CN107922496B - IL2Rβ/通用γ链抗体 - Google Patents
IL2Rβ/通用γ链抗体 Download PDFInfo
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- CN107922496B CN107922496B CN201680046297.2A CN201680046297A CN107922496B CN 107922496 B CN107922496 B CN 107922496B CN 201680046297 A CN201680046297 A CN 201680046297A CN 107922496 B CN107922496 B CN 107922496B
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Abstract
本发明公开了抗CD122和/或γc抗体及其片段。还公开了包含此类抗体和片段的组合物,以及使用该抗体的用途和方法。
Description
发明领域
本发明涉及结合白细胞介素2受体β(IL-2Rβ;CD122)和通用γ链(γc;CD132)的抗体。
发明背景
IL-2是一种必要的细胞因子,在维持T细胞稳态和介导适当的免疫应答方面发挥主要的作用。它作为免疫刺激剂的高效能已经应用于临床来治疗一系列病症,包括癌症和艾滋病;它也被广泛用作疫苗佐剂以刺激各种效应细胞的活化和增殖。
然而,有效治疗某些疾病所需的高剂量的IL-2是高毒性的。这种治疗的主要副作用包括血管渗漏综合征(VLS),其导致血管内液体在诸如肺和肝的器官中积聚,然后出现肺水肿和肝损伤。除了停止治疗外,没有治疗VLS的方法。
IL-2通过与在不同细胞类型上表达的受体组分的不同组合的结合来发挥其多效功能:α链(IL-2Rα,也称为CD25),β链(IL-2Rβ或CD122)和通用的细胞因子受体γ链(IL-2Rγ,γc或CD132)。
分离的IL-2Rα被称为“低亲和力”IL-2受体(结合亲和力),不参与信号转导。尽管单独的IL-2Rβ的亲和力非常低并且单独γc对IL-2的亲和力几乎检测不到,但是IL-2Rβ和γc的复合物以中等亲和力结合IL-2。有全部三个亚基IL-2Rα、IL-2Rβ和γc的复合物以高亲和力结合IL-2。
IL-2Rβ和γc的异源二聚体对于通过细胞质结构域的相互作用和随后激酶激活的多种信号传导途径来进行有效的信号转导是必要和充分的;IL-2Rα在信号转导中不起作用。
通常在CD4+T调节性细胞(Treg)和最近激活的T细胞上发现高亲和力的α-β-γcIL-2R。在初始CD8+细胞中,中等亲和力的β-γcIL-2R以低水平存在,但是在抗原刺激过的(记忆)和记忆表型(MP)CD8+T细胞以及自然杀伤(NK)细胞方面是显著的。MPCD8+T细胞和NK细胞均表达非常高水平的IL-2Rβ并容易对IL-2产生应答。
先前的研究已经表明,VLS是由IL-2激活的NK细胞释放促炎细胞因子引起的。然而,最近的一项研究表明,IL-2诱发的肺水肿可能是由于IL-2与表达功能性高亲和力的α-β-γcIL-2R的肺内皮细胞的直接结合所致。观察证明,在IL-2Rα缺陷的宿主小鼠中通过阻断抗IL-2Rα单克隆抗体(mAb)来消除IL-2与肺内皮细胞的相互作用,或通过使用IL-2/抗IL-2mAb(IL-2/mAb)复合物,其中所述抗体阻止IL-2/IL-2Rα相互作用,从而预防VLS。
发明概述
本发明涉及与CD122和/或通用γ链(γc)结合的抗体或抗原结合片段。还公开了用于CD122和通用γ链(γc)结合抗体的重链和轻链多肽。抗体、抗原结合片段和多肽可以分离和/或纯化的形式提供,并且可以配制成适合研究、治疗和诊断的组合物。
在第一方面,本发明提供了任选分离的抗体或抗原结合片段,其能够结合CD122和通用γ链(γc)。
在一些实施方式中,抗体或抗原结合片段是双特异性抗体或双特异性抗原结合片段。
另一方面,本发明提供了任选分离的能够结合CD122的抗体或抗原结合片段,其包含氨基酸序列i)至vi):
i)LC-CDR1:TGTSSDIGX1YDFX2S(SEQ ID NO:85)
RAGQAISSWLA(SEQ ID NO:6);
QASQDIGNYLN(SEQ ID NO:10);或
TRSSGSIASNYVQ(SEQ ID NO:14);
ii)LC-CDR2:DX3NNRX4S(SEQ ID NO:86);
KASNLES(SEQ ID NO:7);
DASNLET(SEQ ID NO:11);或
DDNQRPT(SEQ ID NO:15);
iii)LC-CDR3:SAYTSSDTX5V(SEQ ID NO:87);
QQYQSYPYT(SEQ ID NO:8);
LQLYDYPLT(SEQ ID NO:12);或
QSSHSTAVV(SEQ ID NO:16);
iv)HC-CDR1:NYYX6H(SEQ ID NO:88);
TYAMH(SEQ ID NO:40);
SYAMS(SEQ ID NO:44);或
GYYWS(SEQ ID NO:48);
v)HC-CDR2:AIMPSRGGTSYPQKFQG(SEQ ID NO:37);
WINTGNGNTKYSQNFQG(SEQ ID NO:41);
AISGSGGSTYYADSVKG(SEQ ID NO:45);或
EINHSGSTNYNPSLKS(SEQ ID NO:49);
vi)HC-CDR3:GEYYYDSSGYYX7(SEQ ID NO:89);
DLGQLERLYFW(SEQ ID NO:42);
DLGDY(SEQ ID NO:46);或
SSSGDAFD(SEQ ID NO:50);
或其变体,其中序列(i)至(vi)的一个或多个中的一个或两个或三个氨基酸被另一个氨基酸替代,其中X1=H或D;X2=V或I;X3=I,、N或F;X4=P或A;X5=L或V;X6=M或I;和X7=Y或N。
在一些实施方案中,LC-CDR1是TGTSSDIGHYDFVS(SEQ ID NO:2)、TGTSSDIGDYDFVS(SEQ ID NO:18)、TGTSSDIGHYDFIS(SEQ ID NO:25)、RAGQAISSWLA(SEQ ID NO:6)、QASQDIGNYLN(SEQ ID NO:10)或TRSSGSIASNYVQ(SEQ ID NO:14)之一。
在一些实施方案中,LC-CDR2是DINNRPS(SEQ ID NO:3)、DNNNRPS(SEQ ID NO:20)、DFNNRPS(SEQ ID NO:26)、DINNRAS(SEQ ID NO:32)、KASNLES(SEQ ID NO:7)、DASNLET(SEQID NO:11)或DDNQRPT(SEQ ID NO:15)之一。
在一些实施方案中,LC-CDR3是SAYTSSDTLV(SEQ ID NO:4)、SAYTSSDTVV(SEQ IDNO:22)、QYQSYPYT(SEQ ID NO:8)、LQLYDYPLT(SEQ ID NO:12)或QSSHSTAVV(SEQ ID NO:16)之一。
在一些实施方案中,HC-CDR1是NYYMH(SEQ ID NO:36)、NYYIH(SEQ ID NO:54)、TYAMH(SEQ ID NO:40)、SYAMS(SEQ ID NO:44)或GYYWS(SEQ ID NO:48)之一。
在一些实施方案中,HC-CDR2是AIMPSRGGTSYPQKFQG(SEQ ID NO:37)、WINTGNGNTKYSQNFQG(SEQ ID NO:41)、AISGSGGSTYYADSVKG(SEQ ID NO:45)或EINHSGSTNYNPSLKS(SEQ ID NO:49)之一。
在一些实施方案中,HC-CDR3是GEYYYDSSGYYY(SEQ ID NO:38)、GEYYYDSSGYYN(SEQID NO:52)、DLGQLERLYFW(SEQ ID NO:42)、DLGDY(SEQ ID NO:46)或SSSGDAFD(SEQ ID NO:50)之一。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的轻链多肽,其具有包含以下CDR的至少一个轻链可变区:
LC-CDR1:TGTSSDIGHYDFVS(SEQ ID NO:2)
LC-CDR2:DINNRPS(SEQ ID NO:3)
LC-CDR3:SAYTSSDTLV(SEQ ID NO:4)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的轻链多肽,其具有包含以下CDR的至少一个轻链可变区:
LC-CDR1:TGTSSDIGDYDFVS(SEQ ID NO:18)
LC-CDR2:DINNRPS(SEQ ID NO:3)
LC-CDR3:SAYTSSDTLV(SEQ ID NO:4)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的轻链多肽,其具有包含以下CDR的至少一个轻链可变区:
LC-CDR1:TGTSSDIGHYDFVS(SEQ ID NO:2)
LC-CDR2:DNNNRPS(SEQ ID NO:20)
LC-CDR3:SAYTSSDTLV(SEQ ID NO:4)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的轻链多肽,其具有包含以下CDR的至少一个轻链可变区:
LC-CDR1:TGTSSDIGHYDFVS(SEQ ID NO:2)
LC-CDR2:DINNRPS(SEQ ID NO:3)
LC-CDR3:SAYTSSDTVV(SEQ ID NO:22)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的轻链多肽,其具有包含以下CDR的至少一个轻链可变区:
LC-CDR1:TGTSSDIGHYDFIS(SEQ ID NO:25)
LC-CDR2:DFNNRPS(SEQ ID NO:26)
LC-CDR3:SAYTSSDTLV(SEQ ID NO:4)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的轻链多肽,其具有包含以下CDR的至少一个轻链可变区:
LC-CDR1:TGTSSDIGHYDFVS(SEQ ID NO:2)
LC-CDR2:DNNNRPS(SEQ ID NO:20)
LC-CDR3:SAYTSSDTVV(SEQ ID NO:22)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的轻链多肽,其具有包含以下CDR的至少一个轻链可变区多肽:
LC-CDR1:TGTSSDIGHYDFVS(SEQ ID NO:2)
LC-CDR2:DNNNRAS(SEQ ID NO:32)
LC-CDR3:SAYTSSDTVV(SEQ ID NO:22)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的轻链多肽,其具有包含以下CDR的至少一个轻链可变区:
LC-CDR1:TGTSSDIGDYDFVS(SEQ ID NO:18)
LC-CDR2:DINNRPS(SEQ ID NO:3)
LC-CDR3:SAYTSSDTVV(SEQ ID NO:22)
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的轻链多肽,其具有包含以下CDR的至少一个轻链可变区多肽:
LC-CDR1:RAGQAISSWLA(SEQ ID NO:6)
LC-CDR2:KASNLES(SEQ ID NO:7)
LC-CDR3:QQYQSYPYT(SEQ ID NO:8)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的轻链多肽,其具有包含以下CDR的至少一个轻链可变区:
LC-CDR1:QASQDIGNYLN(SEQ ID NO:10)
LC-CDR2:DASNLET(SEQ ID NO:11)
LC-CDR3:LQLYDYPLT(SEQ ID NO:12)
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的轻链多肽,其具有包含以下CDR的至少一个轻链可变区:
LC-CDR1:TRSSGSIASNYVQ(SEQ ID NO:14)
LC-CDR2:DDNQRPT(SEQ ID NO:15)
LC-CDR3:QSSHSTAVV(SEQ ID NO:16)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的重链多肽,其具有包含以下CDR的至少一个重链可变区:
HC-CDR1:NYYMH(SEQ ID NO:36)
HC-CDR2:AIMPSRGGTSYPQKFQG(SEQ ID NO:37)
HC-CDR3:GEYYYDSSGYYY(SEQ ID NO:38)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的重链多肽,其具有包含以下CDR的至少一个重链可变区:
HC-CDR1:NYYMH(SEQ ID NO:36)
HC-CDR2:AIMPSRGGTSYPQKFQG(SEQ ID NO:37)
HC-CDR3:GEYYYDSSGYYN(SEQ ID NO:52)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的重链多肽,其具有包含以下CDR的至少一个重链可变区:
HC-CDR1:NYYIH(SEQ ID NO:54)
HC-CDR2:AIMPSRGGTSYPQKFQG(SEQ ID NO:37)
HC-CDR3:GEYYYDSSGYYY(SEQ ID NO:38)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的重链多肽,其具有包含以下CDR的至少一个重链可变区:
HC-CDR1:TYAMH(SEQ ID NO:40)
HC-CDR2:WINTGNGNTKYSQNFQG(SEQ ID NO:41)
HC-CDR3:DLGQLERLYFW(SEQ ID NO:42)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的重链多肽,其具有包含以下CDR的至少一个重链可变区:
HC-CDR1:SYAMS(SEQ ID NO:44)
HC-CDR2:AISGSGGSTYYADSVKG(SEQ ID NO:45)
HC-CDR3:DLGDY(SEQ ID NO:46)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的重链多肽,其具有包含以下CDR的至少一个重链可变区:
HC-CDR1:GYYWS(SEQ ID NO:48)
HC-CDR2:EINHSGSTNYNPSLKS(SEQ ID NO:49)
HC-CDR3:SSSGDAFD(SEQ ID NO:50)。
另一方面,本发明提供了任选分离的能够与CD122结合的抗体或抗原结合片段,其包含轻链和重链可变区序列,其中:
轻链包含与LC-CDR1具有至少85%总体序列同一性的LC-CDR1,LC-CDR2,LC-CDR3:TGTSSDIGX1YDFX2S(SEQ ID NO:85)、RAGQAISSWLA(SEQ ID NO:6)中的一个;QASQDIGNYLN(SEQ ID NO:10);或
TRSSGSIASNYVQ(SEQ ID NO:14);LC-CDR2:DX3NNRX4S(SEQ ID NO:86);KASNLES(SEQ ID NO:7);DASNLET(SEQ ID NO:11);或DDNQRPT(SEQ ID NO:15)中的一个;LC-CDR3:SAYTSSDTX5V(SEQ ID NO:87);QQYQSYPYT(SEQ ID NO:8);LQLYDYPLT(SEQ ID NO:12);或QSSHSTAVV(SEQ ID NO:16)中的一个;和
所述重链包含与HC-CDR1具有至少85%总体序列同一性的HC-CDR1,HC-CDR2,HC-CDR3:NYYX6H(SEQ ID NO:88);TYAMH(SEQ ID NO:40);SYAMS(SEQ ID NO:44);或GYYWS(SEQID NO:48)之一;HC-CDR2:AIMPSRGGTSYPQKFQG(SEQ ID NO:37);WINTGNGNTKYSQNFQG(SEQID NO:41);AISGSGGSTYYADSVKG(SEQ ID NO:45);或EINHSGSTNYNPSLKS(SEQ ID NO:49)之一;HC-CDR3:GEYYYDSSGYYX7(SEQ ID NO:89);DLGQLERLYFW(SEQ ID NO:42);DLGDY(SEQ IDNO:46);或SSSGDAFD(SEQ ID NO:50)之一;
其中X1=H或D;X2=V或I;X3=I、N或F;X4=P或A;X5=L或V;X6=M或I;和X7=Y或N。
在一些实施方案中,序列同一性的程度可以是86、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的一种。
另一方面,本发明提供了任选分离的能够与CD122结合的抗体或抗原结合片段,其包含轻链和重链可变区序列,其中:
所述轻链序列与SEQ ID NO:1、17、19、21、23、24、27、28、29、30、31、33、34、148、149、5、9或13之一的轻链序列具有至少85%的序列同一性(图1),并且;
所述重链序列与SEQ ID NO:35、51、53、55、56、57、58、59、60、61、62、63、64、65、66、150、151、39、43或47之一的重链序列具有至少85%的序列同一性(图2)。
在一些实施方案中,序列同一性的程度可以是86、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的一种。
另一方面,本发明提供了任选分离的能够结合CD122的抗体或抗原结合片段,所述CD122是双特异性抗体或双特异性抗原结合片段,其包含(i)本发明所述的抗原结合片段,和(ii)能够与通用γ链(γc)结合的抗原结合片段。
另一方面,本发明提供了任选分离的能够结合通用γ链(γc)的抗体或抗原结合片段,其包含氨基酸序列i)至vi):
i)LC-CDR1:RSSQSLLHSNGYNYLD(SEQ ID NO:68);或
SGDALPKQFAF(SEQ ID NO:72);
ii)LC-CDR2:LGSNRDS(SEQ ID NO:69);或
KDTERPS(SEQ ID NO:73);
iii)LC-CDR3:MQGTHWPWT(SEQ ID NO:70);或
QSPDSSGTVEV(SEQ ID NO:74);
iv)HC-CDR1:GYYWS(SEQ ID NO:48);或
SSSYYWG(SEQ ID NO:79);
v)HC-CDR2:EINHX8GSTNYNPSLKS(SEQ ID NO:90);或
SIYYSGSTYYNPSLK(SEQ ID NO:80);
vi)HC-CDR3:SPGGYSGGYFQH(SEQ ID NO:77);或
DILTGYALDY(SEQ ID NO:81);
或其变体,其中序列(i)至(vi)的一个或多个中的一个或两个或三个氨基酸被另一个氨基酸替代,其中X8=S或F。
在一些实施方案中,LC-CDR1是RSSQSLLHSNGYNYLD(SEQ ID NO:68)或SGDALPKQFAF(SEQ ID NO:72)。
在一些实施方案中,LC-CDR2是LGSNRDS(SEQ ID NO:69)或KDTERPS(SEQ ID NO:73)。
在一些实施方案中,LC-CDR3是MQGTHWPWT(SEQ ID NO:70)或QSPDSSGTVEV(SEQ IDNO:74)。
在一些实施方案中,HC-CDR1是GYYWS(SEQ ID NO:48)或SSSYYWG(SEQ ID NO:79)。
在一些实施方案中,HC-CDR2是EINHSGSTNYNPSLKS(SEQ ID NO:49)、EINHFGSTNYNPSLKS(SEQ ID NO:83)或SIYYSGSTYYNPSLK(SEQ ID NO:80)之一。
在一些实施方案中,HC-CDR3是SPGGYSGGYFQH(SEQ ID NO:77)或DILTGYALDY(SEQID NO:81)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的轻链多肽,其具有包含以下CDR的至少一个轻链可变区:
LC-CDR1:RSSQSLLHSNGYNYLD(SEQ ID NO:68)
LC-CDR2:LGSNRDS(SEQ ID NO:69)
LC-CDR3:MQGTHWPWT(SEQ ID NO:70)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的轻链多肽,其具有包含以下CDR的至少一个轻链可变区:
LC-CDR1:SGDALPKQFAF(SEQ ID NO:72)
LC-CDR2:KDTERPS(SEQ ID NO:73)
LC-CDR3:QSPDSSGTVEV(SEQ ID NO:74)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的重链多肽,其具有包含以下CDR的至少一个重链可变区:
HC-CDR1:GYYWS(SEQ ID NO:48)
HC-CDR2:EINHSGSTNYNPSLKS(SEQ ID NO:49)
HC-CDR3:SPGGYSGGYFQH(SEQ ID NO:77)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的重链多肽,其具有包含以下CDR的至少一个重链可变区:
HC-CDR1:GYYWS(SEQ ID NO:48)
HC-CDR2:EINHFGSTNYNPSLKS(SEQ ID NO:83)
HC-CDR3:SPGGYSGGYFQH(SEQ ID NO:77)。
在根据各个方面的一些实施方式中,本发明提供抗体或片段或分离的重链多肽,其具有包含以下CDR的至少一个重链可变区:
HC-CDR1:SSSYYWG(SEQ ID NO:79)
HC-CDR2:SIYYSGSTYYNPSLK(SEQ ID NO:80)
HC-CDR3:DILTGYALDY(SEQ ID NO:81)。
另一方面,本发明提供了任选地分离的能够与通用γ链(γc)结合的抗体或抗原结合片段,所述抗体或抗原结合片段包含重链和轻链可变区序列,其中:
所述轻链包含与LC-CDR1:RSSQSLLHSNGYNYLD(SEQ ID NO:68)或SGDALPKQFAF(SEQID NO:72);LC-CDR2:LGSNRDS(SEQ ID NO:69)或KDTERPS(SEQ ID NO:73);LC-CDR3:MQGTHWPWT(SEQ ID NO:70)或QSPDSSGTVEV(SEQ ID NO:74)具有至少85%总体序列同一性的LC-CDR1、LC-CDR2、LC-CDR3;和
所述重链包含与HC-CDR1:GYYWS(SEQ ID NO:48)或SSSYYWG(SEQ ID NO:79);HC-CDR2:EINHX8GSTNYNPSLKS(SEQ ID NO:90)或SIYYSGSTYYNPSLK(SEQ ID NO:80);HC-CDR3:SPGGYSGGYFQH(SEQ ID NO:77)或DILTGYALDY(SEQ ID NO:81)具有至少85%总体序列同一性的HC-CDR1、HC-CDR2、HC-CDR3;其中X8=S或F。
在一些实施方案中,序列同一性程度可以是86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的一种。
另一方面,本发明提供了一种任选分离的抗体或抗原结合片段,其能够结合包含轻链和重链可变区序列的通用γ链(γc),其中:
所述轻链序列与SEQ ID NO:67、152、71或75之一的轻链序列具有至少85%的序列同一性(图3),并且;
所述重链序列与SEQ ID NO:76、153、78、82或84之一的重链序列具有至少85%的序列同一性(图4)。
在一些实施方案中,序列同一性程度可以是86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的一种。
另一方面,本发明提供了任选地分离的能够与通用γ链(γc)结合的抗体或抗原结合片段,其是双特异性抗体或双特异性抗原结合片段,其包含(i)本发明所述的抗原结合片段,和(ii)能够结合CD122的抗原结合片段。
另一方面,本发明提供能够结合通用γ链(γc)和CD122的任选分离的抗体或抗原结合片段,其包含:
(i)本发明所述的γc-结合的抗原结合片段;和
(ii)本发明所述的CD122结合的抗原结合片段。
另一方面,本发明提供任选分离的体外复合物,其包含与CD122结合的本发明的抗体或抗原结合片段,任选地其中所述抗体或抗原结合片段与通用γ链(γc)结合。
另一方面,本发明提供一种任选地分离的体外复合物,其包含与通用γ链(γc)结合的本发明所述的抗体或抗原结合片段,任选地其中所述抗体或抗原结合片段与CD122结合。
在一些实施方案中,本发明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。
另一方面,本发明提供了包含本发明所述的抗原结合片段,任选的双特异性抗原结合片段的嵌合抗原受体(CAR)。
另一方面,本发明提供了包含本发明所述的嵌合抗原受体(CAR)的细胞。
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、偶联物、嵌合抗原受体(CAR)或细胞,和至少一种药学上可接受的载体、赋形剂、佐剂或稀释剂。
另一方面,本发明提供了编码本发明所述的抗体、抗原结合片段、偶联物或嵌合抗原受体(CAR)的分离的核酸。核酸可以具有SEQ ID NO130、131、132、133、134、135、136、137、138、19、140、141、142、143、144、145、146或147中之一的序列(图17和18),或由于遗传密码而简并的编码序列,或可具有与其具有至少70%同一性的核苷酸序列,任选地,75%、80%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的一种。
另一方面,本发明提供了包含本发明核酸的载体。
另一方面,本发明提供了包含本发明载体的宿主细胞。例如,宿主细胞可以是真核的或哺乳动物的,例如,中国仓鼠卵巢(CHO)或人或可以是原核细胞,例如大肠杆菌(E.coli)。
另一方面,本发明提供了一种制备本发明的抗体、抗原结合片段、偶联物或嵌合抗原受体(CAR)的方法,包括在适于表达编码抗体、抗原结合片段、偶联物或CAR的载体的条件下培养本发明所述的宿主细胞,以及回收所述抗体、抗原结合片段、多肽、偶联物或CAR。
另一方面,本发明提供本发明所述的抗体、抗原结合片段、多肽、偶联物、嵌合抗原受体(CAR)、细胞或组合物在治疗或医疗方法中的应用。
另一方面,本发明提供了本发明所述的抗体、抗原结合片段、多肽、偶联物、嵌合抗原受体(CAR)、细胞或组合物在癌症治疗中的应用。
另一方面,本发明提供了本发明所述的抗体、抗原结合片段、多肽、偶联物、嵌合抗原受体(CAR)、细胞或组合物在感染性疾病治疗中的应用。
另一方面,本发明提供了本发明所述的抗体、抗原结合片段、多肽、偶联物、嵌合抗原受体(CAR)、细胞或组合物在制备用于治疗癌症的药物的用途。
另一方面,本发明提供了本发明所述的抗体、抗原结合片段、多肽、偶联物、嵌合抗原受体(CAR)、细胞或组合物在制备用于治疗感染性疾病的药物的用途。
另一方面,本发明提供了一种治疗癌症的方法,包括向患有癌症的患者施用本发明所述的抗体、抗原结合片段、多肽、偶联物、嵌合抗原受体(CAR)、细胞或组合物。
另一方面,本发明提供了一种治疗感染性疾病的方法,包括向患有感染性疾病的患者施用本发明所述的抗体、抗原结合片段、多肽、偶联物、嵌合抗原受体(CAR)、细胞或组合物。
另一方面,本发明提供了一种方法,该方法包括将包含或可能包含CD122和/或通用γ链(γc)的样品与本发明的抗体、抗原结合片段、多肽、偶联物、嵌合抗原受体(CAR)、细胞或组合物,并检测抗体、抗原结合片段、偶联物、CAR或细胞接触,优选体外接触,并检测所述抗体、抗原结合片段、偶联物、CAR、细胞与与CD122和/或γc形成的复合物。
另一方面,本发明提供了一种诊断受试者中的疾病或病症的方法,所述方法包括将来自受试者的样品与本发明所述的抗体、抗原结合片段、偶联物、嵌合抗原受体(CAR)、细胞或组合物接触,优选体外接触,以及检测抗体、抗原结合片段、偶联物、CAR或细胞与CD122和/或通用γ链(γc)形成的复合物。
另一方面,本发明提供一种选择或分层受试者以用CD122和/或通用的γ链(γc)靶向剂治疗的方法,所述方法包括将来自受试者的样品与本发明所述的抗体、抗原结合片段、偶联物、嵌合抗原受体(CAR)、细胞或组合物接触,优选体外接触,以及检测抗体、抗原结合片段、偶联物、CAR或细胞与CD122和/或γc形成的复合物。
另一方面,本发明提供了本发明所述的抗体、抗原结合片段、偶联物、嵌合抗原受体(CAR)、细胞或组合物在体外或体内检测CD122和/或通用γ链(γc)的应用。
另一方面,本发明提供了本发明所述的抗体、抗原结合片段、偶联物、嵌合抗原受体(CAR)、细胞或组合物作为体外或体内诊断剂或预后剂的应用。
另一方面,本发明提供了用于扩增T细胞群和/或NK细胞群的方法,其中将T细胞和/或NK细胞与本发明的抗体、抗原结合片段、偶联物、嵌合抗原受体(CAR)、细胞或组合物在体外、体内或离体接触。
另一方面,本发明提供了一种治疗受试者中的感染性疾病或癌症的方法,所述方法包括在本发明所述的抗体、抗原结合片段、偶联物、嵌合抗原受体(CAR)、细胞或组合物存在下,培养从受试者血液样品获得的T细胞和/或NK细胞,以扩增T细胞和/或NK细胞群,收集扩增的T细胞和/或NK细胞,并且向需要治疗的受试者施用扩增的T细胞和/或NK细胞。
另一方面,本发明提供了一种治疗受试者中的感染性疾病或癌症的方法,所述方法包括向所述受试者施用本发明所述的抗体、抗原结合片段、偶联物、嵌合抗原受体(CAR)、细胞或组合物,以扩增T细胞和/或NK细胞群。
以下编号的段落描述了本发明的其他方面:
1.分离的IL-2R双特异性抗原结合蛋白,其包含:
(i)第一IL-2Rβ结合多肽:
(a)由SEQ ID NO:1、5、9或13的氨基酸序列,或其变体组成的结合单元VL1,其在结合单元VL1中含有至少一个氨基酸的取代、插入或缺失;
(b)由SEQ ID NO:35、39、43或47的氨基酸序列,或其变体组成的结合单元VH1,其在结合单元VH1中含有至少一个氨基酸的取代、插入或缺失;
(ii)第二IL-2Rγ结合多肽:
(c)由SEQ ID NO:67或71的氨基酸序列,或其变体组成的结合单元VL2,其在结合单元VL2中含有至少一个氨基酸的取代、插入或缺失,和
(d)由SEQ ID NO:76或78的氨基酸序列,或其变体组成的结合单元VH2,其在结合单元VH2中含有至少一个氨基酸的取代、插入或缺失。
2.如段落1中所定义的分离的IL-2R双特异性抗原结合蛋白,其中所述第一IL-2Rβ结合多肽和所述第二IL-2Rγ结合多肽通过肽接头连接。
3.如段落2中所定义的分离的IL-2R双特异性抗原结合蛋白,其中所述肽接头的长度为5-23个氨基酸。
4.如段落1中所定义的分离的IL-2R双特异性抗原结合蛋白,其中所述第一IL-2Rβ结合多肽还包含含有CH3结构域的Fc部分,其中所述CH3结构域包含或由SEQ ID NO:92的氨基酸序列组成,并且其中所述第二IL-2Rγ结合多肽还包含含有CH3结构域的Fc部分,其中CH3结构域包含或由SEQ ID NO:94的氨基酸序列组成。
5.如段落4所定义的分离的IL-2R双特异性抗原结合蛋白,其中所述第一和第二多肽在CH3结构域内的工程化的接口(engineered interface)连接(meet),其中所述第一多肽在所述接口中包含至少一个工程化的突起,所述突起包含至少一个改变的接触残基(contact residue),并且所述第二多肽在其所述接口中包含至少一个工程化的腔,所述腔包括至少一个改变的接触残基以便形成隆起到腔的配对。
