CN114366818A - 抗体药物偶联物及其应用 - Google Patents
抗体药物偶联物及其应用 Download PDFInfo
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- CN114366818A CN114366818A CN202011105383.0A CN202011105383A CN114366818A CN 114366818 A CN114366818 A CN 114366818A CN 202011105383 A CN202011105383 A CN 202011105383A CN 114366818 A CN114366818 A CN 114366818A
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Abstract
本发明涉及抗体药物偶联物及其应用,具体提供了抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,所述抗体药物偶联物具有式Ⅰ所示的结构,其中,Ab为抗Claudin 18.2抗体。本发明的抗体药物偶联物在体内和体外都具有良好的抑制肿瘤细胞生长活性,且细胞毒性低,具有良好的应用前景。Ab‑(L‑D)p式Ⅰ。
Description
技术领域
本发明涉及药物化学领域,具体地,涉及抗体药物偶联物及其应用。
背景技术
胃癌是世界范围内最常见的癌症之一,其中东亚、东欧和南美洲胃癌发病率较高,北美和非洲发病率较低。晚期或复发胃癌标准初始治疗是化疗。尽管由于手术技术以及围手术治疗的发展,胃癌患者的预后已经显著改善,但是其5年总生存率仅为10-15%。靶向治疗为复发/晚期胃癌治疗带来了新的希望,将曲妥珠单抗联合化疗可为有HER2阳性的患者带来一定获益,但只有15%的患者有HER2阳性表达,受益人群有限。近年来,免疫治疗给复发/晚期胃癌治疗带来了新的希望;但是根据KEYNOTE-12研究的结果,适用该治疗的PD-L1阳性人群比率也仅占复发/晚期胃或胃食管结合部腺癌患者的40%左右。因此,开发新的胃癌治疗药物仍然迫在眉睫。
发明内容
本申请的发明人通过大量实验和创造性劳动,制备得到了抗Claudin 18.2抗体药物偶联物,并证实其具有良好的生物学活性,由此完成了本发明。
为此,在本发明的第一方面,本发明提供了抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,所述抗体药物偶联物具有式Ⅰ所示的结构,
Ab-(L-D)p
式Ⅰ
其中:
Ab为抗Claudin 18.2抗体,所述抗Claudin 18.2抗体包含重链和轻链,重链可变区CDR1包含选自SEQ ID NO:2、10、18、26、34、42、68、76、84、92、100、108或116所示的序列或其突变体,重链可变区CDR2包含选自SEQ ID NO:3、11、19、27、35、43、69、77、85、93、101、109或117所示的序列或其突变体,重链可变区CDR3包含选自SEQ ID NO:4、12、20、28、36、44、70、78、86、94、102、110或118所示的序列或其突变体,轻链可变区CDR1包含选自SEQ ID NO:50、58、124或132所示的序列或其突变体,轻链可变区CDR2包含选自SEQ ID NO:51、59、125或133所示的序列或其突变体,轻链可变区CDR3包含选自SEQ ID NO:52、60、126或134所示的序列或其突变体;
D为细胞毒剂;
L为接头,用于连接所述抗Claudin 18.2抗体和所述细胞毒剂;
p为2.0-8.0(例如2.0-7.0、2.0-6.0、2.0-5.0、2.0-4.0、3.0-7.0、3.0-6.0、3.0-5.0或3.0-4.0,或者例如3.0、4.0、5.0、6.0或7.0)。
本发明的抗体药物偶联物在体内和体外都具有良好的抑制肿瘤细胞生长活性,具有良好的应用前景。本发明的抗体药物偶联物由抗Claudin 18.2抗体和海兔毒素的衍生物MMAE通过MC-vc-PAB链接体连接而成,其抗肿瘤作用机理为:抗体药物偶联物与肿瘤细胞表面的Claudin 18.2结合后,通过内吞进入肿瘤细胞内并运输到溶酶体,再经溶酶体内蛋白酶降解释放出MMAE,MMAE进入细胞质后与微管蛋白结合并抑制其聚合,从而阻断微管蛋白参与的包括有丝分裂在内的细胞各项生理功能,进而抑制肿瘤细胞增殖并导致肿瘤细胞死亡。
需要说明的是,所述“抗体药物偶联物”为含有相同或不同DAR值的ADC分子的组合物。具体地,本发明提供了包含多个ADC分子的组合物。在某些情况下,该组合物中,多个ADC分别包含相同数目的药物分子。在其他情况下,该组合物中,多个ADC分别包含不同数目的药物分子。
上述药物抗体比(DAR)是指偶联到抗体的药物分子的个数(例如,式I中的p)。本发明所述的抗体药物偶联物中包含的药物分子的个数(例如,式I中的p)通常是整数,当本发明所述的抗体药物偶联物中包含的药物分子的个数(例如,式I中的p)是分数时,该分数指的是包含多个ADC分子的组合物中,每个抗体偶联的药物分子的平均数量。
