗原结合片段可以与能够结合该抗体/片段的第二结合剂(例如第二抗体)联用,该结合剂与药物部分(如细胞毒性小分子)偶联。
在一些实施方案中,该部分选自如在Vankemmelbeke和Durrant Ther.Deliv.(2016)7(3),141-144或Diamantis和Banjeri,British Journal of Cancer(2016)114,362-367描述的部分,这两篇文献都通过引用整体并入本文。在一些实施方案中,药物部分选自PNU159682(PNU)和吡咯并苯并二氮杂(PBD)。在一些实施方案中,药物部分是蒽环类衍生物。
本发明还提供了分离的重链可变区多肽和分离的轻链可变区多肽。
在一些方面,提供了一种分离的轻链可变区多肽,其包含本文所述的任一抗体克隆的LC-CDR 1-3。在一些方面,提供了一种分离的轻链可变区多肽,其包含与本文描述的任一抗体克隆的轻链可变区的氨基酸序列具有至少70%,更优选至少75%,80%,85%,86%,87%,88%,89%的90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%之一的序列同一性的氨基酸序列。
在一些方面,提供了一种分离的重链可变区多肽,其包含本文所述的任一抗体克隆的HC-CDR 1-3。在一些方面,提供了一种分离的重链可变区多肽,其包含与本文描述的任一抗体克隆的重链可变区的氨基酸序列具有至少70%,更优选至少75%,80%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%之一的序列同一性的氨基酸序列。
抗体/片段的功能特性
可以通过参考某些功能特性,来描述本发明所述的抗体和片段的特性。具体地,本发明所述的抗体或抗原结合片段可具有以下一种或多种性质:
a)特异性结合含p53肽和MHC I类分子的肽-MHC复合物,例如,含p53125-134和MHC I类分子的肽-MHC复合物,所述MHC I类分子包含由HLA-A*24等位基因编码的MHC I类α链;
b)与包含p53肽和MHC I类分子的肽-MHC复合物结合(例如含p53125-134和MHC I类分子的肽-MHC复合物,所述MHC I类分子包含由HLA-A*24等位基因编码的MHC I类α链)的结合亲和力≤5μM,例如,通过表面等离子体共振(SPR)确定;
c)在不存在p53肽的情况下(如在没有p53125-134的情况下),不特异性结合MHC I类分子(例如,包含由HLA-A*24等位基因编码的MHC I类α链的MHC I类分子);
d)不特异性结合不包含p53肽(如p53125-134)的肽-MHC复合物(例如包含MHC I类分子,其包含由HLA-A*24等位基因编码的MHC I类α链);
e)在不存在MHC I类分子的情况下(例如,不存在包含由HLA-A*24等位基因编码的MHC I类α链的MHC I类分子),不特异性结合p53肽(例如p53125-134);
f)对包含/表达肽-MHC复合物的细胞表现出抗体依赖性细胞介导的细胞毒性(ADCC),所述肽-MHC复合物含p53肽和MHC I类分子(例如,包含p53125-134和MHC I类分子的肽-MHC复合物,所述MHC I类分子包含由HLA-A*24等位基因编码MHC I类α链);
g)在不存在p53肽的情况下(例如在没有p53125-134),对包含/表达MHC I类分子(例如,包含由HLA-A*24等位基因编码的MHC I类α链的MHC I类分子)的细胞不表现出ADCC;
h)对包含/表达不含p53肽(例如p53125-134)的肽-MHC复合物(例如,包含由HLA-A*24等位基因编码的MHC I类α链的MHC I类分子)的细胞不表现出ADCC;
i)通过包含/表达肽-MHC复合物的细胞表现出内化作用,所述肽-MHC复合物包含p53肽和MHC I类分子(例如,包含p53125-134和MHC I类分子的肽-MHC复合物,所述MHC I类分子包含由HLA-A*24等位基因编码的MHC I类α链);
j)在不存在p53肽的情况下(例如在没有p53125-134),包含/表达MHC I类分子(例如,包含由HLA-A*24等位基因编码的MHC I类α链的MHC I类分子)的细胞不表现出内化作用;
k)包含/表达不含p53肽(例如p53125-134)的肽-MHC复合物(例如,包含由HLA-A*24等位基因编码的MHC I类α链的MHC I类分子)的细胞不表现出内化作用;
一种特异性结合含p53肽和MHC I类分子的肽-MHC复合物(例如,包含p53125-134和MHC I类分子的肽-MHC复合物,所述MHC I类分子包含由HLA-A*24等位基因编码的MHC I类α链)的抗体/片段,与其他非靶分子/复合物结合相比,所述的抗体/片段与含p53肽和MHC I类分子的肽-MHC复合物的结合亲和力更大和/或持续时间更长。
在一些实施方案中,本发明所述的抗体/片段可结合含p53肽和MHC I类分子的肽-MHC复合物(例如,含p53125-134和MHC I类分子的肽-MHC复合物,所述MHC I类分子包含由HLA-A*24等位基因编码MHC I类α链),其亲和力大于在不存在p53肽的情况下(例如,不存在p53125-134)结合MHC I类分子(例如,包含由HLA-A*24等位基因编码的MHC I类α链的MHC I类分子)的亲和力,和/或大于结合不含p53肽(例如p53125-134)的肽-MHC复合物(例如,包含MHCI类分子,所述MHC I类分子包含由HLA-A*24等位基因编码的MHC I类α链)的亲和力。
在一些实施方案中,经测量,抗体与非靶标的结合程度小于抗体与靶标结合的约10%,所述测量如通过ELISA、SPR、生物层干涉测量法(BLI)、MicroScale测量、热泳(MST)、或通过放射免疫测定(RIA)。或者,结合特异性可以反映在结合亲和力方面,本发明所述的抗体/片段结合含p53肽和MHC I类分子的肽-MHC复合物(例如,包含p53125-134和MHC I类分子的肽-MHC复合物,所述MHC I类分子包含由HLA-A*24等位基因编码的MHC I类α链)的KD为至少大于与非靶向分子/复合物结合的KD 0.1个数量级(即0.1×10n,其中n是表示数量级的整数)。这可以任选地为至少0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、1.5或2.0中的一个。
抗体或抗原结合片段对其靶标的结合亲和力通常以其解离常数(KD)来描述。结合亲和力可以通过本领域已知的方法测量,例如通过ELISA、表面等离子体共振(SPR;参见例如Hearty等,Methods Mol Biol(2012)907:411-442;或Rich等,Anal Biochem.2008年2月1日;373(1):112-20)、生物层干涉测量法(参见例如Lad等,(2015)J Biomol Screen 20(4):498-507;或Concepcion等,Comb Chem High Throughput Screen.2009年9月;12(8):791-800)、微量热泳(MST)分析(参见例如Jerabek-Willemsen等,Assay Drug DevTechnol.2011年8月;9(4):342-353)或通过抗体和抗原分子的Fab形式进行的放射性标记的抗原结合测定(RIA)。
在一些实施方案中,本发明所述的抗体/片段与含p53肽和MHC I类分子的肽-MHC复合物(例如,包含p53125-134和MHC I类分子的肽-MHC复合物,所述MHC I类分子包含由HLA-A*24等位基因编码MHC I类α链)结合,其KD为10μM或更低,优选≤5μM,≤1μM,≤900nM,≤800nM,≤700nM,≤600nM,≤500nM,≤400nM,≤300nM,≤200nM,≤100nM,≤75nM,≤50nM,≤40nM,≤30nM,≤20nM,≤15nM,≤12.5nM,≤10nM,≤9nM,≤8nM,≤7nM,≤6nM,≤5nM,≤4nM≤3nM,≤2nM,≤1nM,≤500pM,如由SPR分析确定。
在一些实施方案中,本发明所述的抗体/片段与含p53肽和MHC I类分子肽-MHC复合物(例如,包含p53125-134和MHC I类分子的肽-MHC复合物,所述MHC I类分子包含由HLA-A*24等位基因编码MHC I类α链)结合,其结合亲和力EC50=1000ng/ml或更低(例如通过ELISA测定),优选以下之一:≤900ng/ml,≤800ng/ml,≤700ng/ml,≤600ng/ml,≤500ng/ml,≤400ng/ml,≤300ng/ml,≤200ng/ml,≤100ng/ml,≤90ng/ml,≤80ng/ml,≤70ng/ml,≤60ng/ml,≤50ng/ml,≤40ng/ml,≤30ng/ml,≤20ng/ml,≤15ng/ml,≤10ng/ml,≤7.5ng/ml,≤5ng/ml,≤2.5ng/ml,或≤1ng/ml。
可以通过ELISA测定,在体外分析抗体/片段结合的亲和力。合适的测定是本领域熟知的,并且可以由技术人员进行,例如,如《抗体工程化》,第1卷(第2版),SpringerProtocols,Springer(2010),第五部分,第657-665页所述。
在一些实施方案中,所述的抗体/抗原结合片段对包含/表达肽-MHC复合物的细胞表现出抗体依赖性细胞介导的细胞毒性(ADCC),所述肽-MHC复合物包含p53肽和MHC I类分子(例如,包含p53125-134和MHC I类分子的肽-MHC复合物,所述MHC I类分子包含由HLA-A*24等位基因编码MHC I类α链)。抗体/抗原结合片段通常包含Fc区,所述抗体/抗原结合片段对包含/表达肽-MHC复合物的细胞表现出ADCC,所述肽-MHC复合物包含p53肽和MHC I类分子((例如,包含p53125-134和MHC I类分子的肽-MHC复合物,所述MHC I类分子包含由HLA-A*24等位基因编码MHC I类α链)。
抗体依赖性细胞介导的细胞毒性(ADCC)是指细胞介导的免疫应答,其中效应免疫细胞裂解靶细胞,所述靶细胞包被有结合靶细胞表达的抗原的抗体。包括如NK细胞在内的效应免疫细胞通常通过抗体的Fc区与效应细胞表达的Fc受体结合,来识别抗体包被的细胞。Fc受体的交联导致细胞毒性因子(如穿孔素和颗粒酶)从效应细胞中释放,从而引起靶细胞的裂解。
给定抗体/抗原结合片段引发ADCC的能力可以测量,例如,通过使用体外细胞杀伤试验的分析。此类测定通常涉及在抗体和效应免疫细胞存在下,体外培养表达靶抗原的细胞,并测量一段时间后细胞杀伤的量。ADCC测定包括如51Cr释放测定,例如,如Nelson等人,2001年,Curr Protoc Immunol.第7章:第7.27单元所述,其全部内容通过引用结合于此。简言之,靶细胞用51Cr处理,所述51Cr被靶细胞内化。通过ADCC裂解靶细胞,导致放射性51Cr释放到细胞培养上清液中,所述细胞培养上清液中的放射性51Cr可以被检测和定量。对给定的靶细胞表现出ADCC的抗体/抗原结合片段造成的细胞裂解比在不存在所述的抗体/抗原结合片段,或者存在细胞不表达的靶抗原的特异性抗体/片段时观察到的细胞裂解水平更高。
在一些实施方案中,本发明所述的抗体/抗原结合片段一定程度地杀伤包含/表达肽-MHC复合物的细胞,所述复合物包含p53肽和MHC I类分子(例如,包含p53125-134和MHC I类分子的肽-MHC复合物,所述MHC I类分子包含由HLA-A*24等位基因编码的MHC I类α链),在可比较的测定中,所述细胞杀伤程度,超过在缺少抗体/抗原结合片段时、或在对细胞不表达的靶抗原的特异性抗体/片段存在下的细胞杀伤水平1倍,例如≥1.01倍,≥1.02倍,≥1.03倍,≥1.04倍,≥1.05倍,≥1.1倍,≥1.2倍,≥1.3倍,≥1.4倍,≥1.5倍,≥1.6倍,≥1.7倍,≥1.8倍≥1.9倍,≥2倍,≥3倍,≥4倍,≥5倍,≥6倍,≥7倍,≥8倍,≥9倍,≥10倍。
在一些实施方案中,本发明所述的抗原/抗原结合片段表现出由包含/表达肽-MHC复合物的细胞内化,所述肽-MHC复合物包含p53肽和MHC I类分子(例如,包含p53125-134和MHC I类分子的肽-MHC复合物,所述MHC I类分子包含由HLA-A*24等位基因编码的MHC I类α链)。
“内化”是指将抗体摄取到细胞中,例如,通过与细胞表面表达的抗原结合的抗体的胞吞作用。可以通过本领域技术人员熟知的方法分析抗体内化,包括分析抗体,例如用可检测部分标记的抗体的定位/转运。例如,可以如本文实验实施例中所述测量抗体内化,使用pH敏感性染料标记的抗体,当转运至细胞内时产生可检测信号。用于分析抗体内化的测定描述于例如Nath等,J Immunol Methods.2016年;431:11-21,和Liao-Chan等人,PLoSOne.2015年;10(4):e0124708,两者均通过引用整体并入本文。
在一些实施方案中,本发明所述的抗体/抗原结合片段被包含/表达肽-MHC复合物的细胞内化,所述肽-MHC复合物包含p53肽和MHC I类分子(例如,包含p53125-134和MHC I类分子的肽-MHC复合物,所述MHC I类分子包含由HLA-A*24等位基因编码的MHC I类α链),在可比较的测定中,其程度超过合适的对照抗体/片段(例如同种型对照)的内化水平1倍,例如≥1.01倍,≥1.02倍,≥1.03倍,≥1.04倍,≥1.05倍,≥1.1倍,≥1.2倍,≥1.3倍,≥1.4倍,≥1.5倍,≥1.6倍,≥1.7倍,≥1.8倍,≥1.9倍,≥2倍,≥3倍,≥4倍,≥5倍,≥6倍,≥7倍,≥8倍,≥9倍,≥10倍。
在一些实施方案中,本发明所述的抗体/抗原结合片段被包含/表达肽-MHC复合物的细胞内化,所述肽-MHC复合物包含p53肽和MHC I类分子(例如包含p53125-134和MHC I类分子的肽-MHC复合物,所述MHC I类分子包含由HLA-A*24等位基因编码的MHC I类α链),在可比较的测定中,所述的内化水平是不包含/表达包含p53肽和MHC I类分子的肽-MHC复合物(如,不包含/表达包含p53125-134和MHC I类分子的肽-MHC复合物的细胞,所述MHC I类分子包含由HLA-A*24等位基因编码的MHC I类α链)的细胞的内化水平1倍以上,例如,≥1.01倍,≥1.02倍,≥1.03倍,≥1.04倍,≥1.05倍,≥1.1倍,≥1.2倍,≥1.3倍,≥1.4倍,≥1.5倍,≥1.6倍,≥1.7倍,≥1.8倍,≥1.9倍,≥2倍,≥3倍,≥4倍,≥5倍,≥6倍,≥7倍,≥8倍,≥9倍,或≥10倍。
核酸/载体
本发明提供了一种编码本发明所述的抗体、抗原结合片段或CAR的核酸。在一些实施方案中,所述的核酸从,例如其他核酸、或天然存在的生物材料中纯化或分离。
本发明还提供了一种包含编码本发明所述的抗体、抗原结合片段或CAR的核酸的载体。
如本文所用的“载体”是一种核酸(DNA或RNA),用于将外源核酸转移到细胞中的运输工具。所述的载体可以是在细胞中表达核酸的表达载体。此类载体可包括启动子序列,所述启动子序列可操作地连接所述的编码待表达序列的核酸。载体还可包括终止密码子和表达增强子。本领域已知的任何合适的载体、启动子、增强子和终止密码子可用于自本发明所述的载体表达本发明所述的抗体、抗原结合片段或CAR。
在本说明书中,术语“可操作地连接”可包括选定的核酸序列与调节性核酸序列(例如启动子和/或增强子)共价连接的情况,使核苷酸序列在调节序列影响或控制下表达(从而形成表达盒)。因此,如果调节序列能够影响核酸序列的转录,则调控序列与选定的核酸序列是可操作的连接。在适当的情况下,得到的转录物随后可以翻译为所需的多肽。
本发明所述的核酸和/或载体可以用于导入细胞,例如原代人体免疫细胞。合适的载体包括质粒、二元载体、DNA载体、mRNA载体、病毒载体(例如γ逆转录病毒载体(例如鼠白血病病毒(MLV)衍生载体)、慢病毒载体、腺病毒载体、腺相关病毒载体、痘苗病毒载体和疱疹病毒载体)、基于转座子的载体、和人工染色体(例如酵母人工染色体),例如,如Maus等,Annu Rev Immunol(2014)32:189-225或Morgan和Boyerinas,Biomedicines 2016 4,9中所述,两者均通过引用整体并入本文。在一些实施方案中,病毒载体可以是慢病毒、逆转录病毒、腺病毒、或单纯疱疹病毒载体。在一些实施方案中,所述的慢病毒载体可以是pELNS,或可以衍生自pELNS。在一些实施方案中,载体可以是编码CRISPR/Cas9的载体。
包含/表达抗体/片段/CAR的细胞
本发明还提供了一种包含或表达本发明所述的抗体、抗原结合片段或CAR的细胞。还提供了一种包含或表达本发明所述的核酸或载体的细胞。
所述的细胞可以是真核细胞,例如哺乳动物细胞。所述的哺乳动物可以是人或非人哺乳动物(例如兔、豚鼠、大鼠、小鼠或其他啮齿动物(包括啮齿目中的任何动物)、猫、狗、猪、绵羊、山羊、牛(包括牛,例如奶牛,或牛属中的任何动物)、马(包括马科中的任何动物)、驴、和非人灵长类动物的任何动物。
在一些实施方案中,所述的细胞可以来自人受试者,或者可以取自人受试者。
所述的细胞可以是免疫细胞。所述的细胞可以是造血来源的细胞,例如中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、树突细胞、淋巴细胞、或单核细胞。淋巴细胞可以是例如T细胞、B细胞、NK细胞、NKT细胞或先天性淋巴细胞(ILC)、或其前体。所述的细胞可以表达例如CD3多肽(例如CD3γCD3εCD3ζ或CD3δ)、TCR多肽(TCRα或TCFη)、CD27、CD28、CD4或CD8。在一些实施方案中,所述的细胞是T细胞。在一些实施方案中,所述的T细胞是CD3+T细胞。在一些实施方案中,所述的T细胞是CD3+,CD8+T细胞。在一些实施方案中,所述的T细胞是细胞毒性T细胞(例如细胞毒性T淋巴细胞(CTL))。