6.如段落4或段落5所定义的分离的IL-2R双特异性抗原结合蛋白,其中所述结合单元通过接头(linker)连接到所述Fc部分。
7.如段落6所定义的分离的IL-2R双特异性抗原结合蛋白,其中所述接头的长度为5-23个氨基酸。
8.如第4至7段的任一段所定义的分离的IL-2R双特异性抗原结合蛋白,其包含:
(i)第一IL-2Rβ结合多肽:
(a)由SEQ ID NO:1的氨基酸序列,或其变体组成的结合单元VL1,其在结合单元VL1中含有至少一个氨基酸的取代、插入或缺失;
(b)由SEQ ID NO:35的氨基酸序列,或其变体组成的结合单元VH1,或其在结合单元VH1中含有至少一个氨基酸的取代、插入或缺失;
(c)包含CH3结构域的Fc部分,其中CH3结构域包含或由SEQ ID NO:92的氨基酸序列组成,和
(ii)第二IL-2Rγ结合多肽:
(d)由SEQ ID NO:67的氨基酸序列,或其变体组成的结合单元VL2,或其在结合单元VL2中含有至少一个氨基酸的取代、插入或缺失;
(e)由SEQ ID NO:76的氨基酸序列,或其变体组成的结合单元VH2,或其在结合单元VH2中含有至少一个氨基酸的取代、插入或缺失,和
(f)包含CH3结构域的Fc部分,其中CH3结构域包含或由SEQ ID NO:94的氨基酸序列组成。
9.如段落8所定义的分离的IL-2R双特异性抗原结合蛋白,其中所述结合蛋白对人IL-2Rβ的解离常数(KD)为1.46×10-7M,并且对人IL-2Rγ的解离常数(KD)为2.09×10-8M。
10.如段落4-7中任一段所定义的分离的IL-2R双特异性抗原结合蛋白,其包含:
(i)第一IL-2Rβ结合多肽:
(a)由SEQ ID NO:5的氨基酸序列,或其变体组成的结合单元VL1,其在结合单元VL1中含有至少一个氨基酸的取代、插入或缺失;
(b)由SEQ ID NO:39的氨基酸序列,或其变体组成的结合单元VH1,其在结合单元VH1中含有至少一个氨基酸的取代、插入或缺失;
(c)包含CH3结构域的Fc部分,其中CH3结构域包含或由SEQ ID NO:92的氨基酸序列组成,和
(ii)第二IL-2Rγ结合多肽:
(d)由SEQ ID NO:71的氨基酸序列,或其变体组成的结合单元VL2,其在结合单元VL2中含有至少一个氨基酸的取代、插入或缺失;
(e)由SEQ ID NO:78的氨基酸序列,或其变体组成的结合单元VH2,其在结合单元VH2中含有至少一个氨基酸的取代、插入或缺失,和
(f)包含CH3结构域的Fc部分,其中CH3结构域包含或由SEQ ID NO:94的氨基酸序列组成。
11.如段落10所定义的分离的IL-2R双特异性抗原结合蛋白,其中所述结合蛋白对人IL-2Rβ的解离常数(KD)为1.01×10-7M,并且对人IL-2Rγ的解离常数(KD)为7.98×10- 8M。
12.如段落4-7中任一段所定义的分离的IL-2R双特异性抗原结合蛋白,其包含:
(i)第一IL-2Rβ结合多肽:
(a)由SEQ ID NO:9的氨基酸序列,或其变体组成的结合单元VL1,其在结合单元VL1中含有至少一个氨基酸的取代、插入或缺失;
(b)由SEQ ID NO:43的氨基酸序列,或其变体组成的结合单元VH1,其在结合单元VH1中含有至少一个氨基酸的取代、插入或缺失;
(c)包含CH3结构域的Fc部分,其中CH3结构域包含或由SEQ ID NO:92的氨基酸序列组成,和
(ii)第二IL-2Rγ结合多肽:
(d)由SEQ ID NO:67的氨基酸序列,或其变体组成的结合单元VL2,其在结合单元VL2中含有至少一个氨基酸取代、插入或缺失;
(e)由SEQ ID NO:76的氨基酸序列,或其变体组成的结合单元VH2,其在结合单元VH2中含有至少一个氨基酸取代、插入或缺失,和
(f)包含CH3结构域的Fc部分,其中CH3结构域包含或由SEQ ID NO:94的氨基酸序列组成。
13.如段落12所定义的分离的IL-2R双特异性抗原结合蛋白,其中所述结合蛋白对人IL-2Rβ的解离常数(KD)为1.81×10-7M,并且对人IL-2Rγ的解离常数(KD)为7.87×10- 8M。
14.如段落4-7中任一段所定义的分离的IL-2R双特异性抗原结合蛋白,其包含:
(i)第一IL-2Rβ结合多肽:
(a)由SEQ ID NO:13的氨基酸序列,或其变体组成的结合单元VL1,其在结合单元VL1中含有至少一个氨基酸取代、插入或缺失;
(b)由SEQ ID NO:47的氨基酸序列,或其变体组成的结合单元VH1,其在结合单元VH1中含有至少一个氨基酸取代、插入或缺失;
(c)包含CH3结构域的Fc部分,其中CH3结构域包含或由SEQ ID NO:92的氨基酸序列组成,和
(ii)第二IL-2Rγ结合多肽:
(d)由SEQ ID NO:67的氨基酸序列,或其变体组成的结合单元VL2,其在结合单元VL2中含有至少一个氨基酸取代、插入或缺失;
(e)由SEQ ID NO:76的氨基酸序列,或其变体组成的结合单元VH2,其在结合单元VH2中含有至少一个氨基酸取代、插入或缺失,和
(f)包含CH3结构域的Fc部分,其中CH3结构域包含或由SEQ ID NO:94的氨基酸序列组成。
15.如段落14所定义的分离的IL-2R双特异性抗原结合蛋白,其中所述结合蛋白对人IL-2Rβ的解离常数(KD)为1.28×10-7M,并且对人IL-2Rγ的解离常数(KD)为3.37×10- 7M。
16.如段落1至15中任一段所定义的分离的IL-2R双特异性抗原结合蛋白,其中所述IL-2R是人或猿的IL-2R。
17.如段落1至16中任一段所定义的分离的IL-2R双特异性抗原结合蛋白,其中所述抗原结合蛋白是全人的。
18.如上述任一项所定义的分离的IL-2R双特异性抗原结合蛋白,其中所述结合蛋白还包含选自下组的试剂:免疫粘附分子、显像剂、治疗剂和细胞毒性剂。
19.如段落18所述的分离的IL-2R双特异性抗原结合蛋白,其中所述试剂是选自下组的显像剂:放射性标记、酶、荧光标记、发光标记、生物发光标记、磁性标记和生物素。
20.如段落18所述的分离的IL-2R双特异性抗原结合蛋白,其中所述试剂选自下组的治疗剂或细胞毒性剂:抗代谢物、烷化剂、抗生素、抗病毒剂、生长因子、细胞因子、抗血管生成剂、抗有丝分裂剂、蒽环霉素、毒素和凋亡剂。
21.如段落1至20中任一段所定义的分离的IL-2R双特异性抗原结合蛋白,其中所述结合蛋白是IL-2R的激动剂。
22.一种治疗受试者的感染性疾病或癌症的方法,其包括向需要这种治疗的受试者施用如第1至21段中任一段所定义的分离的抗原结合蛋白。
23.如段落22所定义的方法,其中所述癌症是黑素瘤、肾癌或膀胱癌。
24.如段落1至21中任一段所定义的分离的抗原结合蛋白在制备用于治疗感染性疾病或癌症的药物中的应用。
25.如段落24所定义的用途,其中所述癌症是黑素瘤、肾癌或膀胱癌。
26.一种组合物,其包含如段落1至21中任一项所定义的分离的IL-2R双特异性抗原结合蛋白和药学上可接受的载体。
27.如段落26所述的组合物,其还包含一种或多种治疗剂。
28.如段落27所述的组合物,其中所述一种或多种治疗剂选自抗生素剂、抗病毒剂、抗真菌剂、化学治疗剂、小分子抑制剂、免疫治疗剂、疫苗、过继性细胞治疗剂、免疫检查点抑制剂或抗体治疗剂。
29.一种能够产生如段落1-21中任一段所定义的分离的IL-2R双特异性抗原结合蛋白的分离的细胞系。
30.一种试剂盒,其包含如段落1至21中任一段所定义的分离的IL-2R双特异性抗原结合蛋白,和使用说明书。
详述
本发明包括对白细胞介素-2受体(IL-2R)链β和γ具有特异性的双特异性抗体的核苷酸和氨基酸序列,其能够刺激表达中等亲和力的IL-2Rβ-γ的细胞,而不优先刺激表达高亲和力的IL-2Rα-β-γ的细胞。
本发明描述了独立于IL-2Rα的IL-2R激动剂的设计,其中利用具有抗IL-2Rβ(CD122)和抗γc(CD132)特异性的双特异性抗体(或双功能蛋白质),通过β-γc组分的异二聚化实现受体活化。此类分子的使用可以通过激活免疫细胞,特别是T细胞来传递预期的免疫刺激,而不会优先和高度激活表达高亲和力α-β-γcIL-2R的细胞。这样的分子可以用作疫苗佐剂。
描述了与IL-2Rβ(CD122)或IL-2Rγc(CD132)结合的用于两种全人单克隆抗体的分离的核苷酸和氨基酸序列。
描述了显示IL-2Rβ和IL-2Rγc的单价特异性的工程化抗体的核苷酸和氨基酸序列。
描述了双特异性抗体构建体,其含有衍生自上述分离的单克隆抗体的可变区,并且能够结合IL-2Rβ和IL-2Rγc。
描述了包含衍生自上述分离的单克隆抗体的序列的IL-2Rβ和IL-2Rγc结合结构域的双功能蛋白质。
描述了与IL-2Rβ/γc结合并引发STAT5和/或Akt磷酸化的抗体或双功能蛋白。
描述了与IL-2Rβ/γc结合并且不以更高亲和力与IL-2Rα/β/γc(CD25)结合的抗体或双功能蛋白。
描述了与IL-2Rβ/γc激动性结合并触发细胞内信号,并拮抗性结合IL-2Rα/β/γc(CD25)而不触发细胞内信号的抗体或双功能蛋白。
描述了单独或与抗癌或抗感染药物组合使用这些分子中的任何一种在治疗癌症或感染性疾病中的应用。
抗体
本发明所述的抗体优选结合CD122(白细胞介素2受体β(IL-2Rβ))和/或通用γ链(γc)。在一些实施方案中,抗体/片段结合人CD122和/或人γc。在一些实施方案中,抗体/片段结合非人灵长目动物的CD122和/或非人灵长目动物的γc。
就“抗体”而言,我们包括其片段或衍生物,或合成抗体或合成抗体片段。本发明所述的抗体可以以分离的形式提供。
鉴于当今与单克隆抗体有关的技术,可以制备出针对大多数抗原的抗体。抗原结合部分可以是抗体(例如Fab片段)或合成抗体片段(例如单链Fv片段[ScFv])的一部分。针对所选抗原的合适单克隆抗体可通过已知技术制备,例如在“单克隆抗体:技术手册”HZola(CRC出版,1988)和“单克隆杂交瘤抗体:技术和应用”J G R Hurrell(CRC出版,1982)中公开的那些,Neuberger等(1988,第八届国际生物技术论坛(8th InternationalBiotechnology Symposium)部分2,792-799)讨论了嵌合抗体。
单克隆抗体(mAb)可用于本发明的方法,并且是特异性靶向抗原上单个表位的抗体的均质群体。
抗体的抗原结合片段,例如Fab和Fab2片段也可以与遗传工程改造的抗体和抗体片段一样使用/提供。抗体的可变重(VH)和可变轻(VL)结构域参与抗原识别,这一事实首先通过早期蛋白酶消化实验识别。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融合到人源的恒定结构域,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.Sd.USA 81,6851-6855)。
该抗原特异性由可变结构域赋予且独立于恒定结构域,这是从涉及抗体片段的细菌表达的实验中得知的,所述抗体片段全部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)科学240,1041);Fv分子(Skerra等(1988)科学240,1038);单链Fv(ScFv)分子,其中VH和VL配对(partner)结构域通过柔性寡肽连接(Bird等(1988)科学242,423;Huston等(1988)Proc.Natl.Acad.Sd.USA85,5879)和包含分离的V结构域的单结构域抗体(dAb)(Ward等(1989)自然341,544)。在“Winter和Milstein(1991)自然349,293-299”中可以找到参与合成保留其特异性结合位点的抗体片段的技术的一般综述。
“ScFv分子”是指其中VH和VL配对结构域共价连接的分子,例如一种柔性寡肽。
Fab,Fv,ScFv和dAb抗体片段都可以在大肠杆菌中表达和分泌,从而可以容易地产生大量的所述片段。
整个抗体和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。
本发明提供了能够结合CD122和γc的抗体或抗原结合片段。在一些实施方案中,抗体/片段是双特异性抗体或双特异性抗原结合片段。在一些实施方案中,所述双特异性抗体或双特异性抗原结合片段可以是分离的。
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能够结合CD122的抗体/片段,例如,如本文所述的抗体/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能够与γc结合的抗体/片段,例如,如本文所述的抗体/片段。
在一些实施方案中,双特异性抗体/片段包含能够结合CD122的抗体/片段和能够结合另一种靶蛋白的抗体/片段。
在一些实施方案中,双特异性抗体/片段包含能够结合γc的抗体/片段和能够结合另一种靶蛋白的抗体/片段。
能够与另一种靶蛋白结合的抗原结合片段可与另一种不同于CD122或γc的蛋白结合。
在本发明的一个方面中,提供了一种双特异性抗体,其结合γc但不结合CD122。
本发明所述的双特异性抗体/片段的抗原结合片段可以是能够结合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互补决定区(CDR)(即LC-CDR1,LC-CDR2和LC-CDR3)和三个重链CDR(即HC-CDR1,HC-CDR2和HC-CDR3),其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,抗原结合片段可以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,抗原结合片段可以包含抗体或抗原结合片段的轻链多肽和重链多肽。
本发明所述的双特异性抗体和片段可以以任何合适的形式提供,例如在Kontermann《单克隆抗体》2012,4(2):182-197中描述的那些形式,其通过引用整体并入本文。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1IgG、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、电荷对(chargepair)或SEED-体)、小的双特异性抗体分子(例如双链抗体(Db)、dsDb、DART、scDb、tandAbs、串联scFv(taFv)、串联dAb/VHH、三重抗体、三重头(triple head)、Fab-scFv或F(ab’)2-scFv2)、双特异性Fc和CH3融合蛋白(例如taFv-Fc、二-双链抗体、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-IgG、DNL-Fab4-IgG-细胞因子2)。具体参见Kontermann《单克隆抗体》2012,4(2):182-19的图2。
在一些实施方案中,scFv二聚体形式是优选的,其中两个scFv,每一个都表现出对不同抗原的特异性结合,通过接头连接。如图25A所示,右。
接头可以是任何所需长度的氨基酸序列,例如,2至50个氨基酸,5至50个氨基酸,5至40个氨基酸,5至30个氨基酸,5至20个氨基酸或5至10个氨基酸中的一种。
技术人员能够设计和制备本发明所述的双特异性抗体和双特异性抗原结合片段。生产双特异性抗体的方法包括抗体或抗体片段的化学交联,例如用可还原的二硫化物或不可还原的硫醚键,例如,如“Segal和Bast,2001,双特异性抗体的制备。现行免疫学实验方案。14:IV:2.13:2.13.1-2.13.16”中所述,其在此通过引用整体并入本文。例如,N-琥珀酰亚胺基-3-(-2-吡啶基二硫代)丙酸酯(SPDP)可用于化学交联,例如Fab片段经由铰链区SH-基团,以产生二硫键连接的双特异性F(ab)2异二聚体。
生产双特异性抗体的其他方法包括,将产生抗体的杂交瘤,例如与聚乙二醇一起融合产生能够分泌双特异性抗体的四联体细胞,例如“D.M.和Bast,B.J,2001,双特异性抗体的生产。现行免疫学实验方案。14:IV:2.13:2.13.1-2.13.16”中所述。
本发明所述的双特异性抗体和双特异性抗原结合片段也可以重组生产,通过从例如编码抗原结合分子的多肽的核酸构建体表达,如“抗体工程:方法和实验方案,第二版(Humana出版社,2012),第40章:双特异性抗体的制备:双链抗体和串联scFv(Hornig和)”或“法文,如何制备双特异性抗体,Methods Mol.医学.2000;40:333-339”中描述的,其全部内容通过引用并于本文。
例如,编码两个抗原结合片段的轻链和重链可变结构域的DNA构建体(即能够结合CD122或γc的抗原结合片段的轻链和重链可变结构域,以及能够结合另一种靶蛋白的抗原结合片段的轻链和重链可变结构域),并且包括在抗原结合片段之间编码合适的接头或二聚化结构域的序列可以通过分子克隆技术来制备。随后可以通过在合适的宿主细胞(例如哺乳动物宿主细胞)中表达(例如体外)构建体来产生重组双特异性抗体,然后可以任选地纯化表达的重组双特异性抗体。
抗体可以通过亲和力成熟过程产生,其中产生与未修饰的亲本抗体相比,抗体对抗原的亲和力有改善的修饰的抗体。亲和力成熟的抗体可以通过本领域已知的方法生产,例如,Marks等,Rio/Technology 10:779-783(1992);Barbas等,Proc Nat.Acad.Sci.USA91:3809-3813(1994);BSchier等,基因169:147-155(1995);Yelton等,《免疫学期刊》155:1994-2004(1995);Jackson等,《免疫学期刊》154(7):331 0-15 9(1995);Hawkins等,J.Mol.Biol 226:889-896(1992)。
本发明所述的抗体可以表现出与CD122和/或γc的特异性结合。
与靶分子特异性结合的抗体优选以更大的亲和力结合靶标,和/或具有比结合其它靶标具有更长的持续时间。在一些实施方案中,本发明抗体可以以比I型细胞因子受体家族的一个或多个成员更高的亲和力与CD122和/或γc结合。在一些实施方案中,例如通过ELISA、SPR、生物层干涉测量法或放射免疫测定法(RIA)测量,抗体与无关靶标的结合程度小于所述抗体与靶标结合的约10%。或者,结合特异性可反映在结合亲和力方面,其中本发明的抗CD122和/或γc抗体以一个KD结合CD122和/或γc,即比针对另一种靶分子的抗体的KD大至少0.1个数量级(即0.1×10n,其中n是代表数量级的整数)。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中的一种。
常常以其解离常数(KD)来描述抗体对其靶标的结合亲和力。结合亲和力可以通过本领域已知的方法测定,例如通过ELISA、表面等离子体共振(SPR;参见例如Hearty等,《分子生物学方法》(2012)907:411-442)、生物层干涉法(参见Lad等,(2015)《生物分子筛选期刊》20(4):498-507)或通过用Fab形式的抗体和抗原分子进行放射性标记的抗原结合试验(RIA)。
在一些实施方案中,本发明所述的抗体具有选自以下之一的针对CD122的解离常数(KD):≤1x 10-6M,≤7.5x 10-7M,≤5x 10-7M,≤4.5x 10-7M,≤4x 10-7M,≤5x 10-7M,≤4.5x 10-7M,≤3x 10-7M,≤3.5x 10-7M,≤3x 10-7M,≤2.5x 10-7M,≤2x10-7M,≤1.9x 10-7M,≤1.8x 10-7M,≤1.7x 10-7M,≤1.6x 10-7M,≤1.5x 10-7M,≤1.4x 10-7M,≤1.3x 10-7M,≤1.2x 10-7M,≤1.1x 10-7M,≤1x 10-7M,≤8x 10-8M,≤6x 10-8M,≤4x 10-8M,或≤2x 10-8M。
在一些实施方案中,本发明所述的抗体具有选自以下之一的针对γc的KD:≤10x10-7M,≤7.5x 10-7M,≤5x 10-7M,≤2.5x 10-7M,≤1x 10-7M,≤9.5x 10-8M,≤9x 10-8M,≤8.5x 10-8M,≤8x 10-8M,≤7.5x 10-8M,≤7x 10-8M,≤6.5x 10-8M,≤6x 10-8M,≤5.5x 10- 8M,≤5x 10-8M,≤4.5x 10-8M,≤4x 10-8M,≤3.5x 10-8M,≤3x 10-8M,≤2.5x 10-8M,≤2x10-8M,≤1.5x 10-8M,≤1x 10-8M,≤8x 10-9M,≤6x 10-9M,≤4x 10-9M或≤2x 10-9M。
在一些实施方案中,本发明所述的抗体具有选自以下之一的针对CD122的KD:≤1x10-6M,≤7.5x 10-7M,≤5x 10-7M,≤4.5x 10-7M,≤4x 10-7M,≤5x 10-7M,≤4.5x 10-7M,≤3x10-7M,≤3.5x 10-7M,≤3x 10-7M,≤2.5x 10-7M,≤2x 10-7M,≤1.9x 10-7M,≤1.8x 10-7M,≤1.7x 10-7M,≤1.6x 10-7M,≤1.5x 10-7M,≤1.4x10-7M,≤1.3x 10-7M,≤1.2x 10-7M,≤1.1x10-7M,≤1x 10-7M,≤8x 10-8M,≤6x10-8M,≤4x 10-8M,或≤2x 10-8M以及具有选自以下之一的针对γc的KD:≤10x10-7M,≤7.5x 10-7M,≤5x 10-7M,≤2.5x 10-7M,≤1x 10-7M,≤9.5x10-8M,≤9x10-8M,≤8.5x 10-8M,≤8x 10-8M,≤7.5x 10-8M,≤7x 10-8M,≤6.5x 10-8M,≤6x10-8M,≤5.5x 10-8M,≤5x 10-8M,≤4.5x 10-8M,≤4x 10-8M,≤3.5x 10-8M,≤3x10-8M,≤2.5x 10-8M,≤2x 10-8M,≤1.5x 10-8M,≤1x 10-8M,≤8x 10-9M,≤6x10-9M,≤4x 10-9M或≤2x 10-9M。
在一些实施方案中,本发明所述的抗体结合在表达CD122和/或γc的细胞的细胞表面表达的CD122和/或γc。这种结合可以通过分析抗体与抗体温育的PBMC的结合,或用表达CD122和/或γc的构建体转染的细胞来分析,随后分析抗体结合,例如通过流式细胞术进行分析。
在一些实施方案中,本发明所述的抗体是一种或多种信号传导途径的激动剂,其通过包含CD122和/或γc的受体的信号转导而被激活,例如IL-2受体和/或IL-15受体。在一些实施方案中,抗体能够通过一种或多种包含CD122和/或γc的免疫受体复合物来刺激信号传导,例如IL-2受体和/或IL-15受体。
在一些实施方案中,抗体是IL-2受体激动剂。因此,在一些实施方案中,抗体能够激活IL-2/IL-2受体介导的信号传导和相关功能。例如,在一些实施方案中,抗体能够促进表达IL-2受体的细胞的细胞分裂/增殖/存活。
在一些实施方案中,抗体是IL-15受体激动剂。因此,在一些实施方案中,抗体能够激活IL-15/IL-15受体介导的信号传导和相关功能。例如,在一些实施方案中,抗体能够促进表达IL-15受体的细胞的细胞分裂/增殖/存活。
在一些实施方案中,与还包含CD25的受体相比,本发明所述的双特异性抗体可优先结合(例如以更大的亲和力和/或特异性)包含或由CD122和γc或由CD122和γc组成的受体。双特异性抗体可优先刺激包含或由CD122和γc但不包含CD25组成的受体(或表达受体的细胞)。
在一些实施方案中,本发明所述的结合CD122和γc的双特异性抗体优选不表现出对配体与具有通用γ链且不含CD122的受体结合的显著抑制,例如除IL-2R和IL-15R以外的受体。例如,本发明所述的双特异性抗体可以对包含CD122和γc的受体比对包含γc但不包含CD122的受体具有特异性。
在一些实施方案中,本发明所述的抗体能够刺激CD122:γc介导的通过以下细胞内信号传导途径之一的信号传导:STAT5、Akt、ERK。可以通过本领域技术人员熟知的方法分析通过STAT5,Akt,ERK细胞内信号传导途径的信号传导,例如,通过用抗体刺激表达CD122和/或γc的细胞后,分别检测磷酸化的STAT5、磷酸化的Akt和任选的磷酸化的ERK。
在一些实施方案中,本发明所述的抗体是在Treg细胞中比IL-2更弱的有效的细胞内信号传导刺激物。例如,与用IL-2处理相比,用抗体处理可以减少STAT5的磷酸化。
在一些实施方案中,抗体能够在体外和/或体内刺激免疫细胞的增殖。刺激增殖导致其刺激增殖的细胞类型的数量增加,有效实现细胞群的扩增。例如,所述抗体可用于体外或体内刺激白细胞的增殖和/或扩增,与相应量的IL-2的作用相比,优选表现出毒性降低。
在一些实施方案中,抗体能够刺激IL-2依赖性细胞的增殖。在一些实施方案中,抗体能够刺激CD3+T细胞(例如CD4+T细胞,CD8+T细胞)和/或NK细胞的增殖。
可以通过本领域众所周知的方法体外分析抗体是否能够刺激细胞增殖,例如通过分析刺激之前和之后给定细胞类型的数目,和/或通过另一种试验,例如胸苷嘧啶核苷掺入、CFSE稀释(例如,如Anthony等,2012《细胞》1:127-140中所述)、AlamarBlue信号等。
在一些实施方案中,本发明所述的抗体能够结合非人灵长类动物(例如食蟹猴)的CD122和/或γc。抗体对于人和非人灵长类CD122和/或γc可以交叉反应。因此,在一些实施方案中,抗体能够在表达非人灵长类动物(例如食蟹猴)CD122和/或γc的细胞中刺激IL-2/IL-2受体-和/或IL-15/IL-15受体介导的信号传导。
在一些实施方案中,本发明的抗体能够刺激CD3+T细胞的增殖。在一些实施方案中,本发明的抗体能够刺激CD4+T细胞的增殖。在一些实施方案中,本发明的抗体能够刺激CD8+T细胞的增殖。
在一些实施方案中,本发明的抗体能够增加CD8+T细胞与CD4+T细胞的比例。也就是说,在一些实施方案中,与刺激之前相比,在刺激包含CD8+T细胞和CD4+T细胞的细胞群后(例如体外或体内),刺激后CD8+T细胞与CD4+T细胞的比例可能更高。
在一些实施方案中,本发明的抗体不是CD4+FoxP3+细胞增殖的有效刺激物(即Treg)。在一些实施方案中,抗体不刺激Treg的增殖。
在一些实施方案中,本发明的抗体刺激Treg的增殖程度更低于IL-2。也就是说,在一些实施方案中,本发明的抗体作为对Treg的增殖的激动剂没有IL-2有效。在一些实施方案中,在给定的试验中,本发明的抗体刺激Treg增殖的程度是用相当浓度的IL-2处理刺激的Treg的增殖程度的≤1倍、≤0.8倍、≤0.6倍、≤0.4倍、≤0.2倍、≤0.1倍。
在一些实施方案中,本发明的抗体优选刺激增殖CD8+T细胞的效应记忆亚群,超过中央记忆CD8+T细胞和初始CD8+T细胞群体。
在一些实施方案中,在给定测定中,本发明的抗体比相当浓度的IL-2更大程度地刺激效应记忆CD8+T细胞的增殖
在一些实施方案中,本发明的抗体能够刺激抗原特异性T细胞的增殖,例如,抗原特异性CD8+T细胞和/或抗原特异性CD4+T细胞。刺激可以发生在体外或体内。在一些实施方案中,本发明的抗体能够刺激抗原特异性CD8+细胞毒性T淋巴细胞(CTL)的增殖。可以评估细胞刺激抗原特异性T细胞增殖的能力,例如,在抗体存在的情况下,分析与呈递目标抗原的细胞孵育的T细胞的增殖,如本文实施例8和11所述。
在一些实施方案中,在给定的测定中,本发明的抗体能够比相当浓度的IL-2更大程度地刺激抗原特异性T细胞的增殖。
在一些实施方案中,在给定的测定中,本发明的抗体能够比相当浓度的IL-2更大程度地刺激抗原特异性CD8+T细胞的增殖。
在一些实施方案中,本发明的抗体能够增加抗原特异性CD8+T细胞与CD4+T细胞的比例。这可能发生在体外或体内。也就是说,在一些实施方案中,与刺激前相比,在刺激(例如体外)含有抗原特异性CD8+T细胞和CD4+T细胞的细胞群后,刺激后CD8+T细胞与CD4+T细胞的比例更高。在一些实施方案中,在给定的测定中,本发明的抗体能够比相当浓度的IL-2更大程度地增加抗原特异性CD8+T细胞与CD4+T细胞的比例。
在一些实施方案中,本发明的抗体能够刺激CD8+PD1+T细胞(例如抗原特异性CD8+PD1+T细胞)的增殖。在一些实施方案中,在给定的测定中,本发明的抗体能够比相当浓度的IL-2更大的程度刺激CD8+PD1+T细胞的增殖。
在一些实施方案中,本发明的抗体能够降低Tregs占CD4+T细胞比例。也就是说,在一些实施方案中,在用抗体处理CD4+T细胞群后,减少了Treg的CD4+T细胞的百分比。在一些实施方案中,在给定的测定中,本发明的抗体能够比相当浓度的IL-2更大程度地降低Tregs占CD4+T细胞的比例。
在一些实施方案中,本发明的抗体能够刺激CTL细胞毒性。可以通过技术人员已知的方法来测定抗体刺激CTL细胞毒性的能力。可以研究T细胞对给定靶细胞的细胞毒性,例如,使用“Zaritskaya等,Expert Rev Vaccines(2011),9(6):601-616”综述的任何方法,其全部内容通过引用并入本文。
在一些实施方案中,抗体能够刺激体内免疫细胞的增殖。在一些实施方案中,抗体能够体内刺激CD3+细胞的增殖。在一些实施方案中,抗体能够体内刺激CD8+T细胞的增殖。在一些实施方案中,抗体能够刺激体内CD4+T细胞的增殖。在一些实施方案中,抗体能够刺激体内NK细胞的增殖。
在本发明的几个方面和实施方案中,可以在体外或体内刺激或扩增具有期望特征的细胞。体外刺激或扩增可提供富集所需特征的细胞群体,可以将其收集并用于期望的目的,包括对受试者施用。体内刺激或扩增可富集对受试者有益的细胞群体,例如,用于治疗或预防疾病。体内刺激或扩增可能有辅助效果或作用。
在一些方面,本发明的抗体包含CD122结合抗体克隆的抗体/片段。在一些方面,抗体包含克隆P2C4或P2C4的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_A4或P2C4_A4的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_B1或P2C4_B1的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_B5或P2C4_B5的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_C1或P2C4_C1的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_C4或P2C4_C4的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_C7或P2C4_C7的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_D10或P2C4_D10的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_E6或P2C4_E6的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_E7或P2C4_E7的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_F8或P2C4_F8的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_C1D10或P2C4_C1D10的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_FW2或P2C4_FW2的变体的抗体/片段。在一些方面,抗体包含克隆P2H7或P2H7的变体的抗体/片段。在一些方面,抗体包含克隆P2D12或P2D12的变体的抗体/片段。在一些方面,抗体包含克隆P1G11或P1G11的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_A9或P2C4_A9的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_B6或P2C4_B6的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_E9或P2C4_E9的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_B8或P2C4_B8的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_B12或P2C4_B12的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_C12或P2C4_C12的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_E2或P2C4_E2的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_E3或P2C4_E3的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_E8或P2C4_E8的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_F11或P2C4_F11的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_G2或P2C4_G2的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_G11或P2C4_G11的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_H1或P2C4_H1的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_H2或P2C4_H2的变体的抗体/片段。在一些方面,抗体包含克隆P2C4_H3或P2C4_H3的变体的抗体/片段。