上述药物抗体比(DAR)可以通过常规手段来验证,诸如质谱、ELISA测定法、HIC和HPLC。还可以测定ADC在p方面的定量分布。在有些情况中,将p为某数值的同质ADC从具有其它药物载荷的ADC中分离、纯化和验证可以通过诸如反相HPLC或电泳的手段来实现。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区CDR1包含选自SEQ IDNO:2、10、18、26、34或42所示的序列或其突变体,重链可变区CDR2包含选自SEQ ID NO:3、11、19、27、35或43所示的序列或其突变体,重链可变区CDR3包含选自SEQ ID NO:4、12、20、28、36或44所示的序列或其突变体,轻链可变区CDR1包含选自SEQ ID NO:50或58所示的序列或其突变体,轻链可变区CDR2包含选自SEQ ID NO:51或59所示的序列或其突变体,轻链可变区CDR3包含选自SEQ ID NO:52或60所示的序列或其突变体。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区CDR1包含选自SEQ IDNO:68、76、84、92、100、108或116所示的序列或其突变体,重链可变区CDR2包含选自SEQ IDNO:69、77、85、93、101、109或117所示的序列或其突变体,重链可变区CDR3包含选自SEQ IDNO:70、78、86、94、102、110或118所示的序列或其突变体,轻链可变区CDR1包含选自SEQ IDNO:124或132所示的序列或其突变体,轻链可变区CDR2包含选自SEQ ID NO:125或133所示的序列或其突变体,轻链可变区CDR3包含选自SEQ ID NO:126或134所示的序列或其突变体。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区CDR1、CDR2、CDR3选自如下序列组合:
(1)SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4,
(2)SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12,
(3)SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20,
(4)SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28,
(5)SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36,
(6)SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44,
(7)SEQ ID NO:68、SEQ ID NO:69、SEQ ID NO:70,
(8)SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78,
(9)SEQ ID NO:84、SEQ ID NO:85、SEQ ID NO:86,
(10)SEQ ID NO:92、SEQ ID NO:93、SEQ ID NO:94,
(11)SEQ ID NO:100、SEQ ID NO:101、SEQ ID NO:102,
(12)SEQ ID NO:108、SEQ ID NO:109、SEQ ID NO:110,
(13)SEQ ID NO:116、SEQ ID NO:117、SEQ ID NO:118,
所述抗Claudin 18.2抗体的轻链可变区CDR1、CDR2、CDR3选自如下序列组合:
(1)SEQ ID NO:50、SEQ ID NO:51、SEQ ID NO:52,
(2)SEQ ID NO:58、SEQ ID NO:59、SEQ ID NO:60,
(3)SEQ ID NO:124、SEQ ID NO:125、SEQ ID NO:126,
(4)SEQ ID NO:132、SEQ ID NO:133、SEQ ID NO:134。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区CDR1、CDR2、CDR3选自如下序列组合:
(1)SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4,
(2)SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12,
(3)SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20,
(4)SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28,
(5)SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36,
(6)SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44,
所述抗Claudin 18.2抗体的轻链可变区CDR1、CDR2、CDR3选自如下序列组合:
(1)SEQ ID NO:50、SEQ ID NO:51、SEQ ID NO:52,
(2)SEQ ID NO:58、SEQ ID NO:59、SEQ ID NO:60。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区CDR1、CDR2、CDR3选自如下序列组合:
(1)SEQ ID NO:68、SEQ ID NO:69、SEQ ID NO:70,
(2)SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78,
(9)SEQ ID NO:84、SEQ ID NO:85、SEQ ID NO:86,
(4)SEQ ID NO:92、SEQ ID NO:93、SEQ ID NO:94,
(5)SEQ ID NO:100、SEQ ID NO:101、SEQ ID NO:102,
(6)SEQ ID NO:108、SEQ ID NO:109、SEQ ID NO:110,