在一些实施方案中,所述的细胞是抗原特异性T细胞。在本文的实施方案中,“抗原特异性”T细胞是响应于T细胞特异性的抗原而显示T细胞的某些功能特性的细胞,或表达所述抗原的细胞。在一些实施方案中,所述性质是与效应T细胞(如,细胞毒性T细胞)有关的功能特性。在一些实施方案中,抗原特异性T细胞可以显示一种或多种以下特性:细胞毒性,例如对包含/表达T细胞特异性的抗原的细胞的细胞毒性;增殖性,IFNγ表达,CD107a表达,IL-2表达,TNFα表达,穿孔素表达,颗粒酶表达,颗粒溶素表达和/或FAS配体(FASL)表达,例如,响应于T细胞特异性的抗原、或包含/表达T细胞特异性的抗原的细胞。在一些实施方案中,T细胞特异性的抗原可以是病毒的肽或多肽,例如,爱泼斯坦-巴尔病毒(EBV)、流感病毒、麻疹病毒、乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、人类免疫缺陷病毒(HIV)、淋巴细胞脉络丛脑膜炎病毒(LCMV)、单纯疱疹病毒(HSV)或人类乳头状瘤病毒(HPV)。
本发明还提供了一种包含本发明所述的核酸或载体的细胞的制备方法,包括将本发明所述的核酸或载体导入细胞中。本发明还提供了一种表达本发明所述的抗体、抗原结合片段或CAR的细胞的制备方法,包括将本发明所述的核酸或载体导入细胞中。在一些实施方案中,所述的方法还包括在适于细胞表达所述的核酸或载体的条件下培养细胞。在一些实施方案中,所述的方法在体外进行。
在一些实施方案中,将本发明所述的分离的核酸或载体引入细胞中的方法包括转导,例如逆转录病毒转导。因此,在一些实施方案中,所述的分离的核酸或载体包含在病毒载体中,或载体是病毒载体。在一些实施方案中,该方法包括通过电穿孔引入本发明所述的核酸或载体,例如,如Koh等人,《分子疗法-核酸》Molecular Therapy-Nucleic Acids(2013)2,e114中所述,其通过引用整体并入本文。
本发明还提供了通过本发明所述的细胞的制备方法获得的或可获得的细胞。
治疗应用
本发明所述的抗体、抗原结合片段、CAR、核酸、载体、细胞和组合物可以用于医学治疗或预防疾病/病症,或用于减轻该疾病/病症症状的方法。它们可以施用于患有需要治疗的疾病/病症的受试者,和/或施用于有发展或接触该疾病/病症风险的受试者。
所述的受试者可以是任何动物或人。所述的受试者优选为哺乳动物,更优选为人。所述的受试者可以是非人哺乳动物,但更优选是人。所述的受试者可以是男性或女性。所述的受试者可以是患者。受试者可以是已被诊断患有需要治疗的疾病或病症,或怀疑患有此类疾病或病症。
治疗或减轻疾病/病症可有效预防疾病/病症的进展,例如防止病情恶化或减缓发展速度。在一些实施方案中,治疗或缓解可以导致疾病/病症的改善,例如,减少疾病/病症的症状或减少疾病/病症的一些其他关于严重性/活性的方面。
预防疾病/病症可以指预防病症恶化或预防疾病/病症的发展,例如,预防早期疾病/病症发展到后期(慢性)阶段。例如,在癌症中,预防可以是例如预防癌症的发展,或预防转移。
在一些实施方案中,所述疾病/病症可以是与p53相关的疾病/病症,例如,与TP53突变相关的疾病/病症。在一些实施方案中,与TP53突变相关的疾病/病症可以是TP53突变为该疾病/病症的发展或进展的风险因子的疾病/病症。
所述的疾病/病症可能与和MHC I类形成复合物的p53肽表达有关。在一些实施方案中,所述的疾病/病症的效应细胞(例如,直接或间接涉及所述的疾病/病症的病理特性的细胞)表达与MHC I类形成复合物的p53肽。在一些实施方案中,所述疾病/病症与和MHC I类形成复合物的p53肽表达相关,所述MHC I类包含由HLA-A*24等位基因编码的α链。在一些实施方案中,所述疾病/病症与和MHC I类形成复合物的p53125-134表达相关,所述MHC I类包含由HLA-A*24等位基因编码的α链。
如本文所讨论并且例如在Royd等人2006;,Cell Death Differ.13(6):1017-26以及Vousden和Lane 2007,Nat Rev Mol Cell Biol 8,275-283的综述中所述,p53是肿瘤抑制因子,并且TP53中的突变涉及多种癌症的发展/进展。编码或表达突变型p53肽/多肽的癌细胞在细胞表面通常存在与MHC I类形成复合物的p53肽。
在一些实施方案中,本发明所述的待治疗/预防的疾病/病症是癌症。在一些实施方案中,所述的癌症与TP53中的突变相关。在一些实施方案中,所述的癌症包含编码/表达突变体p53肽/多肽的细胞。
可以通过本领域技术人员熟知的任何合适的方法确定编码或表达突变型p53肽/多肽的癌症,例如,基于对生物样品的分析。鉴定编码突变体p53多肽的癌症可以基于检测编码突变的核酸,例如,通过DNA测序等。可以通过检测突变型p53肽/多肽的表达来鉴定表达突变型p53多肽的癌症。表达可以是基因表达或蛋白表达。基因表达可以如通过检测编码突变型p53肽/多肽的mRNA来确定,例如通过定量实时PCR(qRT-PCR)。蛋白表达可以如通过检测突变型p53肽/多肽来确定,例如通过基于抗体的方法,例如通过蛋白印迹、免疫组织化学、免疫细胞化学、流式细胞术、ELISA。
在本文的实施方案中,所述的癌症的一种或多种细胞可以来源于肿瘤。
在一些实施方案中,所述的癌症包含表达与MHC I类形成复合物的p53肽的细胞。在一些实施方案中,所述的癌症包括表达MHC I类的细胞,所述的MHC I类复合物包含由HLA-A*24等位基因编码的α链。在一些实施方案中,所述的癌症包含表达与MHC I类形成复合物的p53肽的细胞,所述的MHC I类包含由HLA-A*24等位基因编码的α链。在一些实施方案中,所述的癌症包含表达与MHC I类形成复合物的p53125-134的细胞,所述的MHC I类包含由HLA-A*24等位基因编码的α链。
在一些实施方案中,本发明所述的抗体/片段能够结合表达靶肽-MHC复合物的细胞并引起细胞的ADCC。在一些实施方案中,所述的抗体/片段结合表达靶肽-MHC复合物的细胞并由其内化,因此可用于靶向递送如药物部分(例如细胞毒性小分子)至表达靶肽-MHC复合物的细胞。
在一些实施方案中,所述的治疗可以旨在减少表达本发明所述的抗体/片段/CAR的靶抗原的细胞数。
在一些实施方案中,所述的治疗可以包括修饰细胞或细胞群以包含/表达本发明所述的抗体/抗原结合片段、CAR、核酸或载体,随后可以用于减少表达所述的抗原/片段/CAR的靶抗原的细胞数量。在一些实施方案中,所述治疗可包括向受试者施用经修饰以包含/表达本发明所述的抗体/抗原结合片段、CAR、核酸或载体的细胞或细胞群。
所述的癌症可以是任何不需要的细胞增殖(或任何通过不需要的细胞增殖表现出来的疾病)、赘生物或肿瘤,或不需要的细胞增殖、赘生物或肿瘤的增加的风险或倾向。所述的癌症可以是良性或恶性的,可以是原发性或继发性(转移性)。肿瘤或肿瘤可以是细胞的任何异常生长或增殖,并且可以位于任何组织中。组织的实例包括肾上腺、肾上腺髓质、肛门、阑尾、膀胱、血液、骨、骨髓、脑、乳腺、盲肠、中枢神经系统(包括或不包括脑)小脑、子宫颈、结肠、十二指肠、子宫内膜、上皮细胞(例如肾上皮细胞)、胆囊、食道、神经胶质细胞、心脏、回肠、空肠、肾、泪腺、喉、肝、肺、淋巴、淋巴结、淋巴母细胞、上颌骨、纵隔、肠系膜、子宫肌层、鼻咽、网膜、口腔、卵巢、胰腺、腮腺、周围神经系统、腹膜、胸膜、前列腺、唾液腺、乙状结肠、皮肤、小肠、软组织、脾、胃、睾丸、胸腺、甲状腺、舌、扁桃体、气管、子宫、外阴、白细胞。
待治疗的肿瘤可以是神经系统或非神经系统肿瘤。神经系统肿瘤可能起源于中枢神经系统或外周神经系统,例如胶质瘤、成神经管细胞瘤、脑膜瘤、神经纤维瘤、室管膜瘤、神经鞘瘤、神经纤维肉瘤、星形细胞瘤和少突神经胶质瘤。非神经系统癌症/肿瘤可能起源于任何其他非神经组织,例如黑色素瘤、间皮瘤、淋巴瘤、骨髓瘤、白血病、非霍奇金淋巴瘤(NHL)、霍奇金淋巴瘤、慢性粒细胞白血病(CML)、急性髓性白血病(AML)、骨髓增生异常综合征(MDS)、皮肤T细胞淋巴瘤(CTCL)、慢性淋巴细胞白血病(CLL)、肝癌、表皮样癌、前列腺癌、乳腺癌、肺癌、结肠癌、卵巢癌、胰腺癌、胸腺癌、NSCLC、血液癌和肉瘤。
在一些实施方案中,所述方法用于治疗/预防癌症,例如上皮细胞癌、乳腺癌、胃肠癌(例如食道癌、胃癌、胰腺癌、肝癌(例如HCC)、胆囊癌、结肠直肠癌、肛门癌、胃肠道类癌)和肺癌(例如非小细胞癌)细胞肺癌(NSCLC)或小细胞肺癌(SCLC)))。
在一些实施方案中,待治疗的癌症是以下的一种或多种:鼻咽癌(NPC;例如Epstein-Barr病毒(EBV)阳性NPC)、宫颈癌(CC;例如人乳头瘤病毒(HPV)阳性CC)、口咽癌(OPC;例如HPV阳性OPC)、胃癌(GC;例如EBV阳性GC)、肝细胞癌(HCC;例如乙型肝炎病毒(HBV)阳性HCC)、肺癌(例如非小细胞肺癌(NSCLC))和头颈癌(例如源自唇、口、鼻、鼻窦、咽或喉的组织的癌症,例如头颈部鳞状细胞癌(HNSCC))。
在一些实施方案中,所述的癌症可能与p53基因或蛋白表达增加相关。例如,与可比较的非癌细胞相比,癌症细胞的p53表达可能增加,或者与在没有癌症的情况下可比较的细胞(例如在健康对照受试者中)的表达水平相比,癌症细胞与其他细胞(例如非癌细胞)的p53表达增加相关联。
在本发明所述的实施方案中,治疗或预防的方法可包括免疫细胞的过继细胞转移。过继细胞转移(ACT)通常是指从受试者获得细胞(例如免疫细胞)的过程,常通过抽取从中分离细胞的血液样品。所述的细胞随后通常以某种方式处理或改变,然后将其施用于同一受试者或不同的受试者。该治疗通常旨在向受试者提供具有某些所需特征的细胞群,或增加该受试者中具有这种特征的细胞的频率。例如,在Kalos和June 2013年,Immunity 39(1):49-60中描述了T细胞的过继转移,全部内容通过引用并入本文。
在本发明中,可以进行过继转移,其目的是将细胞或细胞群引入受试者,和/或增加受试者中细胞或细胞群的频率。在一些实施方案中,过继转移可以是包含/表达本发明所述的抗体、片段或CAR的细胞。
所述的细胞可以是,例如中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、树突细胞、淋巴细胞或单核细胞。所述的淋巴细胞可以是,例如T细胞、B细胞、NK细胞、NKT细胞或先天性淋巴细胞(ILC)、或其前体。在一些实施方案中,所述的细胞是T细胞。在一些实施方案中,所述的T细胞是CD3+T细胞。在一些实施方案中,所述的T细胞是CD3+,CD8+T细胞。在一些实施方案中,所述的T细胞是细胞毒性T细胞(例如细胞毒性T淋巴细胞(CTL))。在一些实施方案中,所述的T细胞是病毒特异性T细胞。在一些实施方案中,所述的T细胞对EBV、HPV、HBV、HCV或HIV具有特异性。
本发明提供了一种治疗或预防受试者的疾病或病症的方法,该方法包括修饰从受试者获得的至少一个细胞以表达或包含本发明所述的抗体、片段、CAR、核酸或载体,任选地扩增所述的经修饰的至少一个细胞,并将经修饰的至少一个细胞施用于受试者。
本发明还提供一种杀死肿瘤细胞的方法,该方法包括将治疗有效量的本发明抗体、抗原结合片段、CAR、核酸、载体或组合物给予所述的细胞。该方法可以在体外或体内进行。还提供了一种杀死受试者中的肿瘤细胞的方法,该方法包括向受试者施用治疗有效量的本发明所述的抗体、抗原结合片段、CAR、核酸、载体或组合物。在一些实施方案中,所述的杀死肿瘤细胞的方法包括将本文所述的抗体、片段、CAR、核酸、载体或组合物与治疗剂组合施用。例如,杀死肿瘤细胞可能是由于膜破裂、细胞裂解、诱导细胞凋亡、抗体依赖性细胞介导的细胞毒性(ADCC)、补体依赖性细胞毒性(CDC)或通过抗体或抗原结合片段与药物偶联的作用。
在一些实施例中,该方法包括:
(a)从受试者中分离至少一个细胞;
(b)修饰该至少一个细胞以表达或包含本发明所述的抗体、抗原结合片段、CAR、核酸或载体,
(c)任选地扩增该经修饰的至少一个细胞,和;
(d)将该经修饰的至少一个细胞给予受试者。
在一些实施方案中,分离细胞的受试者是施用经修饰细胞的受试者(即,过继转移的是自体细胞)。在一些实施方案中,分离细胞的受试者是与施用经修饰细胞的受试者不同的受试者(即,过继转移的是同种异体细胞)。
本发明所述经修饰的至少一个细胞可以根据技术人员熟知的方法进行修饰。修饰可以包括核酸转移,以永久或瞬时表达转移的核酸。
可以使用任何合适的基因工程平台来修饰本发明所述的细胞。用于修饰细胞的合适方法包括使用基因工程平台,例如γ逆转录病毒载体、慢病毒载体、腺病毒载体、DNA转染、基于转座子的基因递送和RNA转染,例如Maus等,Annu Rev Immunol(2014)32:189-225中所述,在此引入作为参考。
在一些实施方案中,所述的方法可包括以下步骤中的一个或多个:从受试者中取血样;从血液样品中分离和/或扩增至少一个细胞;在体外或离体细胞培养中培养所述至少一个细胞;向所述至少一个细胞中引入本发明所述的抗体、抗原结合片段、CAR、核酸或载体,从而修饰所述至少一个细胞;扩增该至少一个经修饰细胞;收集该至少一个经修饰细胞;将该经修饰细胞与佐剂、稀释剂或载体混合;将该经修饰细胞施用于受试者。
在一些实施方案中,所述方法可还包括处理细胞以诱导/增强抗体/片段\CAR\核酸或载体的表达。例如,所述的核酸/载体可以包含响应于特定试剂处理的来自于核酸/载体的控制元件,以诱导上调抗体/片段或CAR表达。在一些实施方案中,可以通过将药剂施用于已经施用本发明的经修饰细胞的受试者,进行体内治疗。在一些实施方案中,可以通过向离体或体外培养的细胞施用药剂来进行离体或体外治疗。
技术人员能够确定用于本发明所述的细胞过继转移的合适的试剂和程序,例如参考Dai等人,2016J Nat Cancer Inst 108(7):djv439,其通过引用全部并入本文。
在相关方面,本发明提供了一种制备修饰细胞的方法,所述的方法包括将本发明所述的CAR\核酸或载体导入细胞,从而修饰该至少一个细胞。所述的方法优选在体外或离体进行。
在一个方面,本发明提供一种治疗或预防受试者的疾病或病症的方法,包括:
(a)从受试者中分离至少一个细胞;
(b)将本发明所述的核酸或载体导入该至少一个细胞,从而修饰该至少一个细胞;和
(c)将该经修饰的至少一个细胞给予受试者。
在一些实施方案中,该方法还包括治疗性或预防性干预,例如,用于治疗或预防癌症。在一些实施方案中,所述的治疗性或预防性干预选自化学疗法、免疫疗法、放射疗法、手术、疫苗接种和/或激素疗法。
本文所述的治疗方法可任选地包括同时施用生物佐剂(例如,白细胞介素、细胞因子、卡介苗、单磷酰脂质A等)与用于治疗癌症的常规疗法的组合,例如用于治疗癌症的治疗剂(例如化疗)、放射或手术。医学治疗方法还可涉及体内、离体和过继免疫疗法,包括使用自体和/或异源细胞或永生化细胞系。本文所述的治疗方法可任选地涉及加强MHC I类表达,例如通过干扰素治疗或HDAC抑制剂治疗。
本发明所述的抗体、片段、CAR核酸、载体和细胞可以配制成临床使用的药物组合物或药物,并且可以包含药学上可接受的载体、稀释剂、赋形剂或佐剂。该组合物可以配制以用于局部、肠胃外、全身、腔内、静脉内、动脉内、肌肉内、鞘内、眼内、结膜内、肿瘤内、皮下、皮内、鞘内、口服或透皮给药途径,所述透皮给药途径可包括注射或输注。合适的制剂可包含无菌或等渗溶剂中的抗体、片段、CAR、核酸、载体或细胞。药物和药物组合物可以配制成流体(包括凝胶)形式。流体制剂可以配制,以用于通过注射或输注(例如通过导管),给予人体或动物体的选定区域。
还提供了一种制备本发明所述药学上有用的组合物的方法,这种制备方法可包括选自以下的一个或多个步骤:分离如本文所述的抗体、片段、CAR、核酸、载体或细胞;和/或将如本文所述的抗体、片段、CAR、核酸、载体或细胞与药学上可接受的载体、佐剂、赋形剂或稀释剂混合。
例如,本发明的另一方面涉及一种配制或生产用于医学治疗方法的药物或药物组合物的方法,该方法包括通过将如本文所述的抗体、片段、CAR、核酸、载体或细胞与药学上可接受的载体、佐剂、赋形剂或稀释剂混合,配制药物组合物或药物。
本发明所述的抗体、片段、CAR、核酸、载体、细胞或组合物的施用,优选为“治疗有效”或“预防有效”量,这足以对受试者显示益处。所述的给药的实际量、给药的速率和时间过程将取决于疾病或病症的性质和严重程度。治疗的处方,例如关于剂量等的决定,由全科医生和其他医生负责,并且通常考虑待治疗的疾病/病症、个体受试者的状况、呈递的部位、给药方法和从业者周知的其他因素。上述技术和方案的实例可以在《雷明顿药物科学》,第20版,2000,Lippincott,Williams&Wilkins.出版社中找到。
给药可以单独给药或与其它治疗组合给药,同时或顺序给药取决于待治疗的状况。本发明所述的抗体、片段、CAR、核酸、载体、细胞或组合物,和治疗剂可以同时或顺序施用。
在一些实施方案中,使用本发明所述的抗体、片段、CAR、核酸、载体、细胞或组合物的治疗用于预防性干预的方法,例如,接种。
在一些实施方案中,使用本发明所述的抗体、片段、CAR、核酸、载体、细胞或组合物治疗可以结合其他治疗性或预防性干预,例如,化学疗法、免疫疗法、放射疗法、手术、疫苗接种和/或激素疗法。