前面段落的CD122结合抗体克隆的VL结构域的氨基酸序列示于图1中,正如根据Kabat系统定义的CDR一样。前段的CD122结合抗体克隆的VH结构域的氨基酸序列显示在图2中,正如根据Kabat系统定义的CDR一样。抗体构建体(包括接头)的完整氨基酸序列显示在图15中,并且编码核苷酸序列显示于图17中。
本发明所述的抗体可包含P2C4、P2C4_A4、P2C4_B1、P2C4_B5、P2C4_C1、P2C4_C4、P2C4_C7、2C4_D10、P2C4_E6、P2C4_E7、P2C4_F8、P2C4_C1D10、P2C4_FW2、P2H7、P2D12、P1G11、P2C4_A9、P2C4_B6、P2C4_E9、P2C4_B8、P2C4_B12、P2C4_C12、P2C4_E2、P2C4_E3、P2C4_E8、P2C4_F11、P2C4_G2、P2C4_G11、P2C4_H1、P2C4_H2或P2C4_H3的CDR。在本发明所述的抗体中,六个CDR序列中的一个或两个或三个或四个可以改变。变体可以在六个CDR序列中的一个或两个中有一个或两个氨基酸的取代。
本发明所述的抗体可以包含VL和/或VH链,其包含氨基酸序列,所述氨基酸序分别与图1和2中所示的一个或多个VL和/或VH氨基酸序列具有高百分比序列同一性。例如,本发明所述的抗体包括结合CD122并且具有VL链的抗体,其包含与图1所示的SEQ ID NO:1、17、19、21、23、24、27、28、29、30、31、33、34、148、149、5、9或13中的一种的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%中的一种的序列同一性的氨基酸序列。本发明所述的抗体包括结合CD122并且具有VH链的抗体,其包含与图2所示的SEQ ID NO:35、51、53、55、56、57、58、59、60、61、62、63、64、65、66、150、151、39、43或47中的一种的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%中的一种的序列同一性氨基酸序列。
本发明所示的抗体包括具有由图17所示的SEQ ID NO:130、131、132、133、134、135、136、137、138、139、140或141中任一个的核苷酸序列编码的氨基酸序列的抗体或其CD122结合片段。本发明的抗体包括含有由图17所示的SEQID NO:130、131、132、133、134、135、136、137、138、139、140或141中任一项的核苷酸序列编码的氨基酸序列的VL和/或VH结构域序列的抗体。
在一些方面,本发明的抗体包含γc结合抗体克隆的抗体/片段。在一些方面,抗体包含克隆P1A3或P1A3的变体的抗体/片段。在一些方面,抗体包含克隆P1A3_B3或P1A3_B3的变体的抗体/片段。在一些方面,抗体包含克隆P1A3_E8或P1A3_E8的变体的抗体/片段。在一些方面,抗体包含克隆P1A3_E9或P1A3_E9的变体的抗体/片段。在一些方面,抗体包含克隆P1A3_B4或P1A3_B4的变体的抗体/片段。在一些方面,抗体包含克隆P1A3_FW2或P1A3_FW2的变体的抗体/片段。在一些方面,抗体包含克隆P2B9或P2B9的变体的抗体/片段。
前面段落的γc-结合抗体克隆的VL结构域的氨基酸序列显示在图3中,正如根据Kabat系统定义的CDR一样。前面段落的γc-结合抗体克隆的VH结构域的氨基酸序列如图4所示,正如根据Kabat系统定义的CDR一样。抗体构建体(包括接头)的完整氨基酸序列显示在图16中,编码的核苷酸序列显示于图18中。
本发明所述的抗体可以包含P1A3、P1A3_B3、P1A3_E8、P1A3_E9、P1A3_B4、P1A3_FW2或P2B9的CDR。在本发明所述的抗体中,六个CDR序列中的一个或两个或三个或四个可以改变。变体可以在六个CDR序列中的一个或两个中有一个或两个氨基酸的取代。
本发明所述的抗体可以包含VL和/或VH链,其包含一氨基酸序列,所述氨基酸序列分别与图3和4中所示的一个或多个VL和/或VH氨基酸序列具有高百分比的序列同一性。例如,本发明所述的抗体包括结合γc并且具有VL链的抗体,其包含与图3所示的SEQ ID NO:67、152、71或75中的一种的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%中的一种的序列同一性的氨基酸序列。本发明所述的抗体包括结合γc并且具有VH链的抗体,其包含与图4所示的SEQ ID NO:76、153、78、82或84中的一种的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%中的一种的序列同一性氨基酸序列。
本发明所示的抗体包括具有由图18所示的SEQ ID NO:142、143、144、145、146或147中任一个的核苷酸序列编码的氨基酸序列的抗体或其γc结合片段。本发明的抗体包括含有由图18所示的SEQ ID NO:142、143、144、145、146或147中任一项的核苷酸序列编码的氨基酸序列的VL和/或VH结构域序列的抗体。
在一些方面,本发明的抗体包含CD122-结合抗体克隆的抗体/片段,例如本文所述的CD122-结合抗体克隆,并且还包含γc-结合克隆,例如如本文所述的γc-结合克隆。
本文公开的轻链和重链CDR也可以特别用于与许多不同的框架区结合。因此,具有LC-CDR1-3或HC-CDR1-3的轻链和/或重链可具有一个可替代的框架区。合适的框架区在本领域中是公知的,并在例如“M.Lefranc和G.Le:franc(2001)“免疫球蛋白书籍(TheImmunoglobulin FactsBook)”,学术出版社”中被描述,通过引用的形式并入本文。
本发明所述的抗体可以被可检测标签标记,或者至少能够被检测到。例如,抗体可以用放射性原子或有色分子或荧光分子或可以很容易的用任何其他方式检测到的分子进行标记。合适的可检测分子包括荧光蛋白、萤光素酶、酶底物和放射性标记。结合部分可以用可检测标记直接标记,或其可以被间接标记。例如,结合部分可以是未标记的抗体,其可以被本身标记的另一种抗体检测到。或者,第二抗体可能已经与生物素结合,并且标记的链霉亲和素与生物素的结合用于间接标记第一抗体。
嵌合抗原受体
本发明提供了能够结合CD122和/或γc的嵌合抗原受体(CAR)。CAR包含一个或多个本发明所述的抗原结合片段或多肽。
嵌合抗原受体(CAR)是提供抗原结合和T细胞活化功能的重组受体。例如在“Dotti等,《免疫评论》(2014)257(1)”中综述了CAR的结构和工程化,其通过引用整体并入本文。
本发明所述的抗原结合片段在本文以作为嵌合抗原受体(CAR)的抗原结合结构域来提供。在一些实施方案中,CAR包含本文所述抗体的任何实施方式中所述的VL结构域和VH结构域、抗原结合片段或多肽。因此,本文所述的CAR结合的抗原是CD122和/或γc。
CAR可以与共刺激配体、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,癌症发现,2013.4;3(4):388-398。doi:10.1158/2159-8290.CD-12-0548,具体地通过引用并入本文)。
本发明还提供了含有本文所述的CAR的细胞。本发明所述的CAR可用于产生靶向表达CD122和/或γc的细胞的T细胞。
将CAR工程化为T细胞可以在体外培养过程中进行,用于转导和扩增,例如,发生在T细胞扩增期间用于过继性T细胞治疗。转导可以利用多种方法,但需要稳定的基因转移才能使CAR持续表达在克隆性扩增和持续性的T细胞中。
CAR通常在单个嵌合蛋白中将抗原结合结构域与CD3-zeta链或FcγRI蛋白的细胞内结构域组合。Sjouke等人描述了CAR的结构特征(第二代嵌合抗原受体的药理学。自然评论药物发现,14,499 509(2015)doi:10.1038/nrd4597)。CAR通常具有与跨膜结构域和胞内结构域连接的细胞外抗原结合结构域。可选的铰链区或间隔区结构域可以使结合部分和跨膜结构域之间分离,并可以充当柔性接头。
根据本发明,CAR的抗原识别结构域是或来源于能够结合本文所述的CD122和/或γc的抗体、抗原结合片段或多肽。
CAR的铰链区或间隔区可以是柔性结构域,使得结合部分定位在不同的方向。铰链区或间隔区可以来源于IgG1或免疫球蛋白的CH2CH3区域。
跨膜结构域可以是跨越细胞膜的疏水性α螺旋。与胞内结构域相关的跨膜结构域是常用的。
胞内结构域负责抗原结合后的受体聚簇/二聚化和用于启动信号转导至细胞。一个常用的跨膜结构域是CD3-zeta跨膜和胞内结构域。来自一种或多种共刺激蛋白质受体的细胞内结构域,如CD28 4-1BB、OX40、ICOS,可以任选地并入CAR的细胞质尾部以提供额外的共刺激信号,这在抗肿瘤活性方面可能是有利的。
在一个实施方案中,CAR包含具有抗原识别结构域、跨膜结构域和细胞质结构域的胞外结构域。可以使用与CAR中的一个结构域天然相关的跨膜结构域,或者可以通过氨基酸取代选择或修饰跨膜结构域,以避免这样的结构域与相同或不同的表面膜蛋白的跨膜结构域结合,从而以减少与受体复合物的其他成员的相互作用。
细胞质结构域可以被设计为自身包含CD28和/或4-1BB信号传导结构域,或者与其他所需的细胞质结构域结合。细胞质结构域可被设计为进一步包含CD3-zeta的信号传导结构域。例如,CAR的细胞质结构域可以包括但不限于CD3-zeta、4-1BB和CD28信号传导模块及其组合。
本发明还提供CAR T细胞,其包含能够结合本发明所述的CD122和/或γc的抗原结合片段的CAR。
本发明的CAR T细胞可以通过将包含所需CAR(例如包含抗IL2Rβ/γc、CD8a铰链和跨膜结构域的CAR以及人4-1BB和CD3zeta信号传导结构域)的体外慢病毒载体导入细胞中来产生。本发明的CAR T细胞能够在体内复制,使CAR T细胞长期持续地控制肿瘤。
在一个实施方案中,本发明涉及给患者施用表达能够结合CD122和/或γc的CAR的遗传修饰的T细胞,用淋巴细胞输注来治疗患有癌症或有患癌症或感染性疾病风险的患者。优选地,在治疗中使用自体淋巴细胞输注。收集需要治疗的患者的自体PBMC,并用本文所述和本领域已知的方法活化和扩增T细胞,然后将其回输入患者体内。
检测方法
本文所述的抗体或抗原结合片段可用于涉及抗体或抗原结合片段与CD122和/或γc结合的方法中。这样的方法可涉及抗体或抗原结合片段与CD122和/或γc的结合复合物的检测。因此,在一个实施方式中,提供了一种方法,所述方法包含将含有或可能含有CD122和/或γc的样品与本文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和CD122和/或γc形成的复合物。
合适的方法在本领域中是众所周知的,包括免疫测定法,如夹心测定法,例如,ELISA。该方法可以包括用可检测标记,例如,荧光,发光或放射标签标记抗体或抗原结合片段或CD122和/或γc或两者。可以通过免疫组织化学(IHC),例如活检获得的组织样品来测量CD122和/或γc的表达。
这种方法可以提供诊断需要检测和/或定量CD122和/或γc的疾病或病症的方法的基础。这种方法可以在患者样品上体外进行,或对患者样品进行处理之后进行。一旦采集到样本,患者不需要进行体外诊断,因此该方法可以不在人体或动物体上实施。
这种方法可以确定患者样品中的CD122和/或γc的量。该方法还可以包括将所确定的量与标准值或参考值进行比较,作为诊断过程的一部分。其他诊断测试可以与本文所述的方法结合使用,以提高诊断或预后的准确性,或确认用本文所述的测试获得的结果。
存在于患者样品中的CD122和/或γc的水平可能表明患者可能对用抗CD122和/或抗γc抗体的治疗有反应。样品中高水平的CD122和/或γc的存在可用于筛选用抗-CD122和/或抗-γc抗体治疗的患者。因此本发明的抗体可用于筛选用抗-CD122和/或抗-γc抗体疗法治疗的患者。
在抗CD122和/或抗γc抗体的样品中的检测可以用于诊断患者中的感染性疾病、自身免疫病或癌症,诊断感染性疾病、自身免疫病或癌症的倾向,或提供感染性疾病、自身免疫病或癌症的预后(预测)。诊断或预后可能与现有的(先前诊断的)感染性疾病、自身免疫性疾病或癌症有关。
样品可以从任何组织或体液中取出。样品可以包含或可以来源于:从个体血液中得到的一定量的血液;一定量的血清,其可以包含在去除纤维蛋白凝块和血细胞后获得的血液流体部分;组织样本或活检;或从所述个体分离的细胞。
本发明所述的方法可以优选体外进行。术语“体外”旨在包括细胞培养的实验,而术语“体内”旨在包括完整的多细胞生物体的实验和/或治疗。
治疗应用
本发明所述的抗体、抗原结合片段和多肽以及包含这些试剂的组合物可以用于医学治疗方法。可以治疗患有需要治疗的疾病或病症的受试者。
医学治疗方法可通过改善、治疗或预防人体中的恶性肿瘤的方法来治疗癌症,其中所述方法的步骤有助于或加强免疫系统在根除癌细胞中的作用。这种方法可包括本发明所述的细胞、抗体、蛋白质或核酸的施用引起活性(或实现被动)免疫应答来破坏癌细胞。治疗方法可以任选地包括生物佐剂(例如白细胞介素、细胞因子、芽孢杆菌Comette-Guerin、单磷酰脂质A等)与常规疗法的联合施用以治疗癌症,如化疗、放疗或手术。治疗方法可以涉及施用组合物作为疫苗,其通过激活免疫系统来预防或破坏癌细胞生长。医疗方法还可以涉及体内、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的那些方法。
疾病或病症可以是感染性疾病、自身免疫性疾病(即克罗恩氏病、多发性硬化症)、癌症、炎性疾病(例如关节炎)、与缺乏IL-2介导的信号传导和/或IL-15介导的信号传导相关的疾病/病症、缺陷的T细胞增殖或T细胞功能障碍之一。
在一些实施方案中,所增加的IL-2介导的信号传导和/或IL-15介导的信号传导对疾病或障碍是治疗性的。
在一些实施方案中,治疗是与缺陷T细胞应答有关的疾病或障碍,例如缺陷CD8+T细胞应答。
治疗可以通过下列中的一种或多种来预防或治疗疾病/病症:增加CD3+T细胞的数量、增加CD4+T细胞的数量、增加CD8+T细胞的数量、增加CD8+效应子T细胞(例如CTL)的数量、增加NK细胞的数量,增加CD8+T细胞与CD4+T细胞的比例、或降低Tregs的比例。
T细胞功能紊乱性疾病可能表现为感染、或无法建立针对感染的有效免疫应答。感染可能是慢性的、持续的、潜伏的或缓慢的,并且可能是细菌、病毒、真菌或寄生虫感染的结果。因此,可以向患有细菌、病毒或真菌感染的患者提供治疗。细菌感染的例子包括感染幽门螺杆菌。病毒感染的例子包括EBV、HIV、乙型肝炎或丙型肝炎的感染。
T细胞功能紊乱性疾病可能与癌症相关,如肿瘤免疫逃逸。许多人类肿瘤表达肿瘤相关抗原被T细胞识别,并能够诱导免疫应答。
在不存在T细胞功能障碍的情况下也可以治疗癌症,但本发明所述的抗体、抗原结合片段或多肽的使用促进了有效的免疫应答。
治疗可以预防与缺陷/减少的IL-2介导的信号传导和/或IL-15介导的信号传导相关的疾病/病症。因此,抗体、抗原结合片段和多肽可用于配制药物组合物或药物,并且可以预防性地治疗受试者以防疾病发展。这可能发生在病情发作之前,和/或可以给予具有较高疾病或病症风险的受试者。
治疗可以包括与疫苗联合治疗,例如T细胞疫苗,其可能涉及同时、分开或顺序治疗,或在单一组合物中联合施用疫苗和抗体、抗原结合片段或多肽。在这种情况下,可以提供抗体、抗原结合片段或多肽作为疫苗的佐剂。
抗体、抗原结合片段或多肽的施用优选为“治疗有效剂量”,这足以向个体显示出有益效果。实际给药量、给药速度和时间过程将取决于所治疗疾病的性质和严重程度。治疗处方,例如剂量等方面的决定是由全科医师和其他医生负责的,并且通常考虑待治疗的病症、个体患者的情况、递送部位、给药方法和执业医师已知的其他因素。上述技术和方案的实例可以在“雷明顿药物科学,第20版,2000出版.Lippincott,Williams&Wilkins”中找到。
CAR和含有本发明的CAR(即CAR-T细胞)的细胞可用于治疗自身免疫病,例如,克罗恩氏病、多发性硬化症。在这样的治疗中,CAR-T细胞有效杀死表达CD122和/或γc的自身免疫攻击细胞(例如自身反应性T细胞)。
配制药学上有用的组合物和药物
本发明所述的抗体、抗原结合片段和多肽、CAR和细胞可以配制成用于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。
本发明还提供了制备药学上有用的组合物的方法,这种制备方法可以包括选自以下的一个或多个步骤:分离如本文所述的抗体、抗原结合片段、多肽、CAR或细胞;和/或将本文所述的分离的抗体、抗原结合片段或多肽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,该方法包括通过将本文所述的抗体、抗原结合片段、多肽、CAR或细胞与药学上可接受的载体、佐剂、赋形剂或稀释剂混合来配制药物组合物或药物。
感染
感染可以是任何感染或感染性疾病,例如细菌、病毒、真菌或寄生虫感染。在一些实施方案中,可能特别希望治疗慢性/持续性感染,例如这种感染与T细胞功能障碍或T细胞耗竭有关。
可以确定T细胞耗竭是许多慢性感染(包括病毒,细菌和寄生虫)期间以及癌症中出现的T细胞功能障碍的状态(Wherry自然免疫学“Nature Immunology”12卷,6期,492-499页,2011年6月)。
可以治疗的细菌感染的实例包括由芽孢杆菌属(Bacillus spp.)、百日咳博德特氏菌(Bordetella pertussis)、梭菌属(Clostridium spp.)、棒状杆菌属(Corynebacterium spp.)、霍乱弧菌(Vibrio chloerae)、葡萄球菌属(Staphylococcusspp.)链球菌属(Streptococcus spp.)、埃希氏杆菌属(Escherichia)、克雷伯菌(Klebsiella)、变形杆菌(Proteus)、耶尔森氏菌(Yersinia)、欧式杆菌(Erwina)、沙门氏菌(Salmonella)、李斯特氏菌(Listeria sp)、幽门螺杆菌(Helicobacter pylori)、分枝杆菌(例如结核分枝杆菌Mycobacterium tuberculosis)和铜绿假单胞菌(Pseudomonasaeruginosa)。感染,例如,细菌感染可能是败血症或结核病。
可以治疗的病毒感染的例子包括艾巴氏病毒、麻疹病毒、乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、人免疫缺陷病毒(HIV)、淋巴细胞性脉络丛脑膜炎病毒(LCMV)、单纯疱疹病毒和人类乳头状瘤病毒的感染。
可以治疗的真菌感染的例子包括链格孢属(Alternaria sp)、曲霉属(Aspergillus sp)、假丝酵母属(Candida sp)和组织胞浆菌属(Histoplasma sp)感染。真菌感染可能是真菌性脓毒症或组织胞浆菌病。可以治疗的寄生虫感染的例子包括疟原虫感染(例如恶性疟原虫、约氏疟原虫、卵形疟原虫、间日疟原虫或疟原虫)。寄生虫感染可能是一种疾病,如疟疾、利什曼病和弓形体病。
癌症
癌症可以是任何有害的细胞增殖,异常新生物或肿瘤,或增加不良细胞增殖,异常新生物或肿瘤的风险或倾向。癌症可能是良性或恶性的,可能是原发性或继发性(转移性)。异常新生物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。组织包括肾上腺髓质、肛门、阑尾、膀胱、血液、骨骼、骨髓、脑、乳房、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、肾脏、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、口腔、腹膜、胸膜、前列腺、唾液腺、乙状结肠、皮肤、小肠、软组织、脾脏、胃、睾丸、胸腺、甲状腺、舌、外阴、白细胞。
要治疗的肿瘤可能是神经系统肿瘤或非神经系统肿瘤。神经系统肿瘤可能起源于中枢或外周神经系统,例如,神经胶质瘤、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/肿瘤可起源于任何其他非神经组织,例如黑素瘤、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、慢性骨髓性白血病(CML)、急性骨髓性白血病(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)、肝细胞瘤、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。具体而言,考虑了黑素瘤,肾癌(肾细胞癌)或膀胱癌的治疗。在一些实施方案中,癌症是EBV或HPV阳性癌症。
过继性细胞转移治疗
过继细胞转移疗法通常是指从受试者中去除白细胞的过程,通常通过从体外或离体扩增分离出白细胞的血液样本,并返回到同一或不同受试者。该治疗通常旨在增加受试者中所需细胞群的活化形式的量/浓度。
本发明的抗体/片段提供了扩增表达CD122和/或γc的细胞的数量和/或增强活性的方法。在一些实施方案中,细胞是T细胞和/或NK细胞。
因此,在本发明的另一方面中,提供了用于扩增细胞群的方法,其中使细胞与本发明的抗体、抗原结合片段、多肽或组合物体外、体内或离体接触。还提供了扩增受试者体内的细胞群体的方法,包括向受试者施用本发明所述的抗体/片段、抗体、抗原结合片段、多肽或组合物。
在一些实施方案中,本发明的抗体/片段能够向表达CD122和/或γc的细胞递送存活信号。在一些实施方案中,抗体/片段可用于例如在体外、体内或离体增强/促进细胞或细胞群的存活(例如T细胞(CD8+T细胞(CTL)、CD4+T细胞)和/或NK细胞)。
因此,在本发明的另一方面中,提供了增强/促进细胞或细胞群存活的方法,其中将细胞在体外、体内或离体与本发明的抗体、抗原结合片段、多肽或组合物接触。还提供了用于增强/促进受试者中细胞或细胞群的存活的方法,其包括向受试者施用本发明所述的抗体/片段、抗原结合片段、多肽或组合物。
所述方法可以可选地包括以下一个或多个步骤:从受试者中取血样;从血样中分离细胞(例如,PBMC、T细胞、NK细胞等之一);在体外或离体细胞培养物(可以与抗体、抗原结合片段或多肽接触)中培养细胞,收集扩增的细胞群;将细胞与佐剂、稀释剂或载体混合;将扩增的细胞施用于受试者。
因此,在本发明的一些方面中,提供了一种治疗受试者(有T细胞功能障碍病症)的方法,该方法包括从需要治疗的受试者获得血液样品,在存在本发明所述的抗体、抗原结合片段、多肽或组合物的情况下培养从血液样品获得的T细胞以扩增T细胞群,收集扩增的T细胞,并将扩增的T细胞施用于需要治疗的受试者。
可以从需要治疗的受试者获得T细胞,并分离和/或纯化。它们可能是CD4+和/或CD8+T细胞群体,也可能是CD122+和/或γc+群体。
在培养过程中,T细胞可以在允许将T细胞扩增到所需的细胞数目的条件下和合适的时间段内,与抗体、抗原结合片段或多肽接触。在合适的时间段之后,可以收集T细胞,任选地进行浓缩,并且可以与合适的载体,佐剂或稀释剂混合并返回到受试者体内。受试者可经历一轮或多轮此类治疗。
T细胞扩增的方法在本领域是公知的,例如在Kalamasz等人,J Immunother 2004年9-10月;27(5):405-18;Montes等人,Clin Exp Immunol 2005年11月;142(2):292-302;和Greenburg自然实验手册(Nature Protocols)9 950-966页2014年3月27日;Trickett和Kwan免疫学方法杂志(Journal of Immunological Methods)275卷1-2期,2003年4月1日,251-255页;Butler等人PLoSONE 7(1)2012年1月12日中描述的那些。
同时或依次施用
取决于待治疗的病症,组合物可以单独或与其它治疗组合施用,或者同时或依次给予。
在本说明书中,本发明的抗体、抗原结合片段、多肽、CAR、细胞或组合物和抗感染剂或化学治疗剂(治疗剂)可以同时或依次施用。
在一些实施方案中,使用本发明的抗体、抗原结合片段或多肽进行治疗可伴随着化学疗法。
同时施用是指将抗体、抗原结合片段或多肽和治疗剂一起施用,例如作为含有两种试剂的药物组合物(组合制剂),或者彼此紧密衔接,并且任选地经由相同的施用途径,例如施用到同一动脉、静脉或其他血管。
依次施用是指施用抗体、抗原结合片段或多肽或治疗剂之一随后在给定的时间间隔之后,分开施用其它药剂。不要求两个试剂通过相同的途径施用,尽管在一些实施方案中是这种情况。时间间隔可以是任何时间间隔。
在一些实施方案中,本发明的抗体、抗原结合片段、多肽或组合物可以通过过继细胞转移施用于正在接受治疗的患者。施用可能指在患者体内刺激过继转移的细胞的增殖。
抗感染剂
在治疗感染时,本发明的抗体、抗原结合片段或多肽可与抗感染剂组合施用,如上所述。抗感染剂可以是已知对负责感染的微生物或病毒具有作用的药剂。
合适的抗感染剂包括抗生素(例如青霉素、头孢菌素、利福霉素、闰年霉素(lipiarmycins)、喹诺酮类、磺胺类、大环内酯类、林可酰胺类(lincosamides)、四环素、环状脂肽、甘氨环素、恶唑烷酮(oxazolidinones)和闰年霉素(lipiarmycins),抗病毒剂(如逆转录酶抑制剂、整合酶抑制剂、转录因子抑制剂、反义和siRNA剂和蛋白酶抑制剂),抗真菌剂(例如多烯、咪唑类、三唑、噻唑、烯丙胺和棘白菌素)和抗寄生虫剂(如抗线虫剂、抗绦虫剂、抗吸虫剂、抗变形虫剂和抗原虫剂)。
化疗
化学疗法和放射疗法分别是指用药物或电离辐射(例如使用X射线或γ射线的放射疗法)治疗癌症。
该药物可以是化学实体,例如小分子药物、抗生素、DNA嵌入剂、蛋白质抑制剂(例如激酶抑制剂),或生物制剂,例如抗体、抗体片段、核酸或肽适体、核酸(DNA、RNA)、肽、多肽或蛋白质。药物可以配制成药物组合物或药物。该制剂可以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。
治疗可以施用一种以上的药物。药物可以单独施用或与其他治疗组合施用,同时或顺序取决于于待治疗的病症。例如,化学疗法可以是两种药物共同治疗,其中一种或多种可以治疗癌症。
化疗可以通过一种或多种施用途径施用,例如,肠胃外、静脉内注射、口服、皮下、皮内或肿瘤内。
化疗可根据治疗方案施用。治疗方案可以是化疗的预定时间表、计划、方案或时间表,其可以由医生或执业医师准备,并可以定制以适合需要治疗的患者。
治疗方案可以是以下中的一个或多个:给予患者的化学疗法的类型;每种药物或辐射的剂量;施用的时间间隔;每次治疗的时长;任何治疗间歇的数量和性质,(如果有的话)等等。对于联合治疗,可以提供单一的治疗方案,其说明每种药物该如何施用。
化疗药物和生物制剂可以选自:烷化剂如顺铂、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(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、紫杉烷类如紫杉醇(TaxolTM)、多西他赛;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托泊替康,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(如蒽环霉素抗生素),如更生霉素、多柔比星(阿霉素)、表柔比星、博来霉素、雷帕霉素;基于抗体的药剂,例如抗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,例如西妥昔单抗、帕尼单抗、英夫利昔单抗、巴利昔单抗、贝伐单抗阿昔单抗、达克珠单抗、吉姆单抗、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Sipuleucel-T
在一个实施方案中,化学治疗剂是抗PD-1抗体、抗PD-L1抗体、抗TIM-3抗体、抗LAG-3、抗CTLA-4、抗-41BB、抗GITR、抗CD27、抗BLTA、抗OX43、抗VEGF、抗TNFα、抗IL2、抗GpIIb/IIIa、抗CD-52、抗CD20、抗RSV、抗HER2/neu(erbB2)、抗TNF受体、抗EGFR或其他抗体。在一些实施方案中,化学治疗剂是免疫检查点抑制剂或共刺激分子。
其他化学治疗药物可以选自:13-顺式-视黄酸、2-氯脱氧腺苷、5-阿扎胞苷、5-氟尿嘧啶、6-巯基嘌呤、6-硫鸟嘌呤、白蛋白结合型紫杉醇(Abraxane)、更生霉素-D阿地白介素、阿伦单抗、爱宁达(ALIMTA)、阿利维甲酸、全变性维酸、α干扰素、六甲蜜胺、氨甲蝶呤、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、ATRA阿扎胞苷、BCG、BCNU、苯达莫司汀、贝伐珠单抗、蓓萨罗丁、比卡鲁胺、BiCNU、博来霉素、硼替佐米、白消安、亚叶酸钙、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、亚叶酸因子、克拉屈滨、可的松、CPT-11、环磷酰胺、阿糖胞苷达克金、更生霉素、阿法达贝泊汀、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、白喉毒素(Diftitox)、DepoCytTM、地塞米松、地醋酸塞米松、地塞米松磷酸钠、地塞米松(Dexasone)、右雷佐生、DHAD、DIC、Diodex、多西他赛、多柔比星、多柔比星脂质体、DroxiaTM、DTIC、EligardTM、EllenceTM、EloxatinTM、表柔比星、依泊亭阿尔法、爱必妥、埃罗替尼、欧文氏菌L-天冬酰胺酶、雌氮芥、依托泊苷、依托泊甙磷酸酯、依维莫司、依西美坦、非格司亭、氟尿苷、氟达拉滨、氟尿嘧啶、氟甲睾酮、氟他胺、亚叶酸、氟维司群、吉非替尼、吉西他滨、吉妥珠单抗奥佐米星、GleevecTM、片、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(Hexadrol)、六甲基三聚氰胺、HMM、Hydrocort氢化可的松、氢化可的松磷酸钠、氢化可的松琥珀酸钠、磷酸氢化可通、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、咪唑羧酰胺、干扰素α、干扰素α-2b(PEG偶联物)、白细胞介素-2、白介素-11、Intron(干扰素α-2b)、伊可替康、异维甲酸、伊沙匹隆、IxempraTM、天冬酰胺酶(Kidrolase)、拉帕替尼、L-天冬酰胺酶、LCR、来那度胺、来曲唑、甲酰四氢叶酸、瘤可宁、LeukineTM、亮丙瑞林、长春新碱、LeustatinTM、脂质体Ara-C、液体罗氮芥、L-PAM、L-沙可来新、Lupron地塞米松(Maxidex)、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、氨甲叶酸、氨甲叶酸钠、甲基强的松龙、丝裂霉素、丝裂霉素-C、米托蒽醌、MTC、MTX、盐酸氮芥、MylocelTM、奈拉滨、NeulastaTM、尼鲁米特、氮芥、奥曲肽、醋酸奥曲肽、OnxalTM、Oprevelkin、奥沙利铂、紫杉醇、紫杉醇蛋白结合、帕米膦酸二钠、帕尼单抗、 PEG干扰素、培加帕加司、培非格司亭、PEG-INTRONTM、PEG-L-天冬酰胺酶、培美曲塞、喷司他丁、苯基丙氨酸芥末、 氢化波尼松、波尼松、甲基苄肼、 具有卡莫司汀植入剂的Prolifeprospan 20雷洛昔芬、利妥昔单抗、(干扰素α-2a)、盐酸红比霉素、善宁沙格司亭、 索拉菲尼、SPRYCELTM、STI-571、链脲霉素、SU11248、舒尼替尼、他莫昔芬、替莫唑胺、西罗莫司脂化物、替尼泊苷、TESPA、沙利多胺、 硫鸟嘌呤、硫鸟嘌呤巯膦酰胺、噻替派、拓扑替康、托瑞米芬、托西莫单抗、曲妥单抗、维甲酸、TrexallTM、TSPA、VCR、VectibixTM、ViadurTM、长春花碱、硫酸长春花碱、Vincasar长春新碱、长春瑞滨、酒石酸长春瑞滨、VLB、VM-26、伏立诺他、VP-16、ZevalinTM、 唑来膦酸、伏立诺他(Zolinza)、