(7)SEQ ID NO:116、SEQ ID NO:117、SEQ ID NO:118,
所述抗Claudin 18.2抗体的轻链可变区CDR1、CDR2、CDR3选自如下序列组合:
(1)SEQ ID NO:124、SEQ ID NO:125、SEQ ID NO:126,
(2)SEQ ID NO:132、SEQ ID NO:133、SEQ ID NO:134。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区FR1包含选自SEQ IDNO:5、13、21、29、37、45、71、79、87、95、103、111或119所示的序列或其突变体,重链可变区FR2包含选自SEQ ID NO:6、14、22、30、38、46、72、80、88、96、104、112或120所示的序列或其突变体,重链可变区FR3包含选自SEQ ID NO:7、15、23、31、39、47、73、81、89、97、105、113或121所示的序列或其突变体,重链可变区FR4包含选自SEQ ID NO:8、16、24、32、40、48、74、82、90、98、106、114或122所示的序列或其突变体,轻链可变区FR1包含选自SEQ ID NO:53、61、127或135所示的序列或其突变体,轻链可变区FR2包含选自SEQ ID NO:54、62、128或136所示的序列或其突变体,轻链可变区FR3包含选自SEQ ID NO:55、63、129或137所示的序列或其突变体,轻链可变区FR4包含选自SEQ ID NO:56、64、130或138所示的序列或其突变体。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区FR1包含选自SEQ IDNO:5、13、21、29、37或45所示的序列或其突变体,重链可变区FR2包含选自SEQ ID NO:6、14、22、30、38或46所示的序列或其突变体,重链可变区FR3包含选自SEQ ID NO:7、15、23、31、39或47所示的序列或其突变体,重链可变区FR4包含选自SEQ ID NO:8、16、24、32、40或48所示的序列或其突变体,轻链可变区FR1包含选自SEQ ID NO:53或61、所示的序列或其突变体,轻链可变区FR2包含选自SEQ ID NO:54或62所示的序列或其突变体,轻链可变区FR3包含选自SEQ ID NO:55或63所示的序列或其突变体,轻链可变区FR4包含选自SEQ ID NO:56或64所示的序列或其突变体。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区FR1包含选自SEQ IDNO:71、79、87、95、103、111或119所示的序列或其突变体,重链可变区FR2包含选自SEQ IDNO:72、80、88、96、104、112或120所示的序列或其突变体,重链可变区FR3包含选自SEQ IDNO:73、81、89、97、105、113或121所示的序列或其突变体,重链可变区FR4包含选自SEQ IDNO:74、82、90、98、106、114或122所示的序列或其突变体,轻链可变区FR1包含选自SEQ IDNO:127或135所示的序列或其突变体,轻链可变区FR2包含选自SEQ ID NO:128或136所示的序列或其突变体,轻链可变区FR3包含选自SEQ ID NO:129或137所示的序列或其突变体,轻链可变区FR4包含选自SEQ ID NO:130或138所示的序列或其突变体。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区FR1、FR2、FR3、FR4选自如下序列组合:
(1)SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8,
(2)SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16,
(3)SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24,
(4)SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ ID NO:32,
(5)SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、SEQ ID NO:40,
(6)SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48,
(7)SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74,
(8)SEQ ID NO:79、SEQ ID NO:80、SEQ ID NO:81、SEQ ID NO:82,
(9)SEQ ID NO:87、SEQ ID NO:88、SEQ ID NO:89、SEQ ID NO:90,
(10)SEQ ID NO:95、SEQ ID NO:96、SEQ ID NO:97、SEQ ID NO:98,
(11)SEQ ID NO:103、SEQ ID NO:104、SEQ ID NO:105、SEQ ID NO:106,
(12)SEQ ID NO:111、SEQ ID NO:112、SEQ ID NO:113、SEQ ID NO:114,
(13)SEQ ID NO:119、SEQ ID NO:120、SEQ ID NO:121、SEQ ID NO:122,
所述抗Claudin 18.2抗体的轻链可变区FR1、FR2、FR3、FR4选自如下序列组合:
(1)SEQ ID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56,
(2)SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64,
(3)SEQ ID NO:127、SEQ ID NO:128、SEQ ID NO:129、SEQ ID NO:130,
(4)SEQ ID NO:135、SEQ ID NO:136、SEQ ID NO:137、SEQ ID NO:138。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区FR1、FR2、FR3、FR4选自如下序列组合:
(1)SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8,
(2)SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16,
(3)SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24,
(4)SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ ID NO:32,
(5)SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、SEQ ID NO:40,
(6)SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48,
所述抗Claudin 18.2抗体的轻链可变区FR1、FR2、FR3、FR4选自如下序列组合:
(1)SEQ ID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56,
(2)SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区FR1、FR2、FR3、FR4选自如下序列组合:
(1)SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74,
(2)SEQ ID NO:79、SEQ ID NO:80、SEQ ID NO:81、SEQ ID NO:82,
(3)SEQ ID NO:87、SEQ ID NO:88、SEQ ID NO:89、SEQ ID NO:90,
(4)SEQ ID NO:95、SEQ ID NO:96、SEQ ID NO:97、SEQ ID NO:98,
(5)SEQ ID NO:103、SEQ ID NO:104、SEQ ID NO:105、SEQ ID NO:106,
(6)SEQ ID NO:111、SEQ ID NO:112、SEQ ID NO:113、SEQ ID NO:114,
(7)SEQ ID NO:119、SEQ ID NO:120、SEQ ID NO:121、SEQ ID NO:122,
所述抗Claudin 18.2抗体的轻链可变区FR1、FR2、FR3、FR4选自如下序列组合:
(1)SEQ ID NO:127、SEQ ID NO:128、SEQ ID NO:129、SEQ ID NO:130,
(2)SEQ ID NO:135、SEQ ID NO:136、SEQ ID NO:137、SEQ ID NO:138。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区选自SEQ ID NO:1、9、17、25、33、41、67、75、83、91、99、107或115所示的序列,
所述抗Claudin 18.2抗体的轻链可变区选自SEQ ID NO:49、57、123或131所示的序列。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区选自SEQ ID NO:1、9、17、25、33或41所示的序列,
所述抗Claudin 18.2抗体的轻链可变区选自SEQ ID NO:49或57所示的序列。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区选自SEQ ID NO:67、75、83、91、99、107或115所示的序列,
所述抗Claudin 18.2抗体的轻链可变区选自SEQ ID NO:123或131所示的序列。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区、轻链可变区选自如下序列组合:
(1)SEQ ID NO:17和SEQ ID NO:57;
(2)SEQ ID NO:41和SEQ ID NO:49;
(3)SEQ ID NO:41和SEQ ID NO:57;
(4)SEQ ID NO:115和SEQ ID NO:131。
在一些实施方案中,所述抗Claudin 18.2抗体的重链可变区、轻链可变区的序列分别为SEQ ID NO:41和SEQ ID NO:49。
在一些实施方案中,所述抗Claudin 18.2抗体的重链恒定区选自人源性IgG(如IgG1、IgG2、IgG3或IgG4)、IgM、IgA、IgD、IgA恒定区或上述恒定区的突变体,优选为人源性IgG1;
所述抗Claudin 18.2抗体的轻链恒定区选自人源性lambda恒定区、kappa恒定区或上述恒定区的突变体,优选为人源性kappa恒定区。
在一些实施方案中,所述抗Claudin 18.2抗体的重链的氨基酸序列包含如SEQ IDNO:65所示的序列,或者包含与SEQ ID NO:65所示序列的同一性大于70%,例如大于75%、80%、85%、90%、95%、99%的序列;