同时给药是指将抗体、片段、CAR、核酸、载体、细胞或组合物和治疗剂一起给药,例如作为含有两种药剂(组合制剂)的药物组合物,或者在彼此之后并且任选地通过相同的给药途径,例如给予到同一动脉、静脉或其他血管。顺序给药是指单独施用另一种药剂后在给定的时间间隔之后施用抗体、片段、CAR、核酸、载体、细胞或组合物或治疗剂中的一种的给药方式。尽管在一些实施方案中如此,但不要求两种药剂通过相同的途径给药。所述的时间间隔可以是任何时间间隔。
化学疗法和放射疗法分别指用药物或用电离辐射(例如使用X射线或γ射线的放射疗法)治疗癌症。所述的药物可以是化学实体,例如,小分子药物、抗生素、DNA嵌入剂、蛋白抑制剂(例如激酶抑制剂)或生物制剂,如抗体、抗体片段、核酸或肽适体、核酸(例如DNA、RNA)、肽、多肽或蛋白。所述的药物可以配制成药物组合物或药剂。所述的制剂可包含一种或多种药物(例如一种或多种活性剂)以及一种或多种药学上可接受的稀释剂、赋形剂或载体。
治疗可包括给予一种以上的药物。药物可以单独给药或与其它治疗组合给药,同时或顺序给药取决于待治疗的状况。例如,所述的化学疗法可以是涉及施用两种药物的共同疗法,其中一种或多种药物可以用于治疗癌症。
所述的化疗可以通过一种或多种给药途径给药,例如,肠胃外、静脉注射、口服、皮下、皮内或瘤内。
可以根据治疗方案施用化学疗法。所述的治疗方案可以是化疗施用的预定时间表、计划、方案或时间表,其可以由医师或医师准备并定制以适合需要治疗的患者。
所述的治疗方案可以指示以下中的一种或多种:给予患者的化疗类型;每种药物或辐射的剂量;施用的时间间隔;每次治疗的时间长短;任何治疗假期的数量和性质,如果有的话等。对于联合治疗,可以提供单一治疗方案,其指示每种药物的施用方式。
化学治疗药物和生物制剂可选自:烷化剂,例如顺铂、卡铂、氮芥、环磷酰胺、苯丁酸氮芥、异环磷酰胺;嘌呤或嘧啶抗代谢物,如硫唑嘌呤或巯嘌呤;生物碱和萜类化合物,如长春花生物碱(如长春新碱、长春碱、长春瑞滨、长春地辛)、鬼臼毒素、依托泊苷、替尼泊苷、紫杉醇如紫杉醇(TaxolTM)、多西紫杉醇;拓扑异构酶抑制剂如I型拓扑异构酶抑制剂喜树碱伊立替康和拓扑替康,或II型拓扑异构酶抑制剂安吖啶、依托泊苷、磷酸依托泊苷、替尼泊苷;抗肿瘤抗生素(如蒽环类抗生素),如放线菌素、多柔比星(AdriamycinTM)、表柔比星、博来霉素、雷帕霉素;基于抗体的药物,如抗PD-1抗体、抗PD-L1抗体、抗TIM-3抗体、抗CTLA-4、抗-4-1BB、抗GITR、抗CD27、抗BLTA、抗OX43、抗VEGF、抗TNFα、抗IL-2、抗GpIIb/IIIa、抗CD-52、抗CD20、抗RSV、抗HER2/neu(erbB2)、抗TNF受体、抗EGFR抗体、单克隆抗体或抗体片段,实例包括:西妥昔单抗、帕尼单抗、英夫利昔单抗、巴利昔单抗、贝伐单抗阿昔单抗、达珠单抗、吉妥珠单抗、阿仑单抗、利妥昔单抗帕利珠单抗、曲妥珠单抗、依那西普、阿达木单抗、尼妥珠单抗;EGFR抑制剂如厄洛替尼、西妥昔单抗和吉非替尼;抗血管生成剂如贝伐单抗癌症疫苗,如
其他化学治疗药物可选自:13-顺式维甲酸、2-氯脱氧腺苷、5-氮杂胞苷、5-氟尿嘧啶、6-巯基嘌呤、6-硫鸟嘌呤、白蛋白结合型紫杉醇、放线菌素-D阿霉素、重组人白介素2、阿仑单抗、力比泰(ALIMTA)、阿利维A酸、全反式维甲酸、α干扰素、六甲密胺、氨甲喋呤、氨磷汀、氨鲁米特、阿那格雷、阿那曲唑、阿糖胞嘧啶、 三氧化二砷、天冬酰胺酶、阿扎胞苷、卡介苗、卡莫司汀、苯达莫司汀、贝伐珠单抗、贝沙罗汀、比卡鲁胺、卡莫司汀注射劑、博来霉素、硼替佐米、白消安、钙甲酰四氢叶酸、喜树碱-11、卡培他滨、CaracTM、卡铂、卡莫司汀、CC-5013、CCI-779、CCNU、CDDP、CeeNU、西妥昔单抗、苯丁酸氮芥、顺铂、嗜橙菌因子、克拉屈滨、可的松、CPT-11、环磷酰胺、阿糖胞苷、 达珂、放线菌素D、阿法达贝泊、达沙替尼、道诺霉素、柔红霉素、盐酸柔红霉素、柔红霉素脂质体、地塞米松、地西他滨、地尼白介素、DepoCytTM、地塞米松、醋酸地塞米松、地塞米松磷酸钠、地塞米松、右雷佐生、DHAD、DIC、二极管Diode、多西紫杉醇、多柔比星、阿霉素脂质体、DroxiaTM、DTIC、 EligardTM、EllenceTM、EloxatinTM、表柔比星、阿法依泊汀、西妥昔单抗、埃罗替尼、欧文氏菌属L-天冬酰胺酶、雌莫司汀、依托泊苷、依托泊苷磷酸盐、依维莫司、依西美坦、非格司亭、氟脲苷、氟达拉滨、氟尿嘧啶、氟甲睾酮、氟他胺、叶酸、氟维司群、吉非替尼、吉西他滨、吉妥珠单抗奥唑米星、GleevecTM、晶圆、戈舍瑞林、粒细胞集落刺激因子、粒细胞巨噬细胞集落刺激因子、地塞米松、六甲基蜜胺、HMM、氢化可的松、氢化可的松磷酸钠、氢化可的松琥珀酸钠、氢化可的松、羟基脲、替伊莫单抗、替坦异贝莫单抗、伊达比星、IFN-α、异环磷酰胺、IL-11、IL-2、甲磺酸伊马替尼、咪唑甲酰胺、干扰素α、干扰素α-2b(PEG结合物)、白细胞介素-2、白细胞介素-11、内含子(干扰素α-2b)、伊立替康、异维A酸、伊沙匹隆、IxempraTM、门冬酰胺酶、拉帕替尼、L-天冬酰胺酶、LCR、来那度胺、来曲唑、甲酰四氢叶酸、留可然、LeukineTM、亮丙瑞林、长春新碱、LeustatinTM、脂质体Ara-C、洛莫司汀、L-PAM、L-溶肉瘤素、地塞米松、氮芥、盐酸氮芥、甲地孕酮、醋酸甲地孕酮、美法仑、巯嘌呤、美司钠、MesnexTM、甲氨喋呤、甲氨蝶呤钠、甲基强的松龙、丝裂霉素、丝裂霉素C、米托蒽醌、MTC、MTX、氮芥、MylocelTM、Nelarabine、NeulastaTM、 尼鲁米特、氮芥菜、奥曲肽、醋酸奥曲肽、OnxalTM、奥普瑞白介素、奥沙利铂、紫杉醇、紫杉醇蛋白结合、帕米磷酸盐、帕尼单抗、PEG干扰素、培门冬酶、乙二醇化非格司亭、PEG-INTRONTM、PEG-L-天冬酰胺酶、培美曲塞、喷司他丁、苯丙氨酸氮芥、泼尼松龙、泼尼松、丙卡巴肼、聚苯丙生20为载体的卡莫司汀植入膜剂(Prolifeprospan20with Carmustine Implant)、雷洛昔芬、 利妥昔单抗、(干扰素Alfa-2a)、盐酸红比霉素、沙格司亭、 索拉非尼、SPRYCELTM、STI-571、链脲佐菌素、SU11248、舒尼替尼、他莫昔芬、 替莫唑胺、替西罗莫司、替尼泊苷、TESPA、沙利度胺、 硫鸟嘌呤、硫鸟嘌呤硫代磷酰胺、塞替派、托泊替康、托瑞米芬、托西莫单抗、曲妥珠单抗、维甲酸、TrexallTM、TSPA、VCR、VectibixTM、ViadurTM、长春碱、长春碱硫酸盐、长春新碱、长春瑞宾、长春瑞滨酒石酸盐、VLB、VM-26、伏立诺他、VP-16、ZevalinTM、唑来膦酸、伏立诺他、
可以提供多剂量的抗体/片段、CAR、核酸、载体、细胞或组合物。一个或多个或每个剂量可以伴随另一种治疗剂的同时或顺序给药。
多剂量可以分开预定的时间间隔,其可以选择为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或31天,或1、2、3、4、5或6个月中的一个。举例来说,可以每7、14、21或28天(加或减3、2或1天)给予一次剂量。
诊断用途
本文所述的抗体和抗原结合片段可用于涉及抗体或抗原结合片段与靶抗原结合的方法中。这些方法包括诊断受试者的疾病或病症。这些方法可涉及检测抗体或抗原结合片段和靶标的结合复合物。因此,在一个实施方案中,提供了一种方法,该方法包括使含有或怀疑含有肽-MHC复合物(例如与MHC I类分子形成复合物的p53肽,例如与包含由HLA-A*24等位基因编码的α链的MHC I类形成复合物的p53125-134)的样品接触如本文所述的抗体或抗原结合片段,并检测抗体或抗原结合片段和肽-MHC复合物的复合物的形成。
合适的方法形式是本领域熟知的,包括免疫测定,例如夹心法测定,如ELISA。所述的方法可以包括用可检测、荧光、发光或电子标签的标记物标记抗体/抗原结合片段或肽-MHC复合物、或两者。所述的肽-MHC复合物的表达可以通过免疫组织化学(IHC)测量,例如通过活组织检查获得的组织样品。在一些实施方案中,所述的标记可以选自:放射性核苷酸、正电子发射放射性核素(如用于正电子发射断层扫描(PET))、MRI造影剂或荧光标记。
肽-MHC复合物的分析可以在体外或体内,并且可以涉及通过检测适当标记的物质的测定,例如通过荧光成像、正电子发射断层扫描(PET)或磁共振成像(MRI)。
这种方法可以为需要检测和/或定量肽-MHC复合物的疾病或病症的诊断方法提供基础。这些方法可以在受试者样品上体外进行,或者在对受试者样品进行处理之后进行。一旦收集样品,就不需要受试者进行体外诊断方法,因此该方法可以是不在人体或动物体上实施的方法。本发明提供了本文所述的抗体或抗原结合片段用体外检测肽-MHC复合物的用途。
术语“体外”旨在包括培养细胞的实验,而术语“体内”旨在包括原位的多细胞生物的实验和/或处理。
这些方法也可以在体内进行,例如,在向受试者施用本发明所述的抗体、抗原结合片段、CAR、核酸、载体、细胞或组合物之后。
此类方法可涉及检测受试者或受试者样品中存在的肽-MHC复合物的存在和/或确定其量。所述的方法可以进一步包括比较测定的量与标准值或参考值,作为实现诊断结果的过程的一部分。其他诊断测试可以与这里描述的那些一起使用,以增强诊断或预后的准确性或确认通过使用这里描述的测试获得的结果。
在一些情况下,用于检测肽-MHC复合物存在的体外或体内方法可涉及增强MHC I类表达,例如通过干扰素治疗或HDAC抑制剂治疗。
所述的肽-MHC复合物的存在或受试者样品中所述的肽-MHC复合物的水平可以指示受试者患有疾病/病症,例如,本文所述的疾病/病症。所述的肽-MHC复合物的检测(例如,在从受试者获得的样品中)可用于诊断受试者中的癌症状况、诊断癌症状况的倾向或提供癌症状况的预后(预测)。所述的诊断或预后可能涉及现有的(先前诊断的)癌症状况。
所述的肽-MHC复合物的存在或受试者样品中存在的肽-MHC复合物的水平可以指示受试者可以对本发明所述的抗体、抗原结合片段、CAR、核酸、载体、细胞或组合物的治疗有反应。检测所述的肽-MHC复合物的存在,或检测肽-MHC复合物的特定水平可用于为利用本发明所述地抗体、抗原结合片段、CAR、核酸、载体、细胞或组合物的治疗选择受试者。检测所述的肽-MHC复合物的存在,或检测肽-MHC复合物的特定水平可为利用另一种药剂治疗疾病/病症选择受试者。
可以从任何组织或体液中取样。所述的样品可包含或可源自:一定量的血液;来自个体血液的一定量血清,其可包括去除纤维蛋白凝块和血细胞后获得的血液的液体部分;组织样本或活组织检查;胸水;脑脊液(CSF);或从所述个体分离的细胞。在一些实施方案中,样品可以从受疾病/病症影响的组织或组织获得或衍生(例如,疾病症状表现或涉及疾病/病症的发病机理的一个或多个组织)。在一些实施方案中,所述的样品可以从癌细胞或肿瘤活组织检查获得或衍生。
蛋白表达
适于在细胞中产生本发明所述的蛋白(例如抗体、抗原结合片段和CAR)的分子生物学技术是本领域熟知的,例如Sambrook等人,《分子克隆:实验室手册》,纽约:冷泉港出版社,1989年。多肽可以从核酸序列表达。所述的核酸序列可以包含在细胞中存在的载体中,或者可以掺入细胞的基因组中。
适合于表达多肽的任何细胞,可用于产生本发明所述的蛋白。所述的细胞可以是原核生物或真核生物。合适的原核细胞包括大肠杆菌。真核细胞的实例包括酵母细胞、植物细胞、昆虫细胞或哺乳动物细胞(例如中国仓鼠卵巢(CHO)细胞)。在一些情况下,所述的细胞不是原核细胞,因为一些原核细胞不能进行与真核生物相同的翻译后修饰。此外,在真核生物中可能具有非常高的表达水平,并且使用适当的标签可以更容易地从真核生物中纯化蛋白。还可以使用特定的质粒,增强蛋白分泌到培养基中。
产生目标多肽的方法可以包括培养或发酵修饰过的表达所述多肽的细胞。培养或发酵可以在生物反应器中进行,所述生物反应器具有适当的营养物、空气/氧气和/或生长因子供应。收集分泌的蛋白可以通过从细胞中分离培养液/发酵液,提取蛋白含量,并分离单独的蛋白以分离分泌的多肽。培养、发酵和分离技术是本领域技术人员所熟知的。
生物反应器包括一个或多个可以培养细胞的容器。生物反应器中的培养可以连续进行,反应物连续流入反应器,以及培养细胞连续流出自反应器。或者,所述的培养可以分批进行。所述的生物反应器监测和控制环境条件,例如pH、氧气、流入和流出的流速、以及容器内的搅拌,从而为培养的细胞提供最佳条件。
在培养表达目的多肽的细胞后,优选分离该多肽。可以使用任何合适的本领域已知的方法,来从细胞培养物中分离多肽。为了从培养物中分离目标多肽,可能需要首先将培养的细胞与含有目标多肽的培养基分离。如果目标多肽是由细胞分泌的,则可以通过离心将细胞与含有分泌的多肽的培养基分离。如果目标多肽聚集在细胞内,则必须在离心之前破坏细胞,例如使用超声处理、快速冻融或渗透裂解。离心将产生含有培养细胞或培养细胞的细胞碎片的沉淀,以及含有培养基和目标多肽的上清液。
然后可能需要从上清液或培养基中分离目标多肽,所述的上清液或培养基中可含有其他蛋白和非蛋白组分。从上清液或培养基中分离多肽组分的常用方法是通过沉淀。不同溶解度的多肽/蛋白在不同浓度的沉淀剂(如硫酸铵)中沉淀。例如,在低浓度的沉淀剂下,提取水溶性蛋白。因此,通过添加增加沉淀剂的浓度,可以区分不同溶解度的蛋白。随后可以使用透析从分离的蛋白中除去硫酸铵。
用于区分不同多肽/蛋白的其他方法是本领域已知的,例如离子交换色谱法和大小色谱法。这些方法可以代替沉淀,或者可以在沉淀之后进行。
一旦从培养物中分离出目的多肽,就可能需要浓缩蛋白。许多浓缩目的蛋白的方法是本领域已知的,例如超滤或冷冻干燥。
试剂盒
在本发明所述的一些方面,提供了诸部件的试剂盒。在一些实施方案中,所述的试剂盒可具有至少一个容器,其具有预定量的本发明所述的抗体、抗原结合片段、CAR、组合物、核酸、载体或细胞。
所述试剂盒可以提供抗体、抗原结合片段、CAR、组合物、核酸、载体或细胞以及给予患者的说明书,以便治疗特定的疾病/病症,例如,癌症)。可以配制所述的抗体、抗原结合片段、CAR、组合物、核酸、载体或细胞,以便适合注射或输注到肿瘤或血液中。
在一些实施方案中,所述的试剂盒可包含用于产生本发明所述细胞的材料。例如,所述的试剂盒可包含用于修饰细胞以表达或包含本发明所述的抗体、抗原结合片段、CAR、核酸或载体的材料,或用于将本发明所述的核酸或载体导入细胞的材料。
在一些实施方案中,所述的试剂盒可以进一步包含至少一个容器,其具有预定量的另一种治疗剂(例如抗感染剂或化学治疗剂)。在此类实施方案中,所述的试剂盒还可包含第二药物或药物组合物,使得两种药物或药物组合物可同时或分开施用,以提供针对特定疾病或病症的组合治疗。治疗剂还可以配制以便适合注射或输注到肿瘤或血液中。
序列同一性
为了确定两个或更多个氨基酸或核酸序列之间的同一性百分比,可以采用本领域技术人员已知的各种方式实现成对和多序列比对,例如,使用公众可获得的计算机软件,例如ClustalOmega(Soding,J.2005,Bioinformatics 21,951-960),T-coffee(Notredame等人2000年,J.Mol.Biol.(2000)302,205-217),Kalign(Lassmann和Sonnhammer 2005,BMCBioinformatics,6(298))和MAFFT(Katoh和Standley 2013,Molecular Biology andEvolution,30(4)772-780软件。使用此类软件时,优选使用默认参数,例如空位罚分和延伸罚分。
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本发明包括所述诸方面和优选特征的组合,除非明显不允许或明确避免这种组合。
本文所用的章节标题仅用于组织目的,不应解释为限制所描述的主题。
现在将通过示例以及参考附图,说明本发明所述的各方面和实施方案。其他方面和实施方案对于本领域技术人员而言是显而易见的。本文中提到的所有文献都通过引用并入本文。
在整个说明书中,包括随后的权利要求,除非上下文另有要求,否则词语“包括”和诸如“包括”和“包含”的变体将被理解为暗示包括所述整数、或步骤、或整数或步骤的组合,但不排除任何其他整数、或步骤、或整数或步骤的组合。
必须注意,如说明书和所附权利要求中所使用的,单数形式“一”,“一个”和“该”包括复数指示物,除非上下文另有明确说明。范围在本文中可以表示为,从“约”一个特定值,和/或到“约”另一个特定值。当表达这样的范围时,另一个实施例包括从一个特定值和/或到另一个特定值。类似地,当通过使用先行词“约”将值表示为近似值时,将理解该特定值形成另一个实施例。
附图简述
现在将参照附图,讨论说明本发明原理的实施方式和实验。
图1.抗p53-A24抗体克隆的轻链可变结构域序列。CDR加下划线并单独显示。
图2.抗p53-A24抗体克隆的重链可变结构域序列。CDR加下划线并单独显示。
图3.显示抗p53-A24抗体克隆的轻链CDR序列的表。
图4.显示抗p53-A24抗体克隆的重链CDR序列的表。
图5.显示抗p53-A24抗体克隆的轻链CDR序列和共有序列的表,(A)LC-CDR1、(B)LC-CDR2和(C)LC-CDR3。
图6.显示抗p53-A24抗体克隆的重链CDR序列和共有序列的表,(A)HC-CDR1,(B)HC-CDR2和(C)HC-CDR3。
图7.编码抗p53-A24抗体克隆的VL区的核苷酸序列。
图8.编码抗p53-A24抗体克隆的VH区的核苷酸序列。
图9.显示抗p53-A24抗体克隆与(A)p53125-134-A24单体和(B)阴性对照抗原结合的ELISA分析结果的图。