施用途径
可以配制本发明所述的抗体、抗原结合片段、多肽和其他治疗剂、药物和药物组合物,用于多种途径施用,包括但不限于,胃肠外、静脉内、动脉内、肌内、皮下、皮内、瘤内和口服。抗体、抗原结合片段、多肽和其它治疗剂可以配制成流体或固体形式。可以将流体制剂配制成通过注射给人或动物体的选定区域来施用。剂量方案
可以提供抗体、抗原结合片段或多肽的多个剂量。剂量中的一种或多种或每种可伴随着同时或依次施用另一种治疗剂。
多个剂量可以通过预定的时间间隔分开,所述预定时间间隔可以选择为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个月之一。举例来说,剂量可以每7、14、21或28天(加减3、2或1天)施用一次。
与作为治疗剂的IL-2相比,本发明的抗体具有较好的药代动力学。本发明的抗体/片段的优点是体内,例如,在血液或血清中半衰期提高,与IL-2相比,施用抗体/片段的次数较少,和/或试剂的量较少。
试剂盒
在本发明的一些方面中,提供了诸零件形成的试剂盒。在一些实施方案中,试剂盒可具有至少一个具有预定量的抗体、片段、多肽、CAR、细胞或组合物的容器。试剂盒可提供药物或药物组合物形式的抗体、片段、多肽、CAR或细胞,并且可以与用于施用于患者以治疗特定疾病或病症的说明书一起提供。可以配制抗体、片段、多肽、CAR、细胞或组合物以适于注射或输注至肿瘤或血液。
在一些实施方案中,试剂盒还可以包含至少一个具有预定量的另一种治疗剂(例如抗感染剂或化疗剂)的容器。在这样的实施方案中,试剂盒还可以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以同时或分开施用,使得它们为特定疾病或病症提供组合治疗。所述治疗剂也可以配制以便适于注射或输注到肿瘤或血液中。
受试者
待治疗的受试者可以是任何动物或人。受试者优选是哺乳动物,更优选人。受试者可以是非人哺乳动物,但更优选人。受试者可能是男性或女性。受试者可能是病人。受试者可能被诊断为患有需要治疗的疾病或病症,或被怀疑患有这种疾病或病症。
蛋白质表达
适合于在细胞中产生本发明所述的抗体、片段、多肽或CAR的分子生物学技术是本领域众所周知的,例如Sambrook等人,分子克隆:实验手册,纽约:冷泉港出版社,1989(Molecular Cloning:A Laboratory Manual)中所记载的那些。
多肽可以从核苷酸序列表达。核苷酸序列可以包含在存在于细胞中的载体中,或可以整合入细胞的基因组中。
本文所用的“载体”是用作将外源遗传物质转移入细胞的载体的寡核苷酸分子(DNA或RNA)。所述载体可以是用于在细胞中表达所述遗传物质的表达载体。这样的载体可以包括可操作地连接到编码待表达的基因序列的核苷酸序列的启动子序列。载体还可以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从根据本发明的载体表达多肽。合适的载体包括质粒、二元载体、病毒载体和人工染色体(例如酵母人工染色体)。
在本说明书中,术语“可操作地连接”可以包括这种情形,其中所选择的核苷酸序列和调节核苷酸序列(例如启动子和/或增强子)以这样的方式共价连接以将核苷酸序列的表达置于调控序列的影响或控制下(从而形成表达盒)。因此,如果调控序列能够影响核苷酸序列的转录,则调控序列可操作地连接到所选择的核苷酸序列。在合适的情况下,所得到的转录物然后可以翻译成所需的蛋白质或多肽。
适于多肽表达的任何细胞可用于制备根据本发明的肽。所述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。在某些情况下,细胞不是原核细胞,因为一些原核细胞不允许与真核生物相同的翻译后修饰。此外,非常高的表达水平在真核生物中是可能的并且蛋白质可以更容易使用适当的标签从真核生物纯化。还可以使用特异性质粒,其增强蛋白质分泌到培养基中。
产生感兴趣多肽的方法可以涉及经修饰以表达多肽的细胞的培养或发酵。所述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质,空气/氧气和/或生长因子供应。可以通过分离细胞与培养基/发酵液,提取蛋白质内容物,并分离各个蛋白质以分离分泌的多肽来收集分泌的蛋白质。培养、发酵和分离技术是本领域技术人员所熟知的。
生物反应器包括其中可以培养细胞的一个或多个容器。生物反应器中的培养物可以连续发生,反应物连续流入反应器,并从中连续流出培养的细胞。或者,培养物可以分批进行。生物反应器监测和控制环境条件,例如pH、氧气、进入和离开的流速,以及容器内的搅动,以便为被培养的细胞提供最佳条件。
在表达感兴趣的多肽的细胞培养后,优选分离该多肽。可以使用本领域已知用于从细胞培养物分离多肽/蛋白质的任何合适的方法。为了从培养物中分离感兴趣的多肽/蛋白质,可能有必要首先将培养的细胞从含有感兴趣的多肽/蛋白质的培养基中分离出来。如果感兴趣的多肽/蛋白是从细胞分泌的,则可以通过离心从含有分泌的多肽/蛋白质的培养基中分离细胞。如果感兴趣的多肽/蛋白质在细胞内收集,则有必要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物,以及含有培养基和上述感兴趣的多肽/蛋白质的上清液。
然后可能需要从可能含有其它蛋白质和非蛋白质组分的上清液或培养基中分离感兴趣的多肽/蛋白质。从上清液或培养基中分离多肽/蛋白质组分的常见方法是通过沉淀。不同溶解度的多肽/蛋白质在不同浓度的沉淀剂如硫酸铵中沉淀。例如,在低浓度的沉淀剂中,提取水溶性蛋白质。因此,通过添加增加浓度的沉淀剂,可以区分不同溶解度的蛋白质。随后可以使用透析从分离的蛋白质中除去硫酸铵。
用于区分不同多肽/蛋白质的其它方法是本领域已知的,例如离子交换色谱和尺寸色谱。这些可以用作沉淀的替代物,或者可以在沉淀后进行。
一旦已经从培养物中分离出感兴趣的多肽/蛋白质,则可能需要浓缩所述蛋白质。用于浓缩感兴趣的蛋白质的许多方法是本领域已知的,例如超滤或冻干。
序列同一性
用于确定百分比氨基酸或核苷酸序列同一性的比对可以以本领域技术人员已知的各种方式实现,例如使用公知的计算机软件,例如ClustalW 1.82.T-coffee或Megalign(DNASTAR)软件。当使用这样的软件时,优选使用默认参数,例如,对于可空隙罚分和延伸罚分。ClustalW 1.82的默认参数为:蛋白空隙开放罚分=10.0,蛋白空隙延伸罚分=0.2,蛋白矩阵=Gonnet,蛋白/DNA端隙=-1,蛋白/DNA隙距=4。
***
本发明包括所描述的方面和优选特征的组合,除了这种组合是明显不允许的或明确避免的。
本文使用的部分标题仅用于组织目的,不应被解释为限制所描述的主题。
现在将参考附图,通过示例的方式来说明本发明的方面和实施例。其他方面和实施例对于本领域技术人员将是显而易见的。本文中提及的所有文件均通过引用并入本文。
在整个说明书中,包括以下权利要求书,除非上下文另有要求,否则词语“包括”和诸如“包括”和“包含”之类的变体将被理解为意指包含所述整数或步骤或整数或步骤组,但不排除任何其他整数或步骤或整数或步骤组。
必须指出的是,如在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规定。范围可以在本文中表示为“约”一个特定值,和/或“约”另一特定值。当表示这样的范围时,另一个实施例包括从一个特定值和/或到另一特定值。类似地,当值被表示为近似值时,通过使用先行词“约”,可以理解为所述特定值形成另一个实施例。
附图简要说明
现在将参考附图来讨论说明本发明的原理的实施例和实验,其中:
图1.抗IL-2Rβ抗体克隆的轻链可变结构域序列。CDR用下划线表示并分别示出。
图2.抗IL-2Rβ抗体克隆的重链可变结构域序列。CDR用下划线表示并分别示出。
图3.抗γc抗体克隆的轻链可变结构域序列。CDR用下划线表示并分别示出。
图4.抗γc抗体克隆的重链可变结构域序列。CDR用下划线表示并分别示出。
图5.表显示了抗IL-2Rβ抗体克隆的轻链CDR序列。
图6.表显示了抗IL-2Rβ抗体克隆的重链CDR序列。
图7.表显示了抗γc抗体克隆的轻链CDR序列。
图8.表显示了抗γc抗体克隆的重链CDR序列。
图9.表显示了P2C4衍生的抗IL-2Rβ抗体克隆的轻链CDR序列。
图10.表显示了P2C4衍生的抗IL-2Rβ抗体克隆的重链CDR序列。
图11.表显示了P1A3衍生的抗γc抗体克隆的轻链CDR序列。
图12.表显示了P1A3衍生的抗-γc抗体克隆的重链CDR序列。
图13.抗IL-2Rβ抗体克隆P2C4的CH2和CH3结构域序列。
图14.抗-γc抗体克隆P1A3的CH2和CH3结构域序列。
图17.抗IL-2Rβ抗体克隆的核苷酸序列。
图18.抗-γc抗体克隆的核苷酸序列。
图19.双特异性抗IL-2Rβ/γc抗体的示意图。
图20.通过表面等离子体共振分析确定的显示双特异性抗IL-2Rβ/γc抗体与(A)人IL-2Rβ和(B)人γc的结合的传感图。
图21.显示通过流式细胞术测定的双特异性抗IL-2Rβ/γc抗体(A)与表达IL-2Rβ/γc(和对照不表达细胞)IL-2Rβ/γc和(B)PBMC的结合的柱状图。
图22.通过流式细胞术测定,通过用IL-2或双特异性抗IL-2Rβ/γc抗体体外处理NK92细胞,显示诱导STAT5、Akt和ERK介导的信号传导的柱状图。
图23.显示通过流式细胞术测定,响应于用IL-2或双特异性抗IL-2Rβ/γc抗体体外处理不同免疫细胞亚群的STAT5的磷酸化百分比的图。
图24.显示在响应于用双特异性抗IL-2Rβ/γc抗体或仅对IL-2Rβ或γc显示特异性的对照抗体处理时,IL-2依赖性NK92细胞的增殖的图。
图25.显示通过抗IL-2Rβ/γc抗体的结合分析接头长度的结果的图表和示意图。(A)抗体和scFv形式以及接头(以斜体显示的接头)的示意图。(B)显示响应于用包含不同长度接头的双特异性抗-IL-2Rβ/γc抗体处理时NK92细胞的增殖图。(C)图显示响应于用双-scFv形式的双特异性抗-IL-2Rβ/γc处理的NK92细胞的增殖的图,其包含不同长度的接头。
图26.通过流式细胞术测定,通过用IL-2或双特异性抗IL-2Rβ/γc抗体在食蟹猴脾细胞中体外处理诱导STAT5信号传导的柱状图。
图27.显示在重组人IL-2或所示量的双特异性抗IL-2Rβ/γc抗体(Mega2)存在下,培养PBMC 1周后的T细胞数量和比例的图。(A)CD3+细胞,(B)CD4+细胞,(C)CD8+细胞和(D)CD8+与CD4+细胞的比例。
图28.显示在重组人IL-2或所示量的双特异性抗IL-2Rβ/γc抗体(Mega2)存在下,培养PBMC 1周后的Treg百分比的图。
图29.显示在重组人IL-2或所示量的双特异性抗IL-2Rβ/γc抗体(Mega2)存在下,培养PBMC 1周后,CD8+T细胞亚群占CD8+细胞的百分比的图。对于每个亚群,从左到右,数据点是:IL-2 200ng/ml、Mega23ug/ml、Mega21ug/ml、Mega2.3ug/ml、Mega2.3ug/ml和CD3/28。
图30.显示在存在EBV-LCL和重组人IL-2或指定量的双特异性抗IL-2Rβ/γc抗体(Mega2)的情况下,培养来自EBV-血清阳性供体的PBMC后的T细胞数目和比例的图。(A)CD3+细胞,(B)CD4+细胞,(C)CD8+细胞和(D)CD8+与CD4+细胞的比例。
图31.显示在存在EBV-LCL和重组人IL-2或指定量的双特异性抗IL-2Rβ/γc抗体(Mega2)的情况下培养来自EBV-血清阳性供体的PBMC后的T细胞亚群的图。(A)CD8+T细胞亚群占CD8+细胞的百分比。对于每个亚群,从左到右,数据点是:IL-2 200ng/ml、Mega23ug/ml、Mega21ug/ml、Mega2.3ug/ml、Mega2.3ug/ml和CD3/28。(B)CD8+PD1+细胞占CD8+细胞的百分比,和(C)Tregs占CD4+细胞的百分比。
图32.显示在存在EBV-LCL和重组人IL-2或指定量的双特异性抗IL-2Rβ/γc抗体(Mega2)的情况下,培养来自EBV-血清阳性供体的PBMC后的CTL细胞毒性的图。
图33.显示P1A3家族克隆热稳定性的条形图。热处理前后P1A3和突变克隆(A)B4和E9以及(B)B3和E8与γc的结合。显示的是一式两份的平均值±SD。
图34.显示P2C4家族克隆的热稳定性的条形图。热处理前后,P2C4与突变克隆(A)A9、B1、B5、B6、B8、C4、C7、C12、E2、E3、E7、E8、E9、G2、G11、H1、H2和H3,和(B)A4、B12、C1、D10、E6、F8、F11和C1D10、以及IL2-Rβ的结合。显示的是一式两份的平均值±SD。
图35.显示(A)P2C4_FW2单链抗体与IL-2Rβ,以及(B)P1A3_FW2单链抗体与γc的结合的图。
图36.显示对于具有NSGAGTAAA(SEQ ID NO:157)或GGGGSAAA(SEQ IDNO:158)短接头的抗体,双特异性抗体克隆P2C4/P1A3与(A)IL-2Rβ和(B)γc结合的图。
图37.显示双特异性工程抗体克隆与(A)IL-2Rβ和(B)γc的结合的图。
图38.显示通过流式细胞术测量的抗原特异性CD8+T细胞对双特异性抗-IL-2Rβ/γc抗体暴露的体外应答图。(A)CD8+T细胞的双特异性抗IL-2Rβ/γc抗体依赖性扩增。(B)在自体LCL共培养之后,相对于IL-2,暴露于抗体后的CD8:CD4+T细胞比例。*p值<0.05。
图39.显示在(A)抗原特异性或(B)非特异性环境中,通过流式细胞术测量的Treg细胞对双特异性抗IL-2Rβ/γc抗体暴露的体外应答图。*p值<0.05。
图40:在施用抗IL-2Rβ/γc抗体之前和之后,用Luminex分析测定非人灵长类动物的血浆中(A)IFNγ、(B)IL-15、(C)IL-1β、(D)IL-6和(E)TNFα的细胞因子水平的条形图。
图41.通过流式细胞术测量,T细胞亚群对双特异性抗IL-2Rβ/γc抗体注射的体内应答的条形图。(A)T细胞占总白细胞群的比例,(B)Ki-67+阳性CD8+细胞占总CD8+T细胞群体的比例。(C)Ki-67+阳性CD4+细胞占总CD4+T细胞群体的比例。双特异性抗体依赖性扩增通过相对于总白细胞群体的T细胞增加来表示。
图42.通过流式细胞术测量,NK细胞对双特异性抗IL-2Rβ/γc抗体注射的体内应答的条形图。(A)NK细胞占给药前总白细胞总数的比例,(B)Ki-67+阳性NK细胞占总NK细胞总数的比例。
实施例
在以下实施例中,发明人描述了抗IL-2Rβ和抗γc抗体的分离,双特异性抗IL-2Rβ/γc抗体的构建、工程化、体外和体内功能表征。
实施例1:抗人IL-2Rβ和抗人γc抗体的分离
通过体外选择从人抗体噬菌体展示文库中分离抗IL-2Rβ和抗γc抗体。特异性Fab抗体最初通过将重组IL-2Rβ和γc蛋白用作抗原,用ELISA进行鉴定。
实施例2:靶向中等亲和力IL-2Rβ-γc的双特异性抗体的构建
选择在ELISA中显示出强结合的克隆(实施例1),并用于构建基于连接到IgG1主链Fc区的单链可变片段(scFv)的“杵臼”结构的单价双特异性人抗体,如图19所示。
杵臼”结构的形式可防止二价单特异性抗体的同源二聚化和形成。
将LALA突变(由丙氨酸取代野生型重链恒定结构域2中的亮氨酸残基234和235)引入抗体的Fc部分以消除与Fc受体的结合。
scFv结构域和Fc结构域之间的接头大小对构建体的功能没有影响(见实施例6.2和图25)。
双特异性scFv(bis-scFv)形式:
将P1A3和P2C4scFv与接头连接以形成由通过接头连接的两个单链可变结构域组成的双特异性抗体(图25A,右)。测试了不同的接头大小(图25C),并通过测量NK92细胞生长来测试活性。
在没有IL-2的情况下,双scFv可有效维持NK92细胞的增殖。两个单链片段之间的接头大小不影响双特异性化合物活性(图25C)。
实施例3:与IL-2R链结合的分析
通过流式细胞术分析双特异性抗体与IL-2Rβ或γc的结合。
将抗体与预先用编码IL-2Rβ或γc的构建体转染的HEK-293.6E细胞孵育。
用荧光偶联的二抗检测与细胞的结合。使用同种型IgG1作为阴性对照。还测试了对IL-2Rβ或γc和无关靶标具有特异性的双特异性构建体。
显示抗IL-2Rβ/γc抗体结合表达其靶标的细胞(图21A)。
实施例4:IL-2R链的亲和力的分析
使用固定在芯片上的重组IL-2Rβ或γc链在表面等离子共振中测量抗-IL-2Rβ/γc双特异性抗体与受体链的结合/解离,并使各种浓度的抗体流过表面。
抗体对IL-2Rβ或γc链的亲和力非常高,结合非常快且解离非常慢(图20)。
测量双特异性抗IL-2Rβ/γc抗体P2C4/P1A3和其他双特异性抗体的亲和力,如表1所示。
表1:
实施例5:结合到PBMC亚群
对从健康供体分离的PBMC测试双特异性IgG抗IL-2Rβ/γc抗体,以检查其结合哪些细胞亚群。将对照的抗体或同种型IgG加入到PBMC中,并在流式细胞术测定中用荧光偶联的二抗人IgG抗体进行检测。
抗IL-2Rβ/γc双特异性抗体对CD4+或CD8+T细胞没有显示出高结合性。然而,抗体有效地结合CD56+NK细胞,CD19+B细胞和CD14+/CD16+单核细胞(图21B)。
实施例6:抗IL-2Rβ/γc双特异性抗体的活性/IL-2激动作用
6.1信号通路磷酸化
已知IL-2通过STAT5、ERK和Akt途径触发细胞内信号。测试了抗IL-2Rβ/γc双特异性抗体通过这些途径诱导信号的能力。
从血清中剥离IL-2敏感的NK92细胞,然后用IL-2(100U/ml,即)或抗IL-2Rβ/γc抗体(10μg/ml,即)刺激30分钟,并在流式细胞术检测中用荧光抗体检测STAT5、Akt和ERK的磷酸化。
尽管以比IL-2更温和的方式(图22),抗IL-2Rβ/γc抗体诱导STAT5和Akt磷酸化。在该测定中,IL-2Rβ/γc抗体不触发ERK的磷酸化(图22)。
治疗性使用IL-2的最大障碍之一是优先刺激表达高亲和性异源三聚体受体CD25的细胞,例如,调节性T细胞(Treg)、活化的T细胞、活化的B细胞、一些骨髓前体细胞和上皮细胞。
在存在IL-2或抗IL-2Rβ/γc抗体的情况下,通过流式细胞术测量从健康供体获得的Tregs、CD8+T细胞和NK细胞中的STAT5的磷酸化。
少量的IL-2足以激活NK或T细胞,但即使在低水平的IL-2中,Treg也优先被强激活。在NK或CD8+T细胞中施用少于20%的STAT5信号传导途径活化的浓度下,Treg已经显示出100%的活化(图23)。
相比之下,双特异性抗体显示出不同的活化特征,Treg的优先激活较低。在使NK和CD8+T细胞20%激活的浓度下,Treg显示了39至49%的STAT5磷酸化。在NK和CD8+T细胞中活化50%的浓度下,Treg群体仍未完全活化,具有73-78%的STAT5磷酸化(图23)。
6.2IL-2依赖性细胞的增殖
在没有IL-2的情况下用Alamar蓝染料测定NK92细胞的生存能力和生长。
IL-2Rβ/γc抗体能够在没有IL-2的情况下维持NK92细胞的增殖,而仅与IL-2受体的一条链结合的抗体构建体没显示出任何效果(图24)。
为了评估接头的长度是否对抗体的功能有影响,用不同大小接头的抗体进行同样的测定。
NK92细胞的生长不受接头大小的影响(图25B)。图25B中的数据是使用最短和最长的接头(5-23个氨基酸)获得的。
如图25A中示意性表示的,以双特异性抗体形式或双特异性scFv形式分析不同长度的接头,简而言之,将P1A3和P2C4scFv与不同大小的接头连接,并通过测量NK92细胞生长来测试活性。
结果如图25B和25C所示。在不存在IL-2的情况下,双scFv在维持NK92细胞的增殖方面是有效的,并且两个scFv片段之间的接头的大小不影响活性。
6.3与食蟹猴细胞的交叉反应
在非人灵长类动物的细胞上还测试了抗IL-2Rβ/γc抗体。简而言之,将食蟹猴脾细胞在人IL-2或双特异性抗体存在下温育,并测定STAT5的磷酸化。发现抗体与食蟹猴IL-2R具有交叉反应性,并且如同人IL-2一样有效触发STAT5的磷酸化(图26)。
6.4结论
总之,这些数据表明抗IL-2Rβ/γc双特异性抗体对IL-2有一些激动作用,而且这些作用不是高度优先地针对表达CD25的细胞。
实施例7:调节免疫应答:在非特异性刺激环境中控制T细胞扩增
从志愿者供体中分离外周血单核细胞(PBMC),并在重组人IL-2(200ng/ml)、抗IL-2Rβ/γc双特异性抗体(3、1、0.3、0.1或0.03μg/ml)或抗CD3/CD28珠的存在下培养1周作为阳性对照。1周后,通过测量绝对细胞计数来评估细胞扩增;通过FACS测量细胞亚群比例。
7.1T细胞扩增
在相当浓度(IL-2 200ng/ml≈12nM;双特异性抗IL-2Rβ/γc抗体3μg/ml≈20nM)下,抗体触发T细胞增殖的程度低于IL-2(图27A至27C)。双特异性抗体显示对T细胞增殖的剂量依赖性作用(图27A至27D)。在非特异性刺激环境中,与用IL-2培养细胞时相比,在抗IL-2Rβ/γc抗体存在下,CD8:CD4细胞比例没有明显差异(图27D)。
7.2刺激调节性T细胞
调节性T细胞(Treg)表达高亲和力的IL-2受体亚链IL-2Rα。在非特异性刺激环境中,IL-2优先刺激CD3+CD4+T细胞中的调节性T细胞;这种Treg扩增不是由双特异性抗IL-2Rβ/γc抗体触发的(图28)。
7.3刺激效应子与记忆细胞
就记忆性CD8+淋巴细胞而言,双特异性抗IL-2Rβ/γc抗体触发效应子记忆CD8+T细胞亚群的扩增增加,同时与应答IL-2刺激的扩增相比,触发中枢记忆和初始CD8+T细胞亚群的扩增减少(图29)。
实施例8:调节免疫应答:在特异性刺激环境置中控制T细胞扩增
用EBV感染来自EB病毒(EBV)血清反应阳性的志愿者供体的PBMC以产生类淋巴母细胞系(LCL)。将LCL分类并用γ-照射以抑制其随后的增殖。在IL-2、抗IL-2Rβ/γc双特异性抗体或抗CD3/CD28珠(阳性对照)的存在下,将辐照的LCLs以1×10 5个细胞/ml的密度与2×10 6个自体PBMC/ml共培养2周。然后分析细胞的增殖和不同细胞亚群的比例。
使用用于颗粒酶B和半胱天冬酶8的荧光肽底物进行细胞毒性杀伤实验。扩增的T细胞与活的LCL以2:1的比例共同温育1小时。通过流式细胞术分析肽-荧光阳性细胞来测定杀伤,这表明细胞正在经历CTL诱导的程序性细胞死亡。
8.1T细胞扩增
即使在低浓度下,双特异性抗体触发T细胞的扩增。抗-IL-2Rβ/γc双特异性抗体介导的T细胞扩增略高于用IL-2刺激后观察到的扩增(图30A)。虽然抗体不显著影响CD4+T细胞的数量(图30B),但是该抗体比IL-2引起的CD8+T细胞数量增加的程度更大(图30C),因此增加了CD8:CD4细胞比例(图30D)。
8.2对T细胞亚群的影响
与用IL-2刺激相比,在最高浓度(1μg/ml)下,抗IL-2Rβ/γc抗体有利于效应CD8+T细胞相对于CD8+记忆细胞的扩增(图31A)。与用IL-2刺激相比,抗-IL-2Rβ/γc抗体也触发CD8+PD-1+亚群的增加(图31B),同时降低Treg的比例(图31C)。
8.3细胞毒性T淋巴细胞介导的杀伤
抗IL-2Rβ/γc双特异性抗体能够引起CTL细胞毒性。在相当的摩尔浓度(对于IL-2为12nM(200ng/ml),对于抗体为7nM(1μg/mL))下,抗体介导的细胞毒性低于由IL-2触发的细胞毒性(图32)。
8.4结论
总之,数据表明双特异性抗IL-2Rβ/γc抗体触发的作用机制与IL-2不同。抗体优先引起效应CD8+T细胞的扩增。该抗体可刺激细胞毒性T细胞,但不像IL-2那样优先刺激Treg。
实施例9:改造序列以提高稳定性
构建双特异性抗体时最大的挑战之一是异源构建体的稳定性。与单特异性IgG不同,本发明的双特异性抗IL-2Rβ/γc抗体是两种不同的轻/重链对的人工组装。
为了提高构建体的通常的稳定性,工程化原始的抗体克隆P2C4和P1A3以增加它们的热稳定性。
9.1耐高温克隆
从亲本克隆P2C4和P1A3构建随机诱变的克隆文库,并在两轮淘选中筛选突变体与各个靶标的结合,随后进行ELISA。然后将粘合剂加热至55℃。对加热后仍然结合的突变体进行测序,鉴定出单(unique)克隆。
通过在ELISA中测量与它们各自的靶标,γc(图33A和33B)或IL-2Rβ(图34A和34B)的结合,在45℃和65℃之间加热4小时后评估克隆的热稳定性,突变克隆显示比亲本克隆的热稳定性更高。
9.2高度稳定框架的植入
为了进一步提高抗体的稳定性,将克隆移植到已知高度稳定的抗体的框架中。
将P2C4和P1A3移植到到已知具有高稳定性的抗体框架中。进行ELISA实验以确保新克隆保有与IL-2Rβ和γc结合的能力。
P2C4_FW2和P1A3_FW2分别显示对IL-2Rβ和γc的剂量依赖性结合特性(图35A和35B)。
实施例10:新双特异性构建体与IL-2Rβ/γc的结合
10.1可变和恒定域之间的短接头
制备双特异性抗体构建体,包括scFv和恒定结构域(抗体形式:VH结构域-接头-VL结构域-短接头-铰链-CH2结构域(+LALA)-H3结构域(+杵臼+半胱氨酸)):NSGAGTAAA(SEQID NO:157)或GGGGSAAA:158)之间的以下短接头的一种(。
产生具有NSGAGTAAA(SEQ ID NO:157)或GGGGSAAA(SEQ ID NO:158)短接头的双特异性构建体,并通过ELISA测试与IL-2Rβ和γc的结合。
发现双特异性抗体以类似的亲和力结合,而与短接头的特性无关(图36A和36B)。
用新序列构建双特异性抗体,通过ELISA评估IL-2Rβ或IL-2Rγc的结合。发现,新构建体比亲本双特异性抗体与IL-2R结合的亲和力相似或更好(图37A和37B)。
实施例11:T细胞扩增和极化的影响
使用T细胞进行测定,以测量抗IL-2Rβ/γc双特异性抗体对体外T细胞扩增的影响及其对抗原特异性和非特异性定性极化和亚群特异性的影响。用来自EBV阳性个体的外周血来产生EBV转化的类淋巴母细胞B细胞系(LCL)和EBV特异性CTL细胞系。
简而言之,为了产生LCL,在环孢菌素和EBV存在下,将PBMC培养1周,并在含有环孢菌素但不含EBV的新鲜培养基中再培养2周。培养后,将细胞转移到G-Rex柱中并监测生长。为了产生CTL,照射LCL作为CTL的抗原来源。在效应子与刺激物的比例为40:1下,将PBMC与LCL共培养。通过加入IL-2、抗IL-2Rβ/γc双特异性抗体或CD3/28珠来刺激细胞。
7天后,细胞经历培养基的变化和其他刺激。第10天,通过流式细胞术分析细胞的淋巴细胞扩增和表型。
与应答IL-2刺激的扩增相比,发现添加双特异性抗体导致抗原特异性CD8+T细胞扩增的显著增加。(图38A)。此外,体外培养显示抗体刺激后CD8:CD4比例提高(图38B)。
在抗原特异性(自体LCL共培养)和非特异性(抗CD3/CD28微珠)环境下,然后与响应于IL-2刺激的Treg的扩增相比较,测定双特异性抗体对调节性T细胞(Treg)扩增的影响。既在非特异性(图39A),又在抗原特异性刺激环境(图39B)下,与响应于IL-2的Treg扩增相比,双特异性抗体的添加导致Treg的扩增显著降低。
实施例12:非人灵长类动物的体内数据
在食蟹猴中建立剂量递增实验,为了测量静脉内(iv)注射抗IL-2Rβ/γc双特异性抗体的作用,其促进T细胞和NK细胞增殖的能力,以及其通过“细胞因子风暴”的潜在毒性。
三只猕猴通过股动脉静脉内施用单剂量的抗IL-2Rβ/γc抗体;猕猴A施用1mg/kg,猕猴B施用5mg/kg,猕猴C施用10mg/kg。抗体注射前和注射后1小时、24小时、72小时和120小时收集血液。
兽医体格检查显示一般外表、粘膜、心血管、呼吸系统、皮肤、消化系统、肌肉骨骼、神经系统、泌尿生殖系统、听觉或眼系统无异常。动物没有出现发热或有抑郁症的临床表现。一只动物(猕猴B)在研究过程中表现出轻微的体重减轻。动物没有显示出与IL-2施用相关的明显的毒性迹象(PMID:1418698和8454416)。
与这些观察结果一致,细胞因子分析显示,注射后炎症介质仅有轻度增加(图40A至40E)。流式细胞术分析显示CD4+和CD8+T细胞群明显增殖(图41A至41C)。
也观察到NK细胞增殖对抗体处理的响应(图42A和42B)。应该注意的是,与IL-2所需的连续输注或重复剂量相比,单次剂量的抗体后可观察到这种扩增,这表明抗IL-2Rβ/γc双特异性抗体的半衰期比IL-2更长。
序列表
<110> 新加坡科技研究局
<120> IL2Rβ/通用γ 链抗体
<130> RIC/FP7218530
<140> PCT/EP2016/068780
<141> 2016-08-05
<150> SG 10201506227V
<151> 2015-08-06
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Ile Ile Tyr Asp Ile Asn Asn Arg Pro Ser Gly Ile Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Asp Asn Met Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Tyr Thr Ser Ser
85 90 95
Asp Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr
100 105
<210> 18
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LC-CDR1
<400> 18
Thr Gly Thr Ser Ser Asp Ile Gly Asp Tyr Asp Phe Val Ser
1 5 10
<210> 19
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 19
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Ala Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly His Tyr
20 25 30
Asp Phe Val Ser Trp Tyr Gln Gln His Pro Gly Thr Ala Pro Lys Leu
35 40 45