所述抗Claudin 18.2抗体的轻链的氨基酸序列包含如SEQ ID NO:66所示的序列,或者包含与SEQ ID NO:66所示序列的同一性大于70%,例如大于75%、80%、85%、90%、95%、99%的序列。
在一些实施方案中,p为3.0-4.0。
在一些实施方案中,p为3.0-3.8。
在一些实施方案中,p为3.0、3.4、3.5或3.8。
在一些实施方案中,p为3.8。
在一些实施方案中,所述细胞毒剂选自SN-38、吉西他滨(Gemcitabine)、Monomethyl auristatin E(MMAE)、Monomethyl auristatin F(MMAF)、美登木素生物碱(例如Maytansine DM1、Maytansine DM4)、卡奇霉素(calicheamicin)、MGBA(如duocarmycin)、阿霉素(doxorubicin)、蓖麻毒素、白喉毒素等毒素、I131、白介素类、肿瘤坏死因子、趋化因子和纳米颗粒。
在一些实施方案中,所述细胞毒剂为MMAE。
MMAE的结构为:
在一些实施方案中,所述接头选自6-马来酰亚氨基己酰基(MC)、马来酰亚氨基丙酰基(MP)、N-琥珀酰亚氨基4-(2-吡啶基硫代)戊酸酯(SPP)、4-(N-马来酰亚氨基甲基)-环己烷-1-甲酰基(MCC)、N-琥珀酰亚氨基(4-碘-乙酰基)氨基苯甲酸酯(SIAB)、和6-马来酰亚氨基己酰基-缬氨酸-瓜氨酸-对氨基苄氧羰基(MC-vc-PAB)。
在一些实施方案中,所述接头为6-马来酰亚氨基己酰基-缬氨酸-瓜氨酸-对氨基苄氧羰基(MC-vc-PAB)。
在一些实施方案中,式I中所述的L-D为MC-vc-PAB-MMAE,其结构如下式所示:
在一些实施方案中,
Ab包括:
(a)重链可变区CDR1、CDR2、CDR3和轻链可变区CDR1、CDR2、CDR3,其中,重链可变区CDR1的序列如SEQ ID NO:42所示,重链可变区CDR2的序列如SEQ ID NO:43所示,重链可变区CDR3的序列如SEQ ID NO:44所示,轻链可变区CDR1的序列如SEQ ID NO:50所示,轻链可变区CDR2的序列如SEQ ID NO:51所示,轻链可变区CDR3的序列如SEQ ID NO:52所示;
(b)重链可变区和轻链可变区,其中,重链可变区的序列如SEQ ID NO:41所示,轻链可变区的序列如SEQ ID NO:49所示;和/或
(c)重链和轻链,其中,重链的序列如SEQ ID NO:65所示,轻链的序列如SEQ IDNO:66所示;
L为MC-vc-PAB;和
D为MMAE。
在本发明的第二方面,本发明提供了组合物,其包含前述的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物。
在一些实施方案中,所述组合物中还包含已知的用于治疗肿瘤的化疗药物,所述化疗药物例如为阿霉素(Adriamycin)、环磷酰胺、紫杉烷类【如紫杉醇(Taxol)、多西他赛(Taxotere)】、卡培他滨(Xeloda)、吉西他滨(Gemzar)、长春瑞滨(Navelbine)、他莫昔芬、芳香酶抑制剂(瑞宁得、弗隆、阿诺新)、5-FU加亚叶酸、伊立替康(camptosar)、奥沙利铂、顺铂、卡铂、雌莫司汀、米托蒽醌(Novantrone)、泼尼松、长春新碱(Oncovin)、多柔比星、强的松等,或它们的组合。
在一些实施方案中,所述组合物中还包含已知的用于治疗肿瘤的免疫治疗药物,所述免疫治疗药物例如为PD-1单抗(例如帕博利珠单抗、纳武利尤单抗)、PD-L1单抗(例如Atezolizumab)、TIGIT单抗,4-1BB单抗,VEGFR2单抗(例如Ramucirumab、阿帕替尼)、HER2单抗(例如曲妥珠单抗、Trastuzumab biosimilar、Trastuzumab-dkst)等,或它们的组合。
在一些实施方案中,所述组合物中还包含免疫抑制剂,所述免疫抑制剂选自:(1)糖皮质激素类,如可的松和强的松;(2)微生物代谢产物,如环孢菌素和藤霉素等;
(3)抗代谢物,如硫唑嘌呤和6-巯基嘌呤等;(4)多克隆和单克隆抗淋巴细胞抗体,如抗淋巴细胞球蛋白和OKT3等;(5)烷化剂类,如环磷酰胺。具体地,所述免疫抑制剂例如为甲基强的松龙,强的松,硫唑嘌呤,普乐可复,赛尼哌,舒莱,环孢菌素,他克莫司,雷帕霉素,霉酚酸酯,咪唑立宾,环磷酰胺,芬戈莫德等。
在一些实施方案中,所述组合物还包含药学上可接受的载体、稀释剂或赋形剂。
在本发明的第三方面,本发明提供了前述的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物或者前述的组合物在制备药物中的用途,所述药物用于预防和/或治疗与Claudin 18.2相关的疾病。
在一些实施方案中,所述与Claudin 18.2相关的疾病为胃癌、胃食管交界腺癌、胰腺癌。
在一些实施方案中,所述与Claudin 18.2相关的疾病为胃癌。
在本发明的第四方面,本发明提供了预防和/或治疗与Claudin 18.2相关的疾病的方法,其包括:给予有需要的受试者预防和/或治疗有效量的前述的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,或者前述的组合物。
在一些实施方案中,所述与Claudin 18.2相关的疾病为胃癌、胃食管交界腺癌、胰腺癌。
在一些实施方案中,所述与Claudin 18.2相关的疾病为胃癌。
在本发明的第五方面,本发明提供了前述的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,或者前述的组合物,其用于预防和/或治疗与Claudin18.2相关的疾病。
在一些实施方案中,所述与Claudin 18.2相关的疾病为胃癌、胃食管交界腺癌、胰腺癌。