图10.显示(A)P1C1,(B)P1H4和(C)P2B4与表达HLA*A24的HT29细胞的结合的图,未脉冲(1),用无关肽hTERT324-332,hTERT461-469,WT1235-243,WT1417-425或p53204-212脉冲(2至6),或用p53125-134脉冲(7)。
图11.显示P1C1与(A)用p53肽脉冲(上图)或未用p53肽脉冲(下图)的野生型MDA-MB-231细胞(左图)或HLA*A24转导的MDA-MB-231细胞(右图)的结合,和(B)用各种hTERT、WT1或p53肽脉冲之前或之后,HLA*A24+SoaS2细胞的结合的图。如MFI直方图所示。
图12.显示抗体P1C1衍生的抗体克隆与p53-A24的结合亲和力的表。
图13.显示P1C1衍生的克隆、种系版本(P1C1_g1)和2个亲和力成熟的克隆(P1C1_dm和P1C1_tm)与未脉冲的HT29细胞的结合的图。如MFI直方图所示;左侧狭窄、尖锐的峰代表阴性对照(仅二抗),右侧较宽的峰代表测试的克隆。
图14.显示在P1C1_g1或P1C1_tm存在下,在ADCC测定中的HLA*A24阳性细胞的特异性杀伤力的条形图。显示的为三次的平均细胞毒性±SD。
图15.显示HT29脉冲细胞对与p53-A24形成复合物的抗体内化的图和条形图。(A)用pH敏感染料标记的P1C1_tm(左图)或标记的同种型对照抗体(右图),在冰(上图)或37℃(下图)孵育的HT29细胞的MFI曲线。(B)在不同时间点用pH敏感染料标记的P1C1_tm或标记的同种型对照抗体孵育的细胞的MFI值。
图16.显示在不存在(仅PNU/PBD 2dary)或存在(PNU/PBD)P1C1_tm抗体的情况下,PNU和PBD对HT29细胞的细胞毒性作用增加的条形图。将细胞与P1C1_tm和偶联抗Fc抗体的PNU或PBD细胞毒性药物一起温育。测试三种浓度的抗体,对于它们中的每一种,P1C1_tm/抗-Fc抗体的比例为1:1。显示了孵育72小时后,与未处理孔中的细胞数相比,存活细胞的比例。
图17.显示P1C1_tm抗体的体内特异性的照片。该抗体用于追踪NSG小鼠中注射的人肿瘤细胞系。(A)将表达p53和HLA*A24的HT29细胞接种在动物的右胁腹中,并将HLA*A24-/p53+对照细胞接种在左胁腹中。(B)将表达p53和HLA*A24的HT29细胞接种在动物的右胁腹中,并将HLA*A24+/p53-对照细胞接种在左胁腹中。显示了在注射荧光标记的P1C1_tm抗体后,在指定的小时对已建立的肿瘤进行体内成像的代表性图像。
图18.显示p53 CAR T细胞、对照T细胞或无T细胞对HT29肿瘤细胞的%细胞溶解的图。使用基于阻抗的T细胞介导的细胞毒性测定(xCELLigence),测量40小时内的%细胞溶解。
图19.评估抗p53-A24/CD3双特异性抗体通过人原代T细胞诱导肿瘤细胞杀伤的能力。(A)测试了两种不同形式的双特异性抗体:BsAbl和BsAb2。(B)针对HLA-A24+/p53突变体+细胞系HT29(BsAb1:右侧曲线图,BsAb2:左侧曲线图)和HLA-A24+/p53无效细胞系SaOS2,测试BsAb1和BsAb2的靶特异性细胞毒性。
实施例
在以下实施例中,发明人描述了能够结合p53肽:MHC I类复合物的抗体的分离和表征。
实施例1:分离抗p53:MHCI类复合物抗体
将p53125-134肽与可溶性HLA*A2402(p53-A24)连接以形成可溶性肽MHC复合物(pMHC)。然后通过体外选择从人抗体噬菌体展示文库中分离能够结合该pMHC复合物的抗体。在筛选的190个克隆中,分离出ELISA测定显示与pMHC结合最高的36个克隆,其中4个克隆成IgG形式用于进一步表征:P1C1、P1H4、P1A8和P1B11。
其轻链和重链可变区的氨基酸序列分别显示在图1和2中。
实施例2:p53-A24的亲和力和特异性
通过ELISA测定分析抗体克隆P1C1、P1H4、P1A8和P1B11与p53-A24单体的结合、以及与无关抗原的结合,以确定亲合力和特异性。
除P1A8外,所有克隆均显示出以高亲和力结合p53-A24(图9A)。所述的抗体还显示没有或有限的非特异性结合(图9B)。
实施例3:在HLA*A24表达细胞上与p53特异性结合
使用HT29细胞测量识别和结合在细胞表面表达的p53-A24 pMHC的能力。这些细胞组成型表达HLA*A24。
简言之,用p53125-134肽、选自一组无关肽的肽脉冲HT29细胞,或未脉冲,室温下1小时。然后将细胞与P1C1、P1H4或P2B4一起温育,并使用标记的二抗通过流式细胞术测量结合。
结果显示在图10A至10C中。P1C1、P1H4或P2B4抗体仅与已经用p53125-134肽脉冲的细胞结合,证明它们对p53125-134抗原的特异性(图10A至10C)。此外,所述抗体不与未脉冲的HT29细胞结合的事实表明它们仅结合呈递p53抗原的HLA*A24,而不结合不呈递p53的HLA*A24。
实施例4:HLA*A24MHCI类分子和p53-A24的特异性
为了确认HLA*A24单倍型的特异性,在表达不同HLA*A类型的细胞上评估结合:MDA-MB-231细胞,其组成型表达H LA*AO2和p53。还转导了MDA-MB-231细胞以表达HLA*A24。
然后在转导的和未转导的MDA-MB-231细胞上评估P1C1的结合,所述MDA-MB-231细胞用p53125-134肽脉冲或未脉冲。使用标记二抗,通过流式细胞术测量结合。
结果显示在图11A中,P1C1仅结合表达HLA*A24的细胞(即转导的MDA-MB-231),而在非转导的表达HLA*A02的MDA-MB-231细胞上未观察到结合,证实了对于由HLA*A24呈递的p53125-134肽的特异性。
使用p53阴性的SaoS2细胞进行类似的实验。这些细胞组成型表达HLA*A24。细胞用各种p53、WT1、hTERT的肽脉冲,或未脉冲。通过仅用与p53125-134脉冲的细胞结合分析P1C1抗体与细胞的结合,证实了抗体对该抗原的特异性(图11B)。
总之,这些结果证明了抗体对HLA*A24呈递的p53125-134的特异性。
实施例5:亲和力成熟的抗体
将P1C1序列恢复为种系框架,得到克隆P1C1_gl,所述的克隆随后进行亲和力成熟。保留2个亲和力成熟的克隆用于重链(2E3和1E11),并保留1个亲和力成熟的克隆用于轻链(1G7)。
构建2E3和1E11中同时存在的取代的双突变体,命名为克隆P1C1_dm。构建2E3、1E11和1G7同时存在的取代的三重突变体,命名为克隆P1C1_tm。
通过表面等离子体共振分析测量P1C1衍生的不同克隆对p53-A24复合物的亲和力。结果如图12所示,且与P1C1_g1相比,P1C1_tm对p53-A24的亲和力高约10倍。
通过流式细胞术分析P1C1_dm、P1C1_tm和P1C1_g1与未脉冲的HT29细胞结合的能力。与原始种系克隆相比,P1C1_dm和P1C1_tm克隆显示出与未脉冲的HT29细胞的更高结合力(图13)。
实施例6:体外活性:诱导抗体依赖性细胞介导的细胞毒性(ADCC)
为了评估抗体诱导ADCC的能力,将HLA*A24阳性HT29与PBMC以1:10的比例混合,并在存在或不存在P1C1_g1或P1C1_tm的情况下孵育过夜,并测量细胞杀伤。细胞未经脉冲或用p53肽脉冲。
还使用未经转导或经HLA*A24转导的HLA*A24阴性MDA-MB-231细胞评估了抗体诱导ADCC的特异性。
结果如图14所示。与未脉冲细胞相比,在p53肽脉冲的HLA*A24阳性细胞中观察到更有效的剂量依赖性杀伤。在HLA*A24-阴性MDA-MB-231细胞中未观察到显著的ADCC。与P1C1_g1相比,P1C1_tm表现出更有效的ADCC。
实施例7:HT29细胞对P1C1
tm的内化
用pH敏感的pHrodo-Red染料标记P1C1_tm抗体,并与p53肽脉冲的HT29细胞在37℃或冰上孵育不同的时间,然后通过流式细胞术分析内化作用。由于内体的酸性环境,与表面结合的抗体相比,内化的抗体产生显著的荧光。
结果如图15A和15B所示。与p53-A24 pMHC结合后,当复合物被再循环时所述抗体随复合物内化,如通过在P1C1_tm抗体存在下在37℃下孵育的p53肽脉冲的HT29细胞中的荧光移位所证明的(图15A,左下图)。用非特异性对照抗体(图15A,右下图)或在冰上孵育的细胞(因不再循环p53-A24 pMHC)中未观察到这种转变(图15A,左上图)。
实施例8:药物输送到肿瘤细胞
所述的抗体随p53-A24复合物的内化,可以用作特异性靶向肿瘤细胞的药物递送工具。这一点使用药物偶联的二抗与P1C1_tm结合进行了测试。简言之,将HT29细胞与P1C1_tm和与细胞毒性药物PNU159682(PNU)或吡咯并苯并二氮杂(PBD)偶联的抗人Fc特异性二抗一起温育。72小时后,通过MTT测定分析细胞活力。在不存在P1C1_tm的情况下,将一些细胞仅与药物偶联抗体一起孵育作为对照。
实验结果如图16所示。发现P1C1_tm显著增强PNU和PBD的细胞毒性作用。增加的效果可能是由于药物的内化作用,所述药物作为与p53-A24复合物结合的P1C1_tm/药物偶联抗-Fc抗体的免疫复合物的一部分。
这些数据表明,P1C1_tm可用于治疗癌症,用于将药物靶向递送至肿瘤,并通过迫使药物内化进入靶细胞来增加药物的功效。
实施例9:在NSG小鼠中HT29的体内成像
TCR样抗体的应用之一将是通过鉴定经由MHC I类交叉呈递细胞内分子的肿瘤细胞来辅助诊断癌症,所述的分子在本例中为p53。
为了评估P1C1_tm作为诊断抗体的有效性,将HT29细胞(A24和p53均为阳性)、和未转导的MDA-MB-231细胞(表达p53但对A24呈阴性)或SaoS2细胞(表达A24但不是p53)植入NSG小鼠的侧翼,如图17A和17B中示意性地示出并在图例中解释的。
允许肿瘤建立并生长至100-200mm3,然后静脉内施用50μg的AF680标记的P1C1_tm抗体。48和120小时后,通过体内荧光成像采集肿瘤标记。
如图17A和17B所示,所述的抗体能检测HLA*A24+HT29细胞,但不追踪表达HLA*A02的肿瘤(图9A),也不追踪不表达p53的HLA*A24+肿瘤细胞(图9B)
实施例10:T细胞介导的针对HT29肿瘤细胞的细胞毒性
评估表达包含TCR样抗原结合片段的嵌合抗原受体(CAR)的T细胞杀伤HT29肿瘤细胞的能力。
通过添加TransActTM(CD3/CD28激动剂)激活来自健康供体的T细胞,并在补充有50ng/mL IL2的TexMACSTM培养基中维持1-2×106个细胞/ml的密度,持续72小时。刺激后,用或不用基于慢病毒的p53 CAR质粒(每百万个细胞2个)电穿孔细胞。
由于质粒DNA电穿孔引起的大量细胞死亡,在电穿孔后48小时通过免疫磁性阴性筛选从细胞培养物中去除凋亡细胞(膜联蛋白V+)。
将细胞再培养24小时,然后在T细胞介导的细胞毒性测定(xCELLigence)中评估。在该测定中,测量肿瘤细胞的细胞指数值。细胞指数由肿瘤细胞粘附引起的晶体管板上的电流阻抗决定。
使用基于xCELLigence阻抗的系统,在40小时内评估持续的肿瘤细胞杀伤。将HT29肿瘤细胞以每孔15,000个细胞接种于96孔电阻器底板中的完全生长培养基中。18-24小时后,加入3,750个效应T细胞(1:4接种比),此时标准化与HT29粘附相关的细胞指数值。每10分钟记录标准化细胞指数的基于阻抗的测量值,并转换成%细胞溶解。数据表示三次的平均值(±标准偏差)。
结果如图18所示。与对照T细胞相比,p53 CAR T细胞能够杀死更多的HLA*A24阳性HT29肿瘤细胞。
实施例11:抗p53-A24/CD3双特异性抗体对HT29肿瘤细胞的体外细胞毒性
两种不同形式的抗p53-A24/CD3双特异性抗体(BsAb)与人原代T细胞和肿瘤细胞共培养,并评估其诱导肿瘤细胞杀伤的能力。两种BsAb形式(1和2)如图19A所示。
用Oregon Green预先标记肿瘤细胞(靶细胞),并在96孔半区域平底板中培养过夜以进行细胞粘附。第二天,加入从人PBMC分离的原代T细胞,效应物与靶标的比例为10比1(E:T=10:1)。BsAb,用8点10倍滴定法,也制备并添加到每个孔中以达到指示的最终浓度。然后将板在37℃,5%CO2中温育3天。为进行FACS读数,用Accutase轻轻地分离肿瘤细胞,并用碘化丙啶(PI)染色以标记死细胞。在3天共培养后,使用MACSQuant分析仪进行FACS读数,以测量BsAb诱导的细胞毒性。%细胞毒性等于死细胞的细胞计数除以靶细胞的细胞计数。
结果如图19B所示。在HLA-A24+/p53突变体+细胞系HT29中,用两种双特异性构建体观察到靶特异性细胞毒性。BsAb2(EC50=0.48nM;左侧曲线图)显示出比BsAb1更高的效力(EC50=3.05nM;右侧曲线图)。另一方面,在细胞杀伤HLA-A24+/p53无效细胞系SaOS2的两种构建体中均未观察到非特异性细胞毒性,显示双特异性构建体对靶向p53-A24复合物的特异性。
序列表
<110> 新加坡科技研究局
<120> 与p53-MHC I类复合物结合的T细胞受体样抗体
<130> RIC/FP7336001
<150> SG 10201701883R
<151> 2017-08-03
<160> 77
<170> PatentIn version 3.5
<210> 1
<211> 217
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1
<400> 1
Gln Ala Val Leu Thr Gln Pro Ser Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Asp
20 25 30
Tyr Glu Thr His Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Thr Asn Arg Pro Ser Gly Val Pro His Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Asn
85 90 95
Leu Ser Ala Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Ile Leu Ser
100 105 110
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
115 120 125
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
130 135 140
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
145 150 155 160
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys
165 170 175
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
180 185 190
His Lys Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
195 200 205
Lys Thr Val Ala Pro Ala Glu Cys Ser
210 215
<210> 2
<211> 217
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1_gl; P1C1_dm; 2E3; 1E11
<400> 2
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Asp
20 25 30
Tyr Glu Thr His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Thr Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Asn
85 90 95
Leu Ser Ala Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Ile Leu Ser
100 105 110
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
115 120 125
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
130 135 140
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
145 150 155 160
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys
165 170 175
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
180 185 190
His Lys Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
195 200 205
Lys Thr Val Ala Pro Ala Glu Cys Ser
210 215
<210> 3
<211> 217
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1G7; P1C1_tm