Ile Ile Tyr Asp Asn Asn Asn Arg Pro Ser Gly Ile Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Asp Asn Met Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Tyr Thr Ser Ser
85 90 95
Asp Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr
100 105
<210> 20
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LC-CDR2
<400> 20
Asp Asn Asn Asn Arg Pro Ser
1 5
<210> 21
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 21
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly His Tyr
20 25 30
Asp Phe Val Ser Trp Tyr Gln Gln His Pro Gly Thr Ala Pro Lys Leu
35 40 45
Ile Ile Tyr Asp Ile Asn Asn Arg Pro Ser Gly Ile Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Asp Asn Met Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Tyr Thr Ser Ser
85 90 95
Asp Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr
100 105
<210> 22
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LC-CDR3
<400> 22
Ser Ala Tyr Thr Ser Ser Asp Thr Val Val
1 5 10
<210> 23
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 23
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Ala Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly His Tyr
20 25 30
Asp Phe Val Ser Trp Tyr Gln Gln His Pro Gly Thr Ala Pro Lys Leu
35 40 45
Ile Ile Tyr Asp Ile Asn Asn Arg Pro Ser Gly Ile Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Asp Asn Met Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Tyr Thr Ser Ser
85 90 95
Asp Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr
100 105
<210> 24
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 24
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Ala Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly His Tyr
20 25 30
Asp Phe Ile Ser Trp Tyr Gln Gln His Pro Gly Thr Ala Pro Lys Leu
35 40 45
Ile Ile Tyr Asp Phe Asn Asn Arg Pro Ser Gly Ile Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Asp Asn Met Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Tyr Thr Ser Ser
85 90 95
Asp Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr
100 105
<210> 25
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LC-CDR1
<400> 25
Thr Gly Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Ile Ser
1 5 10
<210> 26
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LC-CDR2
<400> 26
Asp Phe Asn Asn Arg Pro Ser
1 5
<210> 27
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 27
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Ala Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly His Tyr
20 25 30
Asp Phe Val Ser Trp Tyr Gln Gln His Pro Gly Thr Ala Pro Lys Leu
35 40 45
Ile Ile Tyr Asp Asn Asn Asn Arg Pro Ser Gly Ile Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Asp Asn Met Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Tyr Thr Ser Ser
85 90 95
Asp Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr
100 105
<210> 28
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 28
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Val Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly His Tyr
20 25 30
Asp Phe Val Ser Trp Tyr Gln Gln His Pro Gly Thr Ala Pro Lys Leu
35 40 45
Ile Ile Tyr Asp Ile Asn Asn Arg Pro Ser Gly Ile Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Asp Asn Met Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Tyr Thr Ser Ser
85 90 95
Asp Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr
100 105
<210> 29
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 29
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Ala Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Asp Tyr
20 25 30
Asp Phe Val Ser Trp Tyr Gln Gln His Pro Gly Thr Ala Pro Lys Leu
35 40 45
Ile Ile Tyr Asp Ile Asn Asn Arg Pro Ser Gly Ile Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Asp Asn Met Ala Ser Leu Ile Ile Ser Gly Leu
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Tyr Thr Ser Ser
85 90 95
Asp Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr
100 105
<210> 30
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 30
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Ala Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly His Tyr
20 25 30
Asp Phe Val Ser Trp Tyr Gln Gln His Pro Gly Thr Ala Pro Lys Leu
35 40 45
Ile Ile Tyr Asp Ile Asn Asn Arg Pro Ser Gly Ile Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Asp Asp Met Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Tyr Thr Ser Ser
85 90 95
Asp Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr
100 105
<210> 31
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 31
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Ala Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly His Tyr
20 25 30
Asp Phe Val Ser Trp Tyr Gln Gln His Pro Gly Thr Ala Pro Lys Leu
35 40 45
Ile Ile Tyr Asp Ile Asn Asn Arg Ala Ser Gly Ile Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Asp Asn Met Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Tyr Thr Ser Ser
85 90 95
Asp Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr
100 105
<210> 32
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LC-CDR2
<400> 32
Asp Ile Asn Asn Arg Ala Ser
1 5
<210> 33
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 33
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Asn Pro Gly Gln
1 5 10 15
Ser Ile Ala Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly His Tyr
20 25 30
Asp Phe Val Ser Trp Tyr Gln Gln His Pro Gly Thr Ala Pro Lys Leu
35 40 45
Ile Ile Tyr Asp Ile Asn Asn Arg Pro Ser Gly Ile Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Asp Asn Met Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Tyr Thr Ser Ser
85 90 95
Asp Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr
100 105
<210> 34
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 34
Gln Ser Thr Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly His Tyr
20 25 30
Asp Phe Val Ser Trp Tyr Gln Gln His Pro Gly Thr Ala Pro Lys Leu
35 40 45
Ile Ile Tyr Asp Ile Asn Asn Arg Pro Ser Gly Ile Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Asp Asn Met Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Tyr Thr Ser Ser
85 90 95
Asp Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr
100 105
<210> 35
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 35
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 36
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR1
<400> 36
Asn Tyr Tyr Met His
1 5
<210> 37
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR2
<400> 37
Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe Gln
1 5 10 15
Gly
<210> 38
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR3
<400> 38
Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr
1 5 10
<210> 39
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 39
Glu Val Gln Leu Val Gln Ser Gly Thr 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 Thr Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Gly Asn Gly Asn Thr Lys Tyr Ser Gln Asn Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Leu Gly Gln Leu Glu Arg Leu Tyr Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 40
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR1
<400> 40
Thr Tyr Ala Met His
1 5
<210> 41
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR2
<400> 41
Trp Ile Asn Thr Gly Asn Gly Asn Thr Lys Tyr Ser Gln Asn Phe Gln
1 5 10 15
Gly
<210> 42
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR3
<400> 42
Asp Leu Gly Gln Leu Glu Arg Leu Tyr Phe Trp
1 5 10
<210> 43
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 43
His Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Leu Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 44
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR1
<400> 44
Ser Tyr Ala Met Ser
1 5
<210> 45
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR2
<400> 45
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 46
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR3
<400> 46
Asp Leu Gly Asp Tyr
1 5
<210> 47
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 47
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ser Ser Ser Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met
100 105 110
Val Thr Val Ser Ser
115
<210> 48
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR1
<400> 48
Gly Tyr Tyr Trp Ser
1 5
<210> 49
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR2
<400> 49
Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 50
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR3
<400> 50
Ser Ser Ser Gly Asp Ala Phe Asp
1 5
<210> 51
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 51
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Asn Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 52
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR3
<400> 52
Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Asn
1 5 10
<210> 53
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 53
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 54
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR1
<400> 54
Asn Tyr Tyr Ile His
1 5
<210> 55
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 55
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Pro Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 56
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 56
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Thr Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 57
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 57
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Asn Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Asn
115 120
<210> 58
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 58
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Glu Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Ile Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 59
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 59
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Asn Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 60
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 60
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Pro Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 61
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 61
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 62
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 62
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 63
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 63
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Asn Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 64
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 64
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Asn Val Ser Ser
115 120
<210> 65
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 65
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 66
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 66
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Thr Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 67
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 67
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 68
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LC-CDR1
<400> 68
Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp
1 5 10 15
<210> 69
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LC-CDR2
<400> 69
Leu Gly Ser Asn Arg Asp Ser
1 5
<210> 70
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LC-CDR3
<400> 70
Met Gln Gly Thr His Trp Pro Trp Thr
1 5
<210> 71
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 71
Ser Tyr Glu Leu Thr Gln Pro Pro Ser Met Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Arg Ile Thr Cys Ser Gly Asp Ala Leu Pro Lys Gln Phe Ala
20 25 30
Phe Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Lys Asp Thr Glu Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Thr Thr Val Thr Leu Thr Ile Thr Gly Val Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Pro Asp Ser Ser Gly Thr Val
85 90 95
Glu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 72
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LC-CDR1
<400> 72
Ser Gly Asp Ala Leu Pro Lys Gln Phe Ala Phe
1 5 10
<210> 73
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LC-CDR2
<400> 73
Lys Asp Thr Glu Arg Pro Ser
1 5
<210> 74
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LC-CDR3
<400> 74
Gln Ser Pro Asp Ser Ser Gly Thr Val Glu Val
1 5 10
<210> 75
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 75
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 76
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 76
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Thr Ser Pro Gly Gly Tyr Ser Gly Gly Tyr Phe Gln His Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 77
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR3
<400> 77
Ser Pro Gly Gly Tyr Ser Gly Gly Tyr Phe Gln His
1 5 10
<210> 78
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 78
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 Thr Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Ser 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 Gly Asp Ile Leu Thr Gly Tyr Ala Leu Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 79
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR1
<400> 79
Ser Ser Ser Tyr Tyr Trp Gly
1 5
<210> 80
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR2
<400> 80
Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys
1 5 10 15
<210> 81
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR3
<400> 81
Asp Ile Leu Thr Gly Tyr Ala Leu Asp Tyr
1 5 10
<210> 82
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 82
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Phe Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Thr Ser Pro Gly Gly Tyr Ser Gly Gly Tyr Phe Gln His Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 83
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR2
<400> 83
Glu Ile Asn His Phe Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 84
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 84