在一些实施方案中,所述与Claudin 18.2相关的疾病为胃癌。
附图说明
图1是本发明实施例的RT-PCR显示HEK293稳转细胞株分别表达紧密连接蛋白18.1和紧密连接蛋白18.2;HEK293-紧密连接蛋白18.2稳转细胞株和对照KATO III细胞均可扩增出紧密连接蛋白18.2特异性的780bp特征条带,而HEK293-紧密连接蛋白18.1只能扩增出504bp的共同片段;
图2是本发明实施例的FACS实验筛选HEK293-紧密连接蛋白18.2高表达稳转细胞株的结果,其中黑色点为阴性对照,灰色点为HEK293-紧密连接蛋白18.2高表达稳转细胞株;
图3是本发明实施例的FACS实验筛选NIH3T3-紧密连接蛋白18.2高表达稳转细胞株的结果,其中黑色的线为阴性对照,灰色的阴影为3T3-紧密连接蛋白18.2稳转细胞株;NO.32-H为高表达的3T3-紧密连接蛋白18.2稳转细胞株,NO.18-M为中表达的3T3-紧密连接蛋白18.2稳转细胞株,NO.6-L为低表达的3T3-紧密连接蛋白18.2稳转细胞株;
图4是本发明实施例的Anti-Claudin18.2抗体ADCC效应结果图;
图5是本发明实施例的Anti-Claudin18.2抗体CDC效应结果图;
图6是本发明实施例的抗体药物偶联物疏水作用色谱图(HIC);
图7是本发明实施例的不同CM311ADC在LT-M11细胞株中的细胞杀伤作用结果图;
图8是本发明实施例的CM311-ADC-1和对照CM311-ADC-2对人胃癌裸小鼠PDX模型STO#025肿瘤生长抑制活性结果图;
图9是本发明实施例的CM311-ADC-1和对照CM311-ADC-2对人胃癌裸小鼠PDX模型STO#025的动物体重的影响结果图;
图10是本发明实施例的CM311-ADC-1和对照CM311-ADC-2对人胃癌裸小鼠PDX模型STO#523肿瘤生长抑制活性结果图;
图11是本发明实施例的CM311-ADC-1和对照CM311-ADC-2对人胃癌裸小鼠PDX模型STO#523的动物体重的影响结果图;
图12是本发明实施例的抗体药物偶联物与抗体的体外细胞活性比较结果图(QCLog变换独立拟合图)。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的蛋白质和核酸化学、分子生物学、细胞和组织培养、微生物学、免疫学相关术语和实验室操作步骤均为相应领域内广泛使用的术语和常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
Claudin蛋白是构成紧密连接结构的骨架蛋白,位于相邻细胞间隙顶侧,其分布具有组织器官特异性,功能主要为细胞间黏附、维持细胞极性、调节细胞旁通透性及参与细胞增殖、分化的调节。在肿瘤中,细胞间的紧密连接遭到破坏,Claudin无法发挥其正常功能。
Claudin l8是Claudin家族成员,具有2种不同的第一个外显子,因此通过选择性剪切可以产生两种亚型:Claudin l8.1和Claudin 18.2,这两种亚型分别在不同的组织中进行转录扩增,其中,Claudin l8.1主要表达在肺组织,而Claudin l8.2则特异性表达于胃组织。Claudin 18.2(GenBank登录号:NM_001002026.3)在除了胃黏膜之外的其他正常组织都不表达,但其在多种肿瘤中有显著上调,包括80%的胃肠道腺瘤、60%的胰腺肿瘤,以及部分胆管、卵巢和肺部等的肿瘤中。
术语“Claudin 18.2相关的疾病”指的是组织细胞中Claudin 18.2的表达不同于(如超过)正常水平的疾病。例如,某组织细胞中Claudin 18.2的表达水平高于参照或对照(即正常组织细胞)中Claudin 18.2的表达水平,则指示所述组织细胞所来源的对象(特别是人)中Claudin 18.2相关疾病的存在。
在本发明中,除非另有说明,否则任何数值范围应理解为包括范围内的任何值或任何子范围。
在本发明中,术语“抗体”是指通常由两对相同的多肽链(每对具有一条“轻”(L)链和一条“重”(H)链)组成的免疫球蛋白分子。抗体的轻链可分为κ和λ两类。重链可分为μ、δ、γ、α或ε五种,依据重链的不同可将抗体分为IgM、IgD、IgG、IgA和IgE五类。在轻链和重链内,可变区和恒定区通过大约12或更多个氨基酸的“J”区连接,重链还包含大约3个或更多个氨基酸的“D”区。各重链由重链可变区(VH)和重链恒定区(CH)组成。重链恒定区由3个结构域(CH1、CH2和CH3)组成。各轻链由轻链可变区(VL)和轻链恒定区(CL)组成。轻链恒定区由一个结构域CL组成。抗体的恒定区可介导免疫球蛋白与宿主组织或因子,包括免疫系统的各种细胞(例如,效应细胞)和补体系统的组分C1q的结合。VH和VL区还可被细分为具有高变性的区域(称为互补决定区(CDR)),其间散布有较保守的称为骨架区(FR)的区域。各VH和VL由按下列顺序:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4从氨基末端至羧基末端排列的3个CDR和4个FR组成。各重链/轻链对的可变区(VH和VL)分别形成抗体结合部位。氨基酸至各区域或结构域的分配遵循Kabat Sequences of Proteins of Immunological Interest(NationalInstitutes of Health,Bethesda,Md.(1987and 1991)),或Chothia&Lesk(1987)J.Mol.Biol.196:901-917;Chothia等人(1989)Nature 342:878-883的定义。