<400> 3
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ala Gly Ser Tyr Ser Asn Ile Gly Asp Asp
20 25 30
Tyr Glu Thr His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Thr Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Asn
85 90 95
Leu Ser Ala Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Ile Leu Ser
100 105 110
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
115 120 125
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
130 135 140
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
145 150 155 160
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys
165 170 175
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
180 185 190
His Lys Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
195 200 205
Lys Thr Val Ala Pro Ala Glu Cys Ser
210 215
<210> 4
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1H4
<400> 4
Glu Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Thr Phe Gly Gly Ala Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 5
<211> 218
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1B11
<400> 5
Gln Ala Val Leu Thr Gln Pro Ser Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Asn Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Asn
85 90 95
Leu Ser Asp Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
115 120 125
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
130 135 140
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
145 150 155 160
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
165 170 175
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
180 185 190
Ser His Lys Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
195 200 205
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215
<210> 6
<211> 217
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1A8
<400> 6
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Asn Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Asn Ser Gly Thr Ser Val Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser
85 90 95
Leu Ser Ala Trp Val Phe Gly Gly Gly Thr Lys Leu Ala Val Leu Gly
100 105 110
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
115 120 125
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
130 135 140
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val
145 150 155 160
Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys
165 170 175
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
180 185 190
His Lys Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
195 200 205
Lys Thr Val Ala Pro Ala Glu Cys Ser
210 215
<210> 7
<211> 216
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P2B4
<400> 7
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Leu Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln Gln Ala Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Ser Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Asp Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Val Phe
85 90 95
Ser Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln
100 105 110
Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Ala Glu Cys Ser
210 215
<210> 8
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1
<400> 8
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Glu Asn Phe Gly Ala Phe Asp His Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 9
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1_gl; 1G7
<400> 9
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Glu Asn Phe Gly Ala Phe Asp His Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 10
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 2E3
<400> 10
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Gly Tyr Tyr Trp Ala Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Glu Asn Phe Gly Ala Phe Asp His Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 11
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1E11
<400> 11
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Glu Asn Phe Gly Ser Tyr Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 12
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1_dm; P1C1_tm
<400> 12
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Gly Tyr Tyr Trp Ala Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Glu Asn Phe Gly Ser Tyr Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 13
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1H4
<400> 13
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Ala Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ala Asp Gly Ile Tyr Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 14
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1B11
<400> 14
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Val Ser Gly Asp Ser Ile Ser Ser Gly
20 25 30
Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Glu Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Thr Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Ile Thr Met Ser Ile Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Val Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Glu Asn Phe Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 15
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1A8
<400> 15
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Arg Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Leu
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Glu Asn Phe Gly Ala Phe Asp His Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 16
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P2B4
<400> 16
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Thr
1 5 10 15
Ser Val Thr Val Ser Cys Arg Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Met Ser Pro Asp Ser Gly Ala Thr Tyr Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Asp Thr Tyr Gly His Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 17
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1; P1C1_gl; P1C1_dm; 2E3; 1E11 LC-CDR1
<400> 17
Thr Gly Ser Ser Ser Asn Ile Gly Ala Asp Tyr Glu Thr His
1 5 10
<210> 18
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1; P1C1_gl; P1C1_dm; 2E3; 1E11 LC-CDR2
<400> 18
Gly Asn Thr Asn Arg Pro Ser
1 5
<210> 19
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1; P1C1_gl; P1C1_dm; 2E3; 1E11 LC-CDR3
<400> 19
Gln Ser Tyr Asp Ser Asn Leu Ser Ala Trp Val
1 5 10
<210> 20
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1G7; P1C1_tm LC-CDR1
<400> 20
Ala Gly Ser Tyr Ser Asn Ile Gly Asp Asp Tyr Glu Thr His
1 5 10
<210> 21
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1H4 LC-CDR1
<400> 21
Arg Ala Ser Gln Ser Ile Gly Thr Asp Leu Ala
1 5 10
<210> 22
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1H4 LC-CDR2
<400> 22
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 23
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1H4 LC-CDR3
<400> 23
Gln Gln Arg Ser Asn Trp Pro Pro Thr
1 5
<210> 24
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1B11 LC-CDR1
<400> 24
Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His
1 5 10
<210> 25
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1B11 LC-CDR2
<400> 25
Gly Asn Asn Asn Arg Pro Ser
1 5
<210> 26
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1B11 LC-CDR3
<400> 26
Gln Ser Tyr Asp Ser Asn Leu Ser Asp Thr Trp Val
1 5 10
<210> 27
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1A8 LC-CDR1
<400> 27
Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val Asn
1 5 10
<210> 28
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1A8 LC-CDR3
<400> 28
Gln Ser Tyr Asp Ser Ser Leu Ser Ala Trp Val
1 5 10
<210> 29
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P2B4 LCl-CDR1
<400> 29
Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser
1 5 10
<210> 30
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P2B4 LC-CDR2
<400> 30
Asp Val Ser Ser Arg Pro Ser
1 5
<210> 31
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P2B4 LC-CDR3
<400> 31
Ser Ser Tyr Thr Val Phe Ser Thr Leu Val
1 5 10
<210> 32
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1; P1C1_gl; 1G7; P1A8 HC-CDR1
<400> 32
Ser Gly Gly Tyr Tyr Trp Ser
1 5
<210> 33
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1; P1C1_gl; 1G7; P1A8 HC-CDR2
<400> 33
Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 34
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1; P1C1_gl; 1G7; P1A8 HC-CDR3
<400> 34
Glu Asn Phe Gly Ala Phe Asp His
1 5
<210> 35
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 2E3 HC-CDR1
<400> 35
Ser Gly Gly Tyr Tyr Trp Ala
1 5
<210> 36
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 1E11 HC-CDR3
<400> 36
Glu Asn Phe Gly Ser Tyr Asp Tyr
1 5
<210> 37
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1H4 HC-CDR1
<400> 37
Gly Tyr Tyr Met His
1 5
<210> 38
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1H4 HC-CDR2
<400> 38
Trp Ile Asn Pro Asn Ser Ala Gly Thr Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 39
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1H4 HC-CDR3
<400> 39
Glu Gly Ala Asp Gly Ile Tyr Tyr Phe Asp Tyr
1 5 10
<210> 40
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1B11 HC-CDR1
<400> 40
Ser Gly Gly Tyr Tyr Trp Ser
1 5
<210> 41
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1B11 HC-CDR2
<400> 41
Tyr Ile Tyr Tyr Ser Gly Thr Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 42
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P1B11 HC-CDR3
<400> 42
Glu Asn Phe Gly Ala Phe Asp Tyr
1 5
<210> 43
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P2B4 HC-CDR1
<400> 43
Asp Tyr Tyr Ile His
1 5
<210> 44
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P2B4 HC-CDR2
<400> 44
Trp Met Ser Pro Asp Ser Gly Ala Thr Tyr Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 45
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> P2B4 HC-CDR3
<400> 45
Asp Thr Tyr Gly His Asp Tyr
1 5
<210> 46
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Sequence family LC-CDR1-1 Family consensus
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa = T or A
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa = S or Y
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa = A or D
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa = G or D
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa = D or E
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa = V or T
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa = H or N
<400> 46
Xaa Gly Ser Xaa Ser Asn Ile Gly Xaa Xaa Tyr Xaa Xaa Xaa
1 5 10
<210> 47
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Sequence Family LC-CDR2-1 family consensus
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = N or T
<400> 47
Gly Asn Xaa Asn Arg Pro Ser
1 5
<210> 48
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Sequence family LC-CDR3-1 family consenus
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa = N or S
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa = Absent or D
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa = A or T
<400> 48
Gln Ser Tyr Asp Ser Xaa Leu Ser Xaa Xaa Trp Val
1 5 10
<210> 49
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Sequence family HC-CDR1-1 family consensus
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = S or A
<400> 49
Ser Gly Gly Tyr Tyr Trp Xaa
1 5
<210> 50
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Sequence family HC-CDR1-2 family consensus
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa = G or D
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa = M or I
<400> 50
Xaa Tyr Tyr Xaa His
1 5
<210> 51
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Sequence family HC-CDR2-1 family consensus
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = S or T
<400> 51
Tyr Ile Tyr Tyr Ser Gly Xaa Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 52
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Sequence family HC-CDR2-2 family consensus
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa = I or M
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa = N or S
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa = N or D
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa = A or G
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa = G or A
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa = N or Y
<400> 52
Trp Xaa Xaa Pro Xaa Ser Xaa Xaa Thr Xaa Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 53
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Sequence family HC-CDR3-1 family consensus
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa = A or S
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa = F or Y
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa = H or Y
<400> 53
Glu Asn Phe Gly Xaa Xaa Asp Xaa
1 5
<210> 54
<211> 651
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1
<400> 54
caggctgtgc tgactcagcc gtcctcagtg tctggggccc cagggcagag ggtcaccatc 60
tcctgcactg ggagcagctc caacatcggg gcagattatg agacacactg gtaccagcac 120
cttccaggaa cggcccccaa actcctcatt tatggtaaca ccaatcggcc ctcaggggtc 180
cctcaccgat tctctggctc caagtctggc acctcagcct ccctggccat cactgggctc 240
caggctgagg atgaggctga ttattattgc cagtcctatg acagcaatct gagtgcttgg 300
gtgttcggcg gagggaccaa gctgaccatc ctaagtcagc ccaaggctgc cccctcggtc 360
actctgttcc caccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc 420
ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag cagccccgtc 480
aaggcgggag tggagaccac cacaccctcc aaacaaagca acaacaagta cgcggccagc 540
agctacctga gcctgacgcc tgagcagtgg aagtcccaca aaagctacag ctgccaggtc 600
acgcatgaag ggagcaccgt ggagaagaca gtggcccctg cagaatgttc a 651
<210> 55
<211> 651
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1_gl; P1C1_dm; 2E3; 1E11
<400> 55
cagtctgtgc tgactcagcc gccctcagtg tctggggccc cagggcagag ggtcaccatc 60
tcctgcactg ggagcagctc caacatcggg gcagattatg agacacactg gtaccagcaa 120
cttccaggaa cggcccccaa actcctcatt tatggtaaca ccaatcggcc ctcaggggtc 180
cctgaccgat tctctggctc caagtctggc acctcagcct ccctggccat cactgggctc 240
caggctgagg atgaggctga ttattattgc cagtcctatg acagcaatct gagtgcttgg 300
gtgttcggcg gagggaccaa gctgaccatc ctaagtcagc ccaaggctgc cccctcggtc 360
actctgttcc caccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc 420
ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag cagccccgtc 480
aaggcgggag tggagaccac cacaccctcc aaacaaagca acaacaagta cgcggccagc 540
agctacctga gcctgacgcc tgagcagtgg aagtcccaca aaagctacag ctgccaggtc 600
acgcatgaag ggagcaccgt ggagaagaca gtggcccctg cagaatgttc a 651
<210> 56
<211> 651
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 1G7; P1C1_tm
<400> 56
cagtctgtgc tgactcagcc gccctcagtg tctggggccc cagggcagag ggtcaccatc 60
tcctgcgctg ggtcttattc taatattggg gatgattatg aaactcattg gtaccagcaa 120
cttccaggaa cggcccccaa actcctcatt tatggtaaca ccaatcggcc ctcaggggtc 180
cctgaccgat tctctggctc caagtctggc acctcagcct ccctggccat cactgggctc 240
caggctgagg atgaggctga ttattattgc cagtcctatg acagcaatct gagtgcttgg 300
gtgttcggcg gagggaccaa gctgaccatc ctaagtcagc ccaaggctgc cccctcggtc 360
actctgttcc caccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc 420
ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag cagccccgtc 480
aaggcgggag tggagaccac cacaccctcc aaacaaagca acaacaagta cgcggccagc 540
agctacctga gcctgacgcc tgagcagtgg aagtcccaca aaagctacag ctgccaggtc 600