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Met Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Phe Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Thr Ser Pro Gly Gly Tyr Ser Gly Gly Tyr Phe Gln His Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 85
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LC-CDR1
<220>
<221> VARIANT
<222> (9)..(9)
<223> Xaa is either his or asp
<220>
<221> VARIANT
<222> (13)..(13)
<223> Xaa is either val or ile
<400> 85
Thr Gly Thr Ser Ser Asp Ile Gly Xaa Tyr Asp Phe Xaa Ser
1 5 10
<210> 86
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LC-CDR2
<220>
<221> VARIANT
<222> (2)..(2)
<223> Xaa is either ile, asn or phe
<220>
<221> VARIANT
<222> (6)..(6)
<223> Xaa is either pro or ala
<400> 86
Asp Xaa Asn Asn Arg Xaa Ser
1 5
<210> 87
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LC-CDR3
<220>
<221> VARIANT
<222> (9)..(9)
<223> Xaa is either leu or val
<400> 87
Ser Ala Tyr Thr Ser Ser Asp Thr Xaa Val
1 5 10
<210> 88
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR1
<220>
<221> VARIANT
<222> (4)..(4)
<223> Xaa is either met or ile
<400> 88
Asn Tyr Tyr Xaa His
1 5
<210> 89
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR3
<220>
<221> VARIANT
<222> (12)..(12)
<223> Xaa is either tyr or asn
<400> 89
Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Xaa
1 5 10
<210> 90
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HC-CDR2
<220>
<221> VARIANT
<222> (5)..(5)
<223> Xaa is either ser or phe
<400> 90
Glu Ile Asn His Xaa Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 91
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 91
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
1 5 10 15
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
20 25 30
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
35 40 45
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
50 55 60
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
65 70 75 80
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
85 90 95
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
100 105 110
Lys
<210> 92
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 92
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp
1 5 10 15
Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
100 105
<210> 93
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 93
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
1 5 10 15
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
20 25 30
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
35 40 45
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
50 55 60
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
65 70 75 80
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
85 90 95
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
100 105 110
Lys
<210> 94
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 94
Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp
1 5 10 15
Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Cys Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
65 70 75 80
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
85 90 95
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
100 105
<210> 95
<211> 480
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 95
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Leu Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Asn Ser Gly Ala Gly Thr Ala Ala Ala Thr
245 250 255
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
260 265 270
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
275 280 285
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
290 295 300
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
305 310 315 320
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
325 330 335
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
340 345 350
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
355 360 365
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
370 375 380
Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys
385 390 395 400
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
405 410 415
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
420 425 430
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
435 440 445
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
450 455 460
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475 480
<210> 96
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 96
Glu Val Gln Leu Val Gln Ser Gly Thr 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 Thr Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Gly Asn Gly Asn Thr Lys Tyr Ser Gln Asn Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Leu Gly Gln Leu Glu Arg Leu Tyr Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Thr
130 135 140
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Leu Ser Cys Arg Ala Gly
145 150 155 160
Gln Ala Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
165 170 175
Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Asn Leu Glu Ser Gly Val
180 185 190
Pro Ser Arg Phe Ser Gly Gly Gly Ser Gly Ala Glu Phe Thr Leu Thr
195 200 205
Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
210 215 220
Tyr Gln Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
225 230 235 240
Arg
<210> 97
<211> 236
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 97
His Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Leu Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
130 135 140
Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Gly Asn
145 150 155 160
Tyr Leu Asn Trp Tyr Gln Leu Lys Pro Gly Lys Ala Pro Lys Leu Leu
165 170 175
Ile Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser
180 185 190
Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln
195 200 205
Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Leu Tyr Asp Tyr Pro
210 215 220
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
225 230 235
<210> 98
<211> 242
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 98
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ser Ser Ser Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asn Phe Met Leu Thr Gln Pro His Ser Val Ser Glu
130 135 140
Ser Pro Gly Lys Thr Val Thr Ile Ser Cys Thr Arg Ser Ser Gly Ser
145 150 155 160
Ile Ala Ser Asn Tyr Val Gln Trp Tyr Gln Gln Arg Pro Gly Ser Ser
165 170 175
Pro Thr Thr Val Ile Phe Asp Asp Asn Gln Arg Pro Thr Gly Val Pro
180 185 190
Asp Arg Phe Ser Ala Ala Ile Asp Thr Ser Ser Ser Ser Ala Ser Leu
195 200 205
Thr Ile Ser Gly Leu Thr Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln
210 215 220
Ser Ser His Ser Thr Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr
225 230 235 240
Val Leu
<210> 99
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 99
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly Asp Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Leu Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 100
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 100
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Asn Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 101
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 101
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Asn Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Leu Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 102
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 102
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 103
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 103
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Pro Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 104
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 104
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Pro Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 105
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 105
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Thr Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Ile Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Phe Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Leu Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 106
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 106
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Pro Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly Asp Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Leu Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 107
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 107
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Asn Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 108
<211> 253
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 108
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Val Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His
245 250
<210> 109
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 109
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Asn Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Asn Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 110
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 110
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 111
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 111
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Glu Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Ile Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 112
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 112
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Asn Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 113
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 113
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly Asp Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Ile Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Leu Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 114
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 114
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asp Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 115
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 115
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Pro Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 116
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 116
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Ala Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 117
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 117
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Asn Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 118
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 118
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Thr Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 119
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 119
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Val Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 120
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 120
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Asn Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 121
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 121
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Asn Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 122
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 122
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 123
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 123
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Thr Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ala Ala Ala His His His His His His
245 250 255
<210> 124
<211> 482
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 124
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Thr Ser Pro Gly Gly Tyr Ser Gly Gly Tyr Phe Gln His Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Ser Pro Leu
130 135 140
Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr
165 170 175
Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser
180 185 190
Asn Arg Asp Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly
210 215 220
Val Tyr Tyr Cys Met Gln Gly Thr His Trp Pro Trp Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Val Glu Ile Lys Asn Ser Gly Ala Gly Thr Ala Ala Ala
245 250 255
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
260 265 270
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
275 280 285
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
290 295 300
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
305 310 315 320
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
325 330 335
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
340 345 350
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
355 360 365
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
370 375 380
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser
385 390 395 400
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
405 410 415
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
420 425 430
Asp Ser Asp Gly Ser Phe Phe Leu Cys Val Ser Lys Leu Thr Val Asp
435 440 445
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
450 455 460
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
465 470 475 480
Gly Lys
<210> 125
<211> 243
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 125
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 Thr Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Ser 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 Gly Asp Ile Leu Thr Gly Tyr Ala Leu Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu Thr Gln Pro Pro Ser
130 135 140
Met Ser Val Ser Pro Gly Gln Thr Ala Arg Ile Thr Cys Ser Gly Asp
145 150 155 160
Ala Leu Pro Lys Gln Phe Ala Phe Trp Tyr Gln Gln Lys Pro Gly Gln
165 170 175
Ala Pro Val Leu Val Ile Tyr Lys Asp Thr Glu Arg Pro Ser Gly Ile
180 185 190
Pro Glu Arg Phe Ser Gly Ser Ser Ser Gly Thr Thr Val Thr Leu Thr
195 200 205
Ile Thr Gly Val Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser
210 215 220
Pro Asp Ser Ser Gly Thr Val Glu Val Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Thr Val Leu
<210> 126
<211> 256
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 126