在本发明中,用于确定序列同一性(同源性)和序列相似性百分数的算法是例如BLAST和BLAST 2.0算法,它们分别描述在Altschul等(1977)Nucl.Acid.Res.25:3389-3402和Altschul等(1990)J.Mol.Biol.215:403-410。采用例如文献中所述或者默认参数,BLAST和BLAST 2.0可以用于确定本发明的氨基酸序列同一性百分数。执行BLAST分析的软件可以通过国立生物技术信息中心为公众所获得。
在本发明中,所述与氨基酸序列具有至少70%的序列同一性的氨基酸序列包括与所述氨基酸序列基本同一的多肽序列,例如当采用本文所述方法(例如采用标准参数的BLAST分析)时,与本发明多肽序列相比含有至少70%序列同一性、优选至少75%、80%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更高的序列同一性的那些序列。
在本发明中,所述氨基酸序列的突变体指的是与所述氨基酸序列的同一性大于70%,例如大于75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%的序列,例如具有3个、2个或1个取代、缺失或添加氨基酸的序列。优选的是,取代、添加或缺失的氨基酸不超过3个氨基酸。更优选的是,取代、添加或缺失的氨基酸不超过2个氨基酸。最优选的是,取代、添加或缺失的氨基酸不超过1个氨基酸。
“取代型”变体是天然序列中至少一个氨基酸残基被除去并被不同的氨基酸插入其相同位置的变体。所述取代可为单个的,其中该分子中仅有一个氨基酸被取代;或可为多个的,其中该相同分子有两个或更多的氨基酸被取代。多个取代可位于连续的位点。同样,一个氨基酸可被多个残基取代,其中这样的变体包括取代和插入二者。“插入型”(或“添加型”)变体是一个或多个氨基酸被插入到紧邻一段天然序列某个特定位置处的氨基酸的变体。紧邻氨基酸意指与该氨基酸的α-羧基或α-氨基官能团连接。“缺失型”变体是天然氨基酸序列中一个或多个氨基酸被除去的变体。通常情况下,缺失型变体在其分子的特定区域内有一个或两个氨基酸被缺失。
在某些实施方案中,在偶联反应中少于理论最大值的药物模块偶联至抗体。一般而言,抗体不包含许多游离的和反应性的半胱氨酸硫醇基,其可连接药物模块;事实上,抗体中的大多数半胱氨酸硫醇基以二硫桥形式存在。在某些实施方案中,可以在部分或完全还原性条件下用还原剂诸如二硫苏糖醇(DTT)或三羰基乙基膦(TCEP)还原抗体以产生反应性半胱氨酸硫醇基。
在一些实施方案中,所述药学上可接受的盐为无机酸盐或有机酸盐,其中,所述无机酸盐为盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸氢盐和碳酸盐、硫酸盐或磷酸盐,所述有机酸盐为甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、α-酮戊二酸盐、α-甘油磷酸盐、烷基磺酸盐或芳基磺酸盐;优选地,所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐;所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐。
药学上可以接受的盐可使用本领域熟知的标准程序获得,例如,通过将足量的碱性化合物和提供药学上可以接受的阴离子的合适的酸反应。
如本文所使用,除非另外说明,术语“前药”是指可以在生物学条件(体外或体内)下水解、氧化或进行其他反应以提供本发明的化合物的衍生物。前药仅在生物学条件下经过该反应成为活性化合物,或者它们在它们不反应的形式中具有活性。通常可以使用公知的方法制备前药,例如Burger's Medicinal Chemistry and Drug Discovery(1995)172-178,949-982(Manfred E.Wolff编,第5版)中描述的那些方法。
在本发明中,溶剂合物表示这些形式的本发明的抗体药物偶联物:所述抗体药物偶联物通过与溶剂分子配位而形成的固态或液态形式的复合物。水合物是溶剂合物的一种具体形式,其具有配位的水分子。在本发明中,水合物是优选的溶剂合物。
制备各种含有一定量的活性成分的药物组合物的方法是已知的,或根据本发明的公开内容对于本领域技术人员是显而易见的。如REMINGTON’S PHARMACEUTICAL SCIENCES,Martin,E.W.,ed.,Mack Publishing Company,19th ed.(1995)所述,制备所述药物组合物的方法包括掺入适当的药学赋形剂、载体、稀释剂等,它们在所采用的剂量和浓度对暴露于其的细胞或哺乳动物是无毒的。
本发明的药物组合物可以包含pH缓冲水溶液。或者包含,缓冲剂,诸如磷酸盐、柠檬酸盐和其它有机酸;抗氧化剂,包括抗坏血酸;低分子量(少于约10个残基)多肽;蛋白质,诸如血清清蛋白、明胶或免疫球蛋白;亲水性聚合物,诸如聚乙烯吡咯烷酮;氨基酸,诸如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸;单糖、二糖和其它碳水化合物,包括葡萄糖、甘露糖,蔗糖,海藻糖或糊精;螯合剂,诸如EDTA;糖醇,诸如甘露醇或山梨醇;成盐反荷离子,诸如钠;和/或非离子表面活性剂,诸如TWEENTM、聚乙二醇(PEG)和PLURONICSTM。
以已知的方法制造本发明的药物制剂,包括常规的混合、溶解或冻干方法。本发明的化合物可以制成药物组合物,并向患者以适于选定的施用方式的各种途径施用,例如,口服或肠胃外(通过静脉内、肌内、局部或皮下途径)。