acgcatgaag ggagcaccgt ggagaagaca gtggcccctg cagaatgttc a 651
<210> 57
<211> 642
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1H4
<400> 57
gaaattgtga tgacgcagtc tcctggcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtattggg accgacttag cctggtacca gcagaaacct 120
ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
gaagattttg cagtttatta ctgtcagcag cgtagtaact ggcctcccac tttcggcgga 300
gcgaccaagg tggagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 58
<211> 654
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1B11
<400> 58
caggctgtgc tgactcagcc gtcctcagtg tctggggccc cagggcagag ggtcaccatc 60
tcctgcactg ggagcagctc caacatcggg gcaggttatg atgtacactg gtaccaacag 120
cttccaggaa cagcccccaa actcctcatt tatggtaaca acaatcgacc ctcaggggtc 180
cctgaccgat tctctggctc caagtctggc acctcagcct ccctggccat cactgggctc 240
caggctgagg atgaggctga ttattactgc cagtcctatg acagcaacct gagtgacacc 300
tgggtattcg gcggagggac caagctgacc gtcctaggtc agcccaaggc tgccccctcg 360
gtcactctgt tcccgccctc ctctgaggag cttcaagcca acaaggccac actggtgtgt 420
ctcataagtg acttctaccc gggagccgtg acagtggcct ggaaggcaga tagcagcccc 480
gtcaaggcgg gagtggagac caccacaccc tccaaacaaa gcaacaacaa gtacgcggcc 540
agcagctacc tgagcctgac gcctgagcag tggaagtccc acaaaagcta cagctgccag 600
gtcacgcatg aagggagcac cgtggagaag acagtggccc ctacagaatg ttca 654
<210> 59
<211> 651
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1A8
<400> 59
cagtctgtgc tgacgcagcc gccctcagtg tctggggccc cagggcagag ggtcaccatc 60
tcctgcactg ggagtagctc caacatcggg gcaggttatg atgtaaactg gtaccagcaa 120
cttccaggaa cagcccccaa actcctcatc tatggaaaca acaatcggcc ctcaggggtc 180
cctgaccgat tctctggctc caactctggc acctcagtct ccctggccat cactgggctc 240
cagcctgagg atgaggctga ttactactgc cagtcctacg acagcagcct gagtgcctgg 300
gtgttcggcg gagggacgaa gctggccgtc ctaggtcagc ccaaggctgc cccctcggtc 360
actctgttcc cgccctcctc tgaggagctc caagccaaca aggccacact agtgtgtctg 420
atcagtgact tctacccggg agctgtgaca gtggcctgga aggcagatgg cagccccgtc 480
aaggcgggag tggagaccac caaaccctcc aaacagagca acaacaagta cgcggccagc 540
agctacctga gcctgacgcc tgagcagtgg aagtcccaca aaagctacag ctgccaggtc 600
acgcatgaag ggagcaccgt ggagaagaca gtggcccctg cagaatgctc t 651
<210> 60
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P2B4
<400> 60
cagtctgccc tgactcagcc tgcctccgtg tctgggtctc ttggacagtc gatcaccatc 60
tcctgcactg ggaccagcag tgacgttggt ggttataact atgtctcctg gtaccaacag 120
caggcaggca aagcccccaa actcatgatt tatgatgtca gtagtcggcc ctcaggggtt 180
tctgatcgct tctctggctc caagtctggc aacacggcct ccctgaccat ctctgggctc 240
caggctgacg acgaggctga ttattactgc agctcatata cagtcttcag cactctagta 300
ttcggcggag ggaccaagtt gaccgtccta ggtcagccca aggctgcccc ctcggtcact 360
ctgttcccac cctcctctga ggaactccaa gccaacaagg ccacactagt gtgtctgatc 420
agtgacttct acccgggagc tgtgacagtg gcctggaagg cagatggcag ccccgtcaag 480
gcgggagtgg agaccaccaa accctccaaa cagagcaaca acaagtacgc ggccagcagc 540
tacctgagcc tgacgcctga gcagtggaag tcccacagaa gctacagctg ccaggtcacg 600
catgaaggga gcaccgtgga gaagacagtg gcccctgcag aatgctca 648
<210> 61
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1
<400> 61
cagctgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60
acctgcgctg tctctggtgg ctccatcagc agtggtggtt actactggag ctggatccgc 120
cagcgcccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac 180
tacaacccgt ccctcaagag tcgacttacc atatcagtag acacgtctaa gaaccagttc 240
tccctgaaac tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagaa 300
aattttggag cgtttgacca ctggggccag ggcaccctgg tcaccgtctc aagc 354
<210> 62
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1_gl; 1G7
<400> 62
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60
acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ctggatccgc 120
cagcacccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac 180
tacaacccgt ccctcaagag tcgagttacc atatcagtag acacgtctaa gaaccagttc 240
tccctgaaac tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagaa 300
aattttggag cgtttgacca ctggggccag ggcaccctgg tcaccgtctc aagc 354
<210> 63
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 2E3
<400> 63
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60
acctgcactg tctctggtgg ctccatcagc tctggtggtt attattgggc ttggatccgc 120
cagcacccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac 180
tacaacccgt ccctcaagag tcgagttacc atatcagtag acacgtctaa gaaccagttc 240
tccctgaaac tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagaa 300
aattttggag cgtttgacca ctggggccag ggcaccctgg tcaccgtctc aagc 354
<210> 64
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 1E11
<400> 64
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60
acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ctggatccgc 120
cagcacccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac 180
tacaacccgt ccctcaagag tcgagttacc atatcagtag acacgtctaa gaaccagttc 240
tccctgaaac tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagaa 300
aattttggat cttatgatta ttggggccag ggcaccctgg tcaccgtctc aagc 354
<210> 65
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1C1_dm; P1C1_tm
<400> 65
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60
acctgcactg tctctggtgg ctccatcagc agtggtggtt actactgggc ctggatccgc 120
cagcacccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac 180
tacaacccgt ccctcaagag tcgagttacc atatcagtag acacgtctaa gaaccagttc 240
tccctgaaac tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagaa 300
aattttggat cttatgatta ttggggccag ggcaccctgg tcaccgtctc aagc 354
<210> 66
<211> 360
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1H4
<400> 66
caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcaatccta acagtgctgg cacaaactat 180
gcacagaagt tccagggcag agtcaccatg accacagaca catccacgag cacagcctac 240
atggagctga ggagcctgag atctgaggac acggctgtgt attactgtgc gagagagggc 300
gcggacggga tttactactt tgactactgg ggccagggca ccctggtcac cgtctcaagc 360
<210> 67
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1B11
<400> 67
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
acgtgcagtg tctctggtga ctccattagt agtggtggtt actactggag ctggatccgc 120
cagcacccag agaagggcct ggagtggatt gggtacatct attacagtgg gaccacctac 180
tacaacccgt ccctcaagag tcgaataacc atgtcaatag acacgtctaa gaaccagttc 240
tccctgaaag tgagctctgt gactgccgcg gacacggccg tttattactg tgcgagagaa 300
aattttggag cgtttgacta ctggggccag ggcaccctgg tcaccgtctc aagc 354
<210> 68
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1A8
<400> 68
cagctgcagc tgcaggagtc cggcccagga ctggtgaagc cttcacagac cctgtccctc 60
acctgcagtg tctctggtgg ctccatcagc agtggtggtt actactggag ctggatccgc 120
cagcgcccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac 180
tacaacccgt ccctcaagag tcgacttacc atatcagtag acacgtctaa gaaccagctc 240
tccctgaaac tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagaa 300
aattttgggg cgtttgacca ctggggccag ggcaccctgg tcaccgtctc aagc 354
<210> 69
<211> 348
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P2B4
<400> 69
caggtccagc tggtgcagtc tggggctgag gtgaagaagc ctgggacctc agtgacggtc 60
tcctgcaggg cttctggatt caccttcagc gactactata tacactgggt gcgacaggcc 120
cctggacaag gacttgagtg gatgggatgg atgagccctg acagtggtgc cacatactat 180
gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccaccaa cacagcctac 240
atggaactga gcagactcac atctgacgac acggccgtgt attattgtgt gagagatact 300
tatggccatg actactgggg ccagggaacc ctggtcaccg tctcaagc 348
<210> 70
<211> 393
<212> PRT
<213> Homo sapiens
<400> 70
Met Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu
20 25 30
Ser Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp
35 40 45
Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro
50 55 60
Arg Met Pro Glu Ala Ala Pro Pro Val Ala Pro Ala Pro Ala Ala Pro