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Phe Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Thr Ser Pro Gly Gly Tyr Ser Gly Gly Tyr Phe Gln His Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Ser Pro Leu
130 135 140
Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr
165 170 175
Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser
180 185 190
Asn Arg Asp Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly
210 215 220
Val Tyr Tyr Cys Met Gln Gly Thr His Trp Pro Trp Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Val Glu Ile Lys Ala Ala Ala His His His His His His
245 250 255
<210> 127
<211> 256
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 127
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Phe Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Thr Ser Pro Gly Gly Tyr Ser Gly Gly Tyr Phe Gln His Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Ser Pro Leu
130 135 140
Ser Leu Pro Val Thr Pro Gly Glu Ser Val Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr
165 170 175
Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser
180 185 190
Asn Arg Asp Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly
210 215 220
Val Tyr Tyr Cys Met Gln Gly Thr His Trp Pro Trp Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Val Glu Ile Lys Ala Ala Ala His His His His His His
245 250 255
<210> 128
<211> 256
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 128
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Met Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Phe Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Thr Ser Pro Gly Gly Tyr Ser Gly Gly Tyr Phe Gln His Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Ser Pro Leu
130 135 140
Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr
165 170 175
Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser
180 185 190
Asn Arg Asp Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly
210 215 220
Val Tyr Tyr Cys Met Gln Gly Thr His Trp Pro Trp Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Val Glu Ile Lys Ala Ala Ala His His His His His His
245 250 255
<210> 129
<211> 255
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 129
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Phe Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Thr Ser Pro Gly Gly Tyr Ser Gly Gly Tyr Phe Gln His Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Glu Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Ser Pro Leu
130 135 140
Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr
165 170 175
Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser
180 185 190
Asn Arg Asp Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly
210 215 220
Val Tyr Tyr Cys Met Gln Gly Thr His Trp Pro Trp Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Val Glu Ile Lys Ala Ala Ala His His His His His
245 250 255
<210> 130
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P2C4 Fab 轻链 ntd (VL, 连接, CL)
<400> 130
cagtctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcgccatt 60
tcctgcactg gaaccagcag tgacattggt cattatgact ttgtctcctg gtaccaacag 120
cacccaggca cagcccccaa actcataatt tatgatatca ataatcggcc ctcagggatt 180
tctaatcgct tctctggctc caagtctgac aatatggcct ccctgaccat ctctgggctc 240
cagcctgagg acgaggctga ttattactgc agtgcatata caagcagcga cactctggtc 300
ttcggcggag ggaccaagtt gaccgtcctc agtcagccca aggctgcccc ctcggtcact 360
ctgttcccac cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata 420
agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag ccccgtcaag 480
gcgggagtgg agaccaccac accctccaaa caaagcaaca acaagtacgc ggccagcagc 540
tacctgagcc tgacgcctga gcagtggaag tcccacaaaa gctacagctg ccaggtcacg 600
catgaaggga gcaccgtgga gaagacagtg gcccctacag aatgttca 648
<210> 131
<211> 672
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P2C4 Fab 重链ntd (VH, 连接, CH)
<400> 131
gaggtccagc tggtacagtc tggggctgag gtgaagaagc ctgggtcctc agtgaaggtt 60
tcctgcaagg catctggata caccttcacc aactactata tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggggca atcatgccta gtcgtggtgg cacaagttac 180
ccacagaagt tccagggcag agtcaccatg accggggaca cgtccacgag cacagtctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaggggag 300
tattactatg atagtagtgg ttattactac tggggccagg gcaccctggt caccgtctca 360
agcgcctcca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420
gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480
tcgtggaact caggcgccct gaccagcggc gtccacacct tcccggctgt cctacagtcc 540
tcaggactct actccctcag cagcgtagtg accgtgccct ccagcagctt gggcacccag 600
acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660
cccaaatctt gt 672
<210> 132
<211> 1440
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P2C4 scFv ntd (具有节修饰的scFv 和 Fc)
<400> 132
gaagtgcagc tggtgcagag cggggcagaa gtgaaaaagc ctgggtcaag cgtgaaggtc 60
tcctgtaaag caagcggata cacattcaca aactactata tgcactgggt gcggcaggcc 120
cccggacagg gcctggagtg gatgggcgct atcatgcctt cccgaggcgg gacttcttac 180
ccacagaagt tccagggaag agtgaccatg acaggcgaca ctagcacctc cacagtctat 240
atggagctga gcagcctgag gagcgaagac actgccgtgt actattgcgc tcgcggagaa 300
tactattacg attctagtgg ctattactat tgggggcagg gaacactggt gactgtctca 360
agcggaggag gaggaagtgg cggaggaggc tccggaggag gcgggtctca gagtgcactg 420
acccagccag catcagtgag cggcagcccc ggccagtcta tcgcaattag ttgtactggg 480
acctcctctg acatcggaca ctacgatttc gtctcttggt atcagcagca ccccggcacc 540
gctcctaagc tgatcatcta cgacatcaac aatcggccca gcggcatttc caacagattt 600
tctgggagta aatcagataa tatggcctca ctgacaatta gcggcctcca gcctgaggac 660
gaagctgatt actattgctc cgcatacact agttcagata ccctggtgtt tggaggcggg 720
accaaactga cagtcctgaa cagcggcgcg ggcaccgcgg ccgcgactca cacatgccca 780
ccgtgcccag cacctgaagc cgcgggggga ccgtcagtct tcctcttccc cccaaaaccc 840
aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 900
cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 960
aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 1020
gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 1080
ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 1140
gtgtacaccc tgcccccatg ccgggatgag ctgaccaaga accaggtcag cctgtggtgc 1200
ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 1260
gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 1320
agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 1380
atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 1440
<210> 133
<211> 642
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P2H7 Fab 轻链 ntd (VL, 连接, CL)
<400> 133
gacatccaga tgacccagtc tccttccaca ttgtctgcat ctgtaggaga cagagtcaca 60
ctctcttgcc gggccggtca ggctattagt agttggttgg cctggtatca acagaaacca 120
ggtaaagccc caaagcttct gatctataag gcatctaatt tagaaagtgg agtcccatca 180
aggttcagcg gcggtggatc tggggcagaa ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccaacag tatcagagct acccttacac ttttggccag 300
gggaccaagc tggagatcag 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> 134
<211> 666
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P2H7 Fab 重链ntd (VH, 连接, CH)
<400> 134
gaggtgcagc tggtgcagtc tgggactgag gtgaagaagc ctggggcctc agtgaaggtt 60
tcctgcaagg cttctggata caccttcact acctatgcta tgcattgggt gcgccaggcc 120
cccggacaaa gccttgagtg gatgggatgg atcaacactg gcaatggtaa cacaaaatat 180
tcacagaact tccagggcag agtcaccatg accagggaca cgtccatcag cacagcctac 240
atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagatctc 300
gggcaactgg aacgactcta cttctggggc cagggcaccc tggtcaccgt ctcaagcgcc 360
tccaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtccac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt agtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 660
tcttgt 666
<210> 135
<211> 1428
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P2H7 scFv ntd (具有节修饰的scFv 和Fc)
<400> 135
gaggtgcagc tggtgcagtc tgggactgag gtgaagaagc ctggggcctc agtgaaggtt 60
tcctgcaagg cttctggata caccttcact acctatgcta tgcattgggt gcgccaggcc 120
cccggacaaa gccttgagtg gatgggatgg atcaacactg gcaatggtaa cacaaaatat 180
tcacagaact tccagggcag agtcaccatg accagggaca cgtccatcag cacagcctac 240
atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagatctc 300
gggcaactgg aacgactcta cttctggggc cagggcaccc tggtcaccgt ctcaagcgga 360
ggaggaggat ctggcggagg aggcagtgga ggaggagggt cacttgacat ccagatgacc 420
cagtctcctt ccacattgtc tgcatctgta ggagacagag tcacactctc ttgccgggcc 480
ggtcaggcta ttagtagttg gttggcctgg tatcaacaga aaccaggtaa agccccaaag 540
cttctgatct ataaggcatc taatttagaa agtggagtcc catcaaggtt cagcggcggt 600
ggatctgggg cagaattcac tctcaccatc agcagcctgc agcctgatga ttttgcaact 660
tattactgcc aacagtatca gagctaccct tacacttttg gccaggggac caagctggag 720
atcagaaaca gcggcgcggg caccgcggcc gcgactcaca catgcccacc gtgcccagca 780
cctgaagccg cggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 840
atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 900
gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 960
cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 1020
gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1080
atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 1140
cccccatgcc gggatgagct gaccaagaac caggtcagcc tgtggtgcct ggtcaaaggc 1200
ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1260
aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 1320
gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcatgaggct 1380
ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa 1428
<210> 136
<211> 642
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P2D12 Fab 轻链 ntd (VL, 连接, CL)
<400> 136
gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc aggcgagtca ggacattggc aactatttaa attggtatca gcttaaacca 120
gggaaagccc ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180
aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240
gaagatattg caacatatta ctgtctacaa ctttatgatt accccctcac tttcggcgga 300
gggaccaagg 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> 137
<211> 651
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P2D12 Fab 重链ntd (VH, 连接, CH)
<400> 137
cacgtgcagc tggtggagac tgggggaggc ttggtgcagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180
gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gagagatctc 300
ggggattatt ggggccaggg aaccctggtc accgtctcaa gcgcctccac caagggccca 360
tcggtcttcc ccctggcacc ctcctccaag agcacctctg ggggcacagc ggccctgggc 420
tgcctggtca aggactactt ccccgaaccg gtgacggtgt cgtggaactc aggcgccctg 480
accagcggcg tccacacctt cccggctgtc ctacagtcct caggactcta ctccctcagc 540
agcgtagtga ccgtgccctc cagcagcttg ggcacccaga cctacatctg caacgtgaat 600
cacaagccca gcaacaccaa ggtggacaag aaagttgagc ccaaatcttg t 651
<210> 138
<211> 1452
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P2D12 scFv ntd (具有节修饰的scFv 和Fc)
<400> 138
caggtccagc tgcaggagtc cgggccaggg ctggtgaaac caagcgaaac actgagtctg 60
acatgtaccg tgagtggggg gtccattaac aatagtaact actattggtc atggatcaga 120
cagagccctg gaagaggcct ggagtggatc ggcgggatct acttcagcgg caccacatac 180
tataacccat cactgcagag ccgggtgact atctccattg acacctctaa gaatcagttc 240
agcctgaagc tgagcagcgt gaccgccgct gatacagcca tctactattg cgtccggcag 300
atgaattact atcacctggg ctctagtgtg gggttcgacc cctggggaca gggagcactg 360
gccaccgtgt caagcgtctc ctctggagga ggaggcagcg gcggaggagg ctctggagga 420
ggcgggagtg atgtggtcat gacacagagc ccagctactc tgtctgtgag tcccggcgaa 480
agggccacac tgagctgtcg cgcttcacag agcgtcagtt caaacctggc atggtaccag 540
cagaagccag gacaggcacc ttccctgctg atctatgagg cttctacacg agcaactggc 600
attcctgcta gattctccgg ctctgggagt ggaaccgact ttactctgac catcagctcc 660
ctgcagagcg aagattttgc aatctactat tgtcagcagt ataacgattg gctgtggacc 720
ttcgggcagg ggactaaagt ggagattcgg aacagcggcg cgggcaccgc ggccgcgact 780
cacacatgcc caccgtgccc agcacctgaa gccgcggggg gaccgtcagt cttcctcttc 840
cccccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg 900
gtggacgtga gccacgaaga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag 960
gtgcataatg ccaagacaaa gccgcgggag gagcagtaca acagcacgta ccgtgtggtc 1020
agcgtcctca ccgtcctgca ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc 1080
tccaacaaag ccctcccagc ccccatcgag aaaaccatct ccaaagccaa agggcagccc 1140
cgagaaccac aggtgtacac cctgccccca tgccgggatg agctgaccaa gaaccaggtc 1200
agcctgtggt gcctggtcaa aggcttctat cccagcgaca tcgccgtgga gtgggagagc 1260
aatgggcagc cggagaacaa ctacaagacc acgcctcccg tgctggactc cgacggctcc 1320
ttcttcctct acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 1380
tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 1440
tctccgggta aa 1452
<210> 139
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1G11 Fab 轻链 ntd (VL, 连接, CL)
<400> 139
aattttatgc tgactcagcc ccactctgtg tcggagtctc cggggaagac ggtaaccatc 60
tcctgcaccc gcagcagtgg cagcattgcc agcaactatg tgcagtggta ccagcagcgc 120
ccgggcagtt cccccaccac ggtcattttt gacgacaatc aaagacccac tggtgtccct 180
gatcgcttct ctgccgccat cgacacctcc tccagttctg cctccctcac catctctgga 240
ctgacggctg aggacgaggc cgattactat tgtcagtcgt ctcatagcac cgctgtcgtc 300
tttggcggag ggaccaagct gaccgtccta agtcagccca aggctgcccc ctcggtcact 360
ctgttcccgc cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata 420
agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag ccccgtcaag 480
gcgggagtgg agaccaccac accctccaaa caaagcaaca acaagtacgc ggccagcagc 540
tacctgagcc tgacgcctga gcagtggaag tcccacaaaa gctacagctg ccaggtcacg 600
catgaaggga gcaccgtgga gaagacagtg gcccctacag aatgttca 648
<210> 140
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1G11 Fab 重链ntd (VH, 连接, CH)
<400> 140
caggtgcagc tacagcagtg gggcgcagga ctgttgaagc cttcggagac cctgtccctc 60
acctgcgctg tctatggtgg gtccttcagt ggttactact ggagctggat ccgccagccc 120
ccagggaagg ggctggagtg gattggggaa atcaatcata gtggaagcac caactacaac 180
ccgtccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240
aagctgagct ctgtgaccgc cgcggacacg gctgtgtatt actgtgcgag aagctcgtcc 300
ggggatgctt ttgatatctg gggccaaggg acaatggtca ccgtctcaag cgcctccacc 360
aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 420
gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 480
ggcgccctga ccagcggcgt ccacaccttc ccggctgtcc tacagtcctc aggactctac 540
tccctcagca gcgtagtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 600
aacgtgaatc acaagcccag caacaccaag gtggacaaga aagttgagcc caaatcttgt 660
<210> 141
<211> 1431
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1G11 scFv ntd (具有节修饰的scFv 和Fc)
<400> 141
caggtgcagc tacagcagtg gggcgcagga ctgttgaagc cttcggagac cctgtccctc 60
acctgcgctg tctatggtgg gtccttcagt ggttactact ggagctggat ccgccagccc 120
ccagggaagg ggctggagtg gattggggaa atcaatcata gtggaagcac caactacaac 180
ccgtccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240
aagctgagct ctgtgaccgc cgcggacacg gctgtgtatt actgtgcgag aagctcgtcc 300
ggggatgctt ttgatatctg gggccaaggg acaatggtca ccgtctcaag cggaggagga 360
ggatctggcg gaggaggcag tggaggagga gggtcactta attttatgct gactcagccc 420
cactctgtgt cggagtctcc ggggaagacg gtaaccatct cctgcacccg cagcagtggc 480
agcattgcca gcaactatgt gcagtggtac cagcagcgcc cgggcagttc ccccaccacg 540
gtcatttttg acgacaatca aagacccact ggtgtccctg atcgcttctc tgccgccatc 600
gacacctcct ccagttctgc ctccctcacc atctctggac tgacggctga ggacgaggcc 660
gattactatt gtcagtcgtc tcatagcacc gctgtcgtct ttggcggagg gaccaagctg 720
accgtcctaa acagcggcgc gggcaccgcg gccgcgactc acacatgccc accgtgccca 780
gcacctgaag ccgcgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 840
ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 900
cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 960
ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1020
caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 1080
cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 1140
ctgcccccat gccgggatga gctgaccaag aaccaggtca gcctgtggtg cctggtcaaa 1200
ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1260
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc 1320
accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 1380
gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa a 1431
<210> 142
<211> 657
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1A3 Fab 轻链 ntd (VL, 连接, CL)
<400> 142
gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
atctcctgca ggtctagtca gagcctcctg catagtaatg gatacaacta tttggattgg 120
tacctgcaga agccagggca gtctccacag ctcctgatct atttgggttc taaccgggac 180
tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240
agcagggtgg aggctgagga tgttggggtt tattactgca tgcaaggtac acactggccg 300
tggacgttcg gccaagggac caaggtggaa atcaaacgaa ctgtggctgc accatctgtc 360
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 657
<210> 143
<211> 669
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1A3 Fab 重链ntd (VH, 连接, CH)
<400> 143
caggtgcagc tacagcagtg gggcgcagga ctgttgaagc cttcggagac cctgtccctc 60
acctgcgctg tctatggtgg gtccttcagt ggttactact ggagctggat ccgccagccc 120
ccagggaagg ggctggagtg gattggggaa atcaatcata gtggaagcac caactacaac 180
ccgtccctca agagtcgagc caccatatca gtagacacgt ccaagaacca gttctccctg 240
aagctgagct ctgtgaccgc cgcggacacg gctgtgtatt actgtgcgac cagcccggga 300
ggctattccg ggggatactt ccagcactgg ggccagggaa ccctggtcac cgtctcaagc 360
gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480
tggaactcag gcgccctgac cagcggcgtc cacaccttcc cggctgtcct acagtcctca 540
ggactctact ccctcagcag cgtagtgacc gtgccctcca gcagcttggg cacccagacc 600
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 660
aaatcttgt 669
<210> 144
<211> 1443
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P1A3 scFv ntd (具有穴修饰的scFv 和 Fc)
<400> 144
caggtccagc tgcagcagtg gggagccggc ctgctgaaac catctgaaac tctgagcctg 60
acttgcgctg tctacggggg gtccttcagt ggctactatt ggtcatggat caggcagccc 120
cctgggaagg gactggagtg gatcggggaa attaaccact ccggatctac aaactacaat 180
cccagtctga aatcacgcgc caccatttct gtggacacca gtaagaatca gttcagcctg 240
aagctgagca gcgtgacagc cgctgatacc gccgtgtact attgcgcaac cagccctggc 300
ggatactccg gaggctattt tcagcattgg ggccagggga ccctggtgac agtctctagt 360
gggggaggag ggtctggagg aggaggaagt ggaggaggag gctccgacgt ggtcatgact 420
cagagcccac tgtccctgcc agtgaccccc ggcgagcctg ctagtatctc atgtcgatca 480
agccagtcac tgctgcacag caacgggtac aattatctgg attggtactt gcagaagcca 540
ggccagtctc cccagctgct gatctatctg ggctccaacc gggactctgg ggtgcctgat 600
agattcagcg gcagcggctc tgggactgac tttaccctga aaatttccag agtcgaggca 660
gaagatgtgg gagtctacta ttgcatgcag ggcactcatt ggccctggac cttcggacag 720
ggcacaaagg tggagatcaa gaacagcggc gcgggcaccg cggccgcgac tcacacatgc 780
ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 840
cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 900
agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 960
gccaagacaa agccgcggga ggagcagtac aacagcacgt accgtgtggt cagcgtcctc 1020
accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 1080
gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1140
caggtgtgca ccctgccccc atcccgggat gagctgacca agaaccaggt cagcctgtcc 1200
tgcgccgtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1260
ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1320
gtgagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1380
gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1440
aaa 1443
<210> 145
<211> 642
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P2B9 Fab 轻链 ntd (VL, 连接, CL)
<400> 145
tcctatgagc tgactcagcc accctcgatg tcagtgtccc caggacagac ggccaggatc 60
acctgctctg gagatgcatt gccaaaacaa tttgcttttt ggtaccagca gaagccaggc 120
caggcccctg tgttggtgat ttataaagac actgagaggc cctcagggat ccctgagcga 180
ttctctggct ccagctcagg gacaacagtc acgttgacca tcactggagt ccaggcagaa 240
gatgaggctg actattactg tcaatctcca gacagcagtg gtaccgtcga agtgttcggc 300
ggagggacca agctgaccgt cctaggtcag cccaaggctg ccccctcggt cactctgttc 360
ccgccctcct ctgaggagct tcaagccaac aaggccacac tggtgtgtct cataagtgac 420
ttctacccgg gagccgtgac agtggcctgg aaggcagata gcagccccgt caaggcggga 480
gtggagacca ccacaccctc caaacaaagc aacaacaagt acgcggccag cagctacctg 540
agcctgacgc ctgagcagtg gaagtcccac agaagctaca gctgccaggt cacgcatgaa 600
gggagcaccg tggagaagac agtggcccct gcagaatgtt ca 642
<210> 146
<211> 669
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P2B9 Fab 重链ntd (VH, 连接, CH)
<400> 146
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctggtgg ctccatcagc agtagtagtt actactgggg ctggatccgc 120
cagcccccag ggaaggggct ggagtggatt gggagtatct attatagtgg gagcacctac 180
tacaacccgt ccctcaagag tcgagtcacc atatccgtag acacgtccaa gaaccagttc 240
tccctgaagc tgagctctgt gaccgccgca gacacggctg tgtattactg tgcgggcgat 300
attttgactg gttatgccct tgactactgg ggccagggaa ccctggtcac cgtctcaagc 360
gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480
tggaactcag gcgccctgac cagcggcgtc cacaccttcc cggctgtcct acagtcctca 540
ggactctact ccctcagcag cgtagtgacc gtgccctcca gcagcttggg cacccagacc 600
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 660
aaatcttgt 669
<210> 147
<211> 1431
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> P2B9 scFv ntd (具有穴修饰的scFv 和 Fc)
<400> 147
caggtgcagc tgcaggaaag cggacccgga ctggtgaagc catctgaaac actgagcctg 60
acttgtaccg tgagcggcgg aagcatcagc tcctctagtt actattgggg atggatcagg 120
cagccccctg gcaaggggct ggagtggatc ggcagcatct actatagcgg ctccacatac 180
tataacccta gcctgaaatc ccgcgtgaca atctctgtgg acactagtaa gaatcagttc 240
tctctgaaac tgtcaagcgt gaccgccgct gatacagctg tctactattg cgcaggcgac 300
attctgaccg ggtacgccct ggattattgg ggacagggca ctctggtgac cgtctcctct 360
ggaggaggag gctcaggagg aggagggtcc ggaggcgggg gaagttcata cgaactgaca 420
cagccaccct ctatgagtgt gtcaccaggg cagactgcac gaatcacctg tagcggagac 480
gccctgccca agcagttcgc tttttggtat cagcagaaac ctggccaggc tccagtgctg 540
gtcatctata aggatactga gcggccctct gggattcctg aaagattcag tggcagcagc 600
agcggaacca cagtgactct gaccattaca ggcgtgcagg cagaggacga agccgattac 660
tattgccagt cccccgacag ttcaggcacc gtggaggtct ttggcggggg aacaaaactg 720
actgtgctga acagcggcgc gggcaccgcg gccgcgactc acacatgccc accgtgccca 780
gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 840
ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 900
cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 960
ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1020
caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 1080
cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtgcacc 1140
ctgcccccat cccgggatga gctgaccaag aaccaggtca gcctgtcctg cgccgtcaaa 1200
ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1260
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcgt gagcaagctc 1320
accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 1380
gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa a 1431
<210> 148
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 148
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Ala Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Asp Tyr
20 25 30
Asp Phe Val Ser Trp Tyr Gln Gln His Pro Gly Thr Ala Pro Lys Leu
35 40 45
Ile Ile Tyr Asp Ile Asn Asn Arg Pro Ser Gly Ile Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Asp Asn Met Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Tyr Thr Ser Ser
85 90 95
Asp Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr
100 105
<210> 149
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 149
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 Thr Ser Ser Asp Ile Gly His Tyr
20 25 30
Asp Phe Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Asp Ile 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 Ser Ala Tyr Thr Ser Ser
85 90 95
Asp Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr
100 105
<210> 150
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 150
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Pro Val Thr Val Ser Ser
115 120
<210> 151
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 151
Glu 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 Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 152
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 152
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Leu Gly Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 153
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 153
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ser Pro Gly Gly Tyr Ser Gly Gly Tyr Phe Gln His Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 154
<211> 246
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 154
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Pro Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ala Leu Thr Gln Pro Ala
130 135 140
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Ala Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly Asp Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
His Pro Gly Thr Ala Pro Lys Leu Ile Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Asp Asn Met
195 200 205
Ala Ser Leu Thr Ile Ser Gly Leu Gln Pro Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu
245
<210> 155
<211> 246
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 155
Glu 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 Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Ile Met Pro Ser Arg Gly Gly Thr Ser Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Tyr Tyr Tyr Asp Ser Ser Gly Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro
130 135 140
Ser Val Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly
145 150 155 160
Thr Ser Ser Asp Ile Gly His Tyr Asp Phe Val Ser Trp Tyr Gln Gln
165 170 175
Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Asp Ile Asn Asn Arg
180 185 190
Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser
195 200 205
Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Ser Ala Tyr Thr Ser Ser Asp Thr Leu Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu
245
<210> 156
<211> 247
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗体序列
<400> 156
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ser Pro Gly Gly Tyr Ser Gly Gly Tyr Phe Gln His Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
130 135 140
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser
145 150 155 160
Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Leu Gly Ser
180 185 190
Asn Arg Asp Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Met Gln Gly Thr His Trp Pro Trp Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Val Glu Ile Lys
245
Claims (15)
1.一种双特异性抗体或双特异性抗原结合片段,其能够结合CD122和通用γ链,其中所述双特异性抗体或双特异性抗原结合片段为IL-2受体激动剂,并且包含:(a)结合CD122的抗原结合片段;所述结合CD122的抗原结合片段含有结合CD122的抗体的轻链可变区和重链可变区,和(b)结合通用γ链的抗原结合片段;所述结合通用γ链的抗原结合片段含有结合通用γ链的抗体的轻链可变区和重链可变区,其中所述的双特异性抗体或双特异性抗原结合片段包含:
(a)结合CD122的抗原结合片段,其包含
(i)轻链可变区,所述轻链可变区包含以下CDR:
LC-CDR1:TGTSSDIGHYDFVS (SEQ ID NO: 2)
LC-CDR2:DINNRPS (SEQ ID NO: 3)
LC-CDR3:SAYTSSDTLV (SEQ ID NO: 4),
和
(ii)重链可变区,所述重链可变区包含以下CDR:
HC-CDR1:NYYMH (SEQ ID NO: 36)
HC-CDR2:AIMPSRGGTSYPQKFQG (SEQ ID NO: 37)
HC-CDR3:GEYYYDSSGYYY (SEQ ID NO: 38);
和
(b)结合通用γ链的抗原结合片段,其包含(i)轻链可变区,所述轻链可变区包含以下CDR:
LC-CDR1:RSSQSLLHSNGYNYLD (SEQ ID NO: 68)
LC-CDR2:LGSNRDS (SEQ ID NO: 69)
LC-CDR3:MQGTHWPWT (SEQ ID NO: 70),
和
(ii)重链可变区,所述重链可变区包含以下CDR:
HC-CDR1:GYYWS (SEQ ID NO: 48)
HC-CDR2:EINHSGSTNYNPSLKS (SEQ ID NO: 49)
HC-CDR3:SPGGYSGGYFQH (SEQ ID NO: 77)。
2.如权利要求1所述的双特异性抗体或双特异性抗原结合片段,其中,所述的双特异性抗体或双特异性抗原结合片段包含:(a)结合CD122的抗原结合片段,其包含:
(i)SEQ ID NO: 1所示的轻链可变区,
和
(ii)SEQ ID NO: 35所示的重链可变区;
和
(b)结合通用γ链的抗原结合片段,其包含:
(i)SEQ ID NO: 67所示的轻链可变区,
和
(ii)SEQ ID NO: 76所示的重链可变区。
3.如权利要求1或2所述的双特异性抗体或双特异性抗原结合片段,其与药物部分或可检测部分偶联。
4.一种体外复合物,其包含权利要求1至3中任一项所述的结合CD122和/或通用γ链的双特异性抗体或双特异性抗原结合片段。
5.一种嵌合抗原受体,其包含权利要求1至3中任一项所述的双特异性抗原结合片段。
6.一种细胞,其包含权利要求5的嵌合抗原受体。
7.一种组合物,其包含权利要求1至3中任一项所述的双特异性抗体或双特异性抗原结合片段、权利要求5所述的嵌合抗原受体或权利要求6所述的细胞以及至少一种药学上可接受的载体。
8.一种分离的核酸,其编码权利要求1至3任一项所述的双特异性抗体或双特异性抗原结合片段,或权利要求5所述的嵌合抗原受体。
9.一种载体,其包含权利要求8所述的核酸。
10.一种宿主细胞,其包含权利要求9所述的载体 。
11.一种制备权利要求1至3中任一项所述的双特异性抗体或双特异性抗原结合片段、或权利要求5所述的嵌合抗原受体的方法,包括在适合于表达载体的条件下培养权利要求10所述的宿主细胞。
12.根据权利要求1至3中任一项所述的双特异性抗体或双特异性抗原结合片段在制备药物中的用途,所述药物用于治疗癌症,所述癌症是肾癌或黑素瘤。
13.如权利要求12所述的用途,所述肾癌是肾细胞癌。
14.一种检测CD122和/或通用γ链的方法,包括在体外,将含有或疑似含有CD122和/或通用γ链的样品与权利要求1至3中任一项所述的双特异性抗体或双特异性抗原结合片段接触,并检测所述双特异性抗体或双特异性抗原结合片段与CD122和/或通用γ链的复合物的形成。
15.一种用于扩增T细胞和/或NK细胞群的方法,其中在体外将T细胞和/或NK细胞与权利要求1至3中任一项所述的双特异性抗体或双特异性抗原结合片段接触。
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TR201901445T4 (tr) | 2019-02-21 |
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KR20180037239A (ko) | 2018-04-11 |
AU2016301970A1 (en) | 2018-03-22 |
US10696747B2 (en) | 2020-06-30 |
DK3328894T3 (en) | 2019-02-04 |
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CN115925939A (zh) | 2023-04-07 |
HUE043421T2 (hu) | 2019-08-28 |
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