65 70 75 80
Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser
85 90 95
Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly
100 105 110
Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro
115 120 125
Ala Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln
130 135 140
Leu Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met
145 150 155 160
Ala Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys
165 170 175
Pro His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln
180 185 190
His Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp
195 200 205
Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu
210 215 220
Val Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser
225 230 235 240
Ser Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr
245 250 255
Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val
260 265 270
Arg Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn
275 280 285
Leu Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr
290 295 300
Lys Arg Ala Leu Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys
305 310 315 320
Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu
325 330 335
Arg Phe Glu Met Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp
340 345 350
Ala Gln Ala Gly Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His
355 360 365
Leu Lys Ser Lys Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met
370 375 380
Phe Lys Thr Glu Gly Pro Asp Ser Asp
385 390
<210> 71
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> p53 peptide
<400> 71
Arg Met Pro Glu Ala Ala Pro Pro Val
1 5
<210> 72
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> p53 peptide
<400> 72
Ser Thr Pro Pro Pro Gly Thr Arg Val
1 5
<210> 73
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> p53 peptide
<400> 73
Leu Leu Gly Arg Asn Ser Phe Glu Val
1 5
<210> 74
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> p53 peptide
<400> 74
Val Val Pro Tyr Glu Pro Pro Glu Val
1 5
<210> 75
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> p53 peptide
<400> 75
Thr Tyr Ser Pro Ala Leu Asn Lys Met Phe
1 5 10
<210> 76
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> p53 peptide
<400> 76
Ala Ile Tyr Lys Gln Ser Gln His Met
1 5
<210> 77
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> p53 peptide
<400> 77
Glu Tyr Leu Asp Asp Arg Asn Thr Phe
1 5
Claims (15)
1.一种嵌合抗原受体(CAR),其包含抗原结合结构域,所述抗原结合结构域包含能够结合包含p53的肽和MHC I类分子的肽-MHC复合物的抗体或抗原结合片段。
2.如权利要求1所述的CAR,其特征在于,所述MHC I类分子包含由HLA-A*24等位基因编码的MHC I类α链。
3.如权利要求1或2所述的CAR,其特征在于,所述p53的肽包含SEQ ID NO:75的氨基酸序列,或由其组成,或其变体,所述变体在氨基酸序列中具有一个或两个或三个氨基酸取代。
4.如权利要求1-3中任一项所述的CAR,其特征在于,所述抗体或抗原结合片段包含氨基酸序列i)至vi):
i)LC-CDR1:X1GSX2SNIGX3X4YX5X6X7(SEQ ID NO:46);
TGTSSDVGGYNYVS(SEQ ID NO:29);或者
RASQSIGTDLA(SEQ ID NO:21);
ii)LC-CDR2:GNX8NRPS(SEQ ID NO:47);
DASNRAT(SEQ ID NO:22);或者
DVSSRPS(SEQ ID NO:30);
iii)LC-CDR3:QSYDSX9LSX10X11WV(SEQ ID NO:48);
QQRSNWPPT(SEQ ID NO:23);或者
SSYTVFSTLV(SEQ ID NO:31);
iv)HC-CDR1:SGGYYWX12(SEQ ID NO:49);或者
X13YYX14H(SEQ ID NO:50);
v)HC-CDR2:YIYYSGX15TYYNPSLKS(SEQ ID NO:51);或者
WX16X17PX18SX19X20TX2`YAQKFQG(SEQ ID NO:52);
vi)HC-CDR3:ENFGX22X23DX24(SEQ ID NO:53);
EGADGIYYFDY(SEQ ID NO:39);或者
DTYGHDY(SEQ ID NO:45);
或其变体,所述变体在序列i)至vi)的一个或多个序列中有一个或两个或三个氨基酸被另一氨基酸取代;
其中X1=T或A,X2=S或Y,X3=A或D,X4=G或D,X5=D或E,X6=V或T,X7=H或N,X8=N或T,X9=N或S,X10=不存在或D,X11=A或T,X12=S或A,X13=G或D,X14=M或I,X15=S或T,X16=I或M,X17=N或S,X18=N或D,X19=A或G,X20=G或A,X21=N或Y,X22=A或S,X23=F或Y,X24=H或Y。
5.如权利要求1-4中任一项所述的CAR,其特征在于,所述抗体或抗原结合片段包含:
(i)至少一个包含以下CDR的轻链可变区:
LC-CDR1:TGSSSNIGADYETH(SEQ ID NO:17)
LC-CDR2:GNTNRPS(SEQ ID NO:18)
LC-CDR3:QSYDSNLSAWV(SEQ ID NO:19);和
至少一个包含以下CDR的重链可变区:
HC-CDR1:SGGYYWS(SEQ ID NO:32)
HC-CDR2:YIYYSGSTYYNPSLKS(SEQ ID NO:33)
HC-CDR3:ENFGAFDH(SEQ ID NO:34);
或
(ii)至少一个包含以下CDR的轻链可变区:
LC-CDR1:TGSSSNIGADYETH(SEQ ID NO:17)
LC-CDR2:GNTNRPS(SEQ ID NO:18)
LC-CDR3:QSYDSNLSAWV(SEQ ID NO:19);和
至少一个包含以下CDR的重链可变区:
HC-CDR1:SGGYYWA(SEQ ID NO:35)
HC-CDR2:YIYYSGSTYYNPSLKS(SEQ ID NO:33)
HC-CDR3:ENFGSYDY(SEQ ID NO:36);
或
(iii)至少一个包含以下CDR的轻链可变区:
LC-CDR1:TGSSSNIGADYETH(SEQ ID NO:17)
LC-CDR2:GNTNRPS(SEQ ID NO:18)
LC-CDR3:QSYDSNLSAWV(SEQ ID NO:19);和
至少一个包含以下CDR的重链可变区:
HC-CDR1:SGGYYWA(SEQ ID NO:35)
HC-CDR2:YIYYSGSTYYNPSLKS(SEQ ID NO:33)
HC-CDR3:ENFGAFDH(SEQ ID NO:34);
或
(iv)至少一个包含以下CDR的轻链可变区:
LC-CDR1:TGSSSNIGADYETH(SEQ ID NO:17)
LC-CDR2:GNTNRPS(SEQ ID NO:18)
LC-CDR3:QSYDSNLSAWV(SEQ ID NO:19);和
至少一个包含以下CDR的重链可变区:
HC-CDR1:SGGYYWS(SEQ ID NO:32)
HC-CDR2:YIYYSGSTYYNPSLKS(SEQ ID NO:33)
HC-CDR3:ENFGSYDY(SEQ ID NO:36);
或
(v)至少一个包含以下CDR的轻链可变区:
LC-CDR1:AGSYSNIGDDYETH(SEQ ID NO:20)
LC-CDR2:GNTNRPS(SEQ ID NO:18)
LC-CDR3:QSYDSNLSAWV(SEQ ID NO:19);和
至少一个包含以下CDR的重链可变区:
HC-CDR1:SGGYYWS(SEQ ID NO:32)
HC-CDR2:YIYYSGSTYYNPSLKS(SEQ ID NO:33)
HC-CDR3:ENFGAFDH(SEQ ID NO:34);
或
(vi)至少一个包含以下CDR的轻链可变区:
LC-CDR1:AGSYSNIGDDYETH(SEQ ID NO:20)
LC-CDR2:GNTNRPS(SEQ ID NO:18)
LC-CDR3:QSYDSNLSAWV(SEQ ID NO:19);和
至少一个包含以下CDR的重链可变区:
HC-CDR1:SGGYYWA(SEQ ID NO:35)
HC-CDR2:YIYYSGSTYYNPSLKS(SEQ ID NO:33)
HC-CDR3:ENFGSYDY(SEQ ID NO:36);
或
(vii)至少一个包含以下CDR的轻链可变区:
LC-CDR1:RASQSIGTDLA(SEQ ID NO:21)
LC-CDR2:DASNRAT(SEQ ID NO:22)
LC-CDR3:QQRSNWPPT(SEQ ID NO:23);和
至少一个包含以下CDR的重链可变区:
HC-CDR1:GYYMH(SEQ ID NO:37)
HC-CDR2:WINPNSAGTNYAQKFQG(SEQ ID NO:38)
HC-CDR3:EGADGIYYFDY(SEQ ID NO:39);
或
(viii)至少一个包含以下CDR的轻链可变区:
LC-CDR1:TGSSSNIGAGYDVH(SEQ ID NO:24)
LC-CDR2:GNNNRPS(SEQ ID NO:25)
LC-CDR3:QSYDSNLSDTWV(SEQ ID NO:26);和
至少一个包含以下CDR的重链可变区:
HC-CDR1:SGGYYWS(SEQ ID NO:40)
HC-CDR2:YIYYSGTTYYNPSLKS(SEQ ID NO:41)
HC-CDR3:ENFGAFDY(SEQ ID NO:42);
或
(ix)至少一个包含以下CDR的轻链可变区:
LC-CDR1:TGSSSNIGAGYDVN(SEQ ID NO:27)
LC-CDR2:GNNNRPS(SEQ ID NO:25)
LC-CDR3:QSYDSSLSAWV(SEQ ID NO:28);和
至少一个包含以下CDR的重链可变区:
HC-CDR1:SGGYYWS(SEQ ID NO:32)
HC-CDR2:YIYYSGSTYYNPSLKS(SEQ ID NO:33)
HC-CDR3:ENFGAFDH(SEQ ID NO:34);
或
(x)至少一个包含以下CDR的轻链可变区:
LC-CDR1:TGTSSDVGGYNYVS(SEQ ID NO:29)
LC-CDR2:DVSSRPS(SEQ ID NO:30)
LC-CDR3:SSYTVFSTLV(SEQ ID NO:31);和
至少一个包含以下CDR的重链可变区:
HC-CDR1:DYYIH(SEQ ID NO:43)
HC-CDR2:WMSPDSGATYYAQKFQG(SEQ ID NO:44)
HC-CDR3:DTYGHDY(SEQ ID NO:45)。
6.如权利要求1-5中任一项所述的CAR,其特征在于,所述抗体或抗原结合片段包括:
所述轻链可变区序列与SEQ ID NO:1至7之一的轻链可变区序列具有至少85%的序列同一性;且
所述重链可变区序列与SEQ ID NO:8-16之一的重链可变区序列具有至少85%的序列同一性。
7.如权利要求1-6中任一项所述的CAR,其特征在于,所述抗体或抗原结合片段包括:
(i)所述轻链可变区序列与SEQ ID NO:1的轻链序列具有至少85%的序列同一性;且
所述重链可变区序列与SEQ ID NO:8的重链序列具有至少85%的序列同一性;
或
(ii)所述轻链可变区序列与SEQ ID NO:2的轻链序列具有至少85%的序列同一性;且
所述重链可变区序列与SEQ ID NO:9的重链序列具有至少85%的序列同一性;
或
(iii)所述轻链可变区序列与SEQ ID NO:2的轻链序列具有至少85%的序列同一性;且
所述重链可变区序列与SEQ ID NO:12的重链序列具有至少85%的序列同一性;
或
(iv)所述轻链可变区序列与SEQ ID NO:2的轻链序列具有至少85%的序列同一性;且
所述重链可变区序列与SEQ ID NO:10的重链序列具有至少85%的序列同一性;
或
(v)所述轻链可变区序列与SEQ ID NO:2的轻链序列具有至少85%的序列同一性;且
所述重链可变区序列与SEQ ID NO:11的重链序列具有至少85%的序列同一性;
或
(vi)所述轻链可变区序列与SEQ ID NO:3的轻链序列具有至少85%的序列同一性;且
所述重链可变区序列与SEQ ID NO:9的重链序列具有至少85%的序列同一性;
或
(vii)所述轻链可变区序列与SEQ ID NO:3的轻链序列具有至少85%的序列同一性;且
所述重链可变区序列与SEQ ID NO:12的重链序列具有至少85%的序列同一性;
或
(viii)所述轻链可变区序列与SEQ ID NO:4的轻链序列具有至少85%的序列同一性;且
所述重链可变区序列与SEQ ID NO:13的重链序列具有至少85%的序列同一性;
或
(ix)所述轻链可变区序列与SEQ ID NO:5的轻链序列具有至少85%的序列同一性;且
所述重链可变区序列与SEQ ID NO:14的重链序列具有至少85%的序列同一性;
或
(x)所述轻链可变区序列与SEQ ID NO:6的轻链序列具有至少85%的序列同一性;且
所述重链可变区序列与SEQ ID NO:15的重链序列具有至少85%的序列同一性;
或
(xi)所述轻链可变区序列与SEQ ID NO:7的轻链序列具有至少85%的序列同一性;且
所述重链可变区序列与SEQ ID NO:16的重链序列具有至少85%的序列同一性。
8.如权利要求1-7中任一项所述的CAR,其特征在于,还包含肽-MHC复合物以外的靶标的特异性抗体或抗原结合片段。
9.如权利要求8所述的CAR,其特征在于,除肽-MHC复合物之外的靶标是免疫细胞表面分子。
10.一种核酸,其编码权利要求1-9中任一项所述的CAR。
11.一种细胞,其含有权利要求1-9中任一项所述的CAR或权利要求10所述的核酸。
12.权利要求11所述的细胞在制备用于治疗或预防癌症的药物中的用途。
13.如权利要求12所述的用途,其特征在于,所述癌症包括表达p53的肽和MHCI类分子的细胞。
14.如权利要求13所述的用途,其特征在于,所述MHC I类分子包含由HLA-A*24等位基因编码的MHCI类α链。
15.如权利要求13或权利要求14所述的用途,其特征在于,所述p53的肽包含SEQ IDNO:75的氨基酸序列或由其组成,或其变体,所述变体在氨基酸序列中具有一个或两个或三个氨基酸取代。
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