因此,本发明的化合物结合药学上可以接受的载体(如惰性稀释剂或可同化的可食用的载体)可以全身施用,例如,口服。它们可以封闭在硬或软壳的明胶胶囊中,可以压为片剂。对于口服治疗施用,活性化合物可以结合一种或多种赋形剂,并以可吞咽的片剂、颊含片剂、含片、胶囊剂、酏剂、悬浮剂、糖浆、圆片等的形式使用。这种组合物和制剂应该包含至少0.1%的活性化合物。这种组合物和制剂的比例当然可以变化,可以占给定的单位剂型重量的大约1%至大约99%。在这种治疗有用的组合物中,活性化合物的量使得能够获得有效剂量水平。
片剂、含片、丸剂、胶囊剂等也可以包含:粘合剂,如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂,如磷酸氢二钙;崩解剂,如玉米淀粉、马铃薯淀粉、藻酸等;润滑剂,如硬脂酸镁;和甜味剂,如蔗糖、果糖、乳糖或阿司帕坦;或调味剂,如薄荷、冬青油或樱桃香味。当单位剂型是胶囊时,除了上面类型的材料,它还可以包含液体载体,如植物油或聚乙二醇。各种其他材料可以存在,作为包衣,或以其他方式改变固体单位剂型的物理形式。例如,片剂、丸剂或胶囊剂可以用明胶、蜡、虫胶或糖等包衣。糖浆或酏剂可以包含活性化合物,蔗糖或果糖作为甜味剂,对羟苯甲酸甲酯或对羟苯甲酸丙酯作为防腐剂,染料和调味剂(如樱桃香料或桔子香料)。当然,用于制备任何单位剂型的任何材料应该是药学上可以接受的且以应用的量基本上无毒。此外,活性化合物可以掺入缓释制剂和缓释装置中。
活性化合物也可以通过输注或注射来静脉内或腹膜内施用。可以制备活性化合物或其盐的水溶液,任选地混和无毒的表面活性剂。也可以制备在甘油、液体聚乙二醇、甘油三乙酸酯及其混合物以及油中的分散剂。在普通的储存和使用条件下,这些制剂包含防腐剂以防止微生物生长。
适于注射或输注的药物剂型可以包括包含适于无菌的可注射或可输注的溶液或分散剂的即时制剂的活性成分(任选封装在脂质体中)的无菌水溶液或分散剂或无菌粉末。在所有情况下,最终的剂型在生产和储存条件下必须是无菌的、液体的和稳定的。液体载体可以是溶剂或液体分散介质,包括,例如水、乙醇、多元醇(例如,甘油、丙二醇、液体聚乙二醇等)、植物油、无毒的甘油酯及其合适的混合物。可以维持合适的流动性,例如,通过脂质体的形成,通过在分散剂的情况下维持所需的粒子大小,或通过表面活性剂的使用。可以通过各种抗细菌剂和抗真菌剂(如对羟苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等)产生预防微生物的作用。在许多情况下,优选包括等渗剂,如糖、缓冲剂或氯化钠。通过使用延缓吸收剂的组合物(例如,单硬脂酸铝和明胶)可以产生可注射的组合物的延长吸收。
通过将合适的溶剂中的需要量的活性化合物与需要的上面列举的各种其他成分结合,然后进行过滤灭菌,制备无菌可注射溶液。在用于制备无菌注射溶液的无菌粉末的情况下,优选的制备方法是真空干燥和冷冻干燥技术,这会产生活性成分加上任何另外需要的以前无菌过滤溶液中存在的成分的粉末。
有用的固体载体包括粉碎的固体(如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等)。有用的液体载体包括水、乙醇或乙二醇或水-乙醇/乙二醇混合物,本发明的化合物可以任选在无毒的表面活性剂的帮助下以有效含量溶解或分散在其中。可以加入佐剂(如香味)和另外的抗微生物剂来优化对于给定用途的性质。
增稠剂(如合成的聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性纤维素或改性无机材料)也可和液体载体用于形成可涂覆的糊剂、凝胶、软膏、肥皂等,直接用于使用者的皮肤上。
上述制剂可以以单位剂型存在,该单位剂型是含有单位剂量的物理分散单元,适于向人体和其它哺乳动物体给药。单位剂型可以是胶囊或片剂,或是很多胶囊或片剂。根据所涉及的具体治疗,活性成分的单位剂量的量可以在大约0.1到大约1000毫克或更多之间进行变化或调整。
此外,还包括各种药物新剂型如乳脂质体、微球和纳米球的应用,如使用微粒分散体系包括聚合物胶束(polymeric micelles)、纳米乳(nanoemulsion)、亚微乳(submicroemuls微囊(microcapsule)、微球(microsphere)、脂质体(liposomes)和类脂囊泡(niosomes)(又称非离子表面活性剂囊泡)等制备的药剂。
本文使用的术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据完全或部分地预防疾病或其症状,可以是预防性的;和/或根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用,可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗,包括:(a)预防易感染疾病或症状但还没诊断出患病的患者所发生的疾病或症状;(b)抑制疾病的症状,即阻止其发展;或(c)缓解疾病的症状,即,导致疾病或症状退化。
在本发明中,“受试者”指脊椎动物。在某些实施方案中,脊椎动物指哺乳动物。哺乳动物包括,但不限于,牲畜(诸如牛)、宠物(诸如猫、犬、和马)、灵长类动物、小鼠和大鼠。在某些实施方案中,哺乳动物指人。
在本发明中,“有效量”指在必需的剂量和时间上有效实现期望的治疗或预防效果的量。本发明的物质/分子的“治疗有效量”可根据诸如个体的疾病状态、年龄、性别和体重及该物质/分子在个体中引发期望应答的能力等因素而变化。治疗有效量还涵盖该物质/分子的治疗有益效果胜过任何有毒或有害后果的量。“预防有效量”指在必需的剂量和时间上有效实现期望的预防效果的量。通常而非必然,由于预防剂量是在疾病发作之前或在疾病的早期用于受试者的,因此预防有效量会低于治疗有效量。在癌症的情况中,药物的治疗有效量可减少癌细胞数;缩小肿瘤体积;抑制(即一定程度的减缓,优选停止)癌细胞浸润到周围器官中;抑制(即一定程度的减缓,优选停止)肿瘤转移;一定程度的抑制肿瘤生长;和/或一定程度的减轻与癌症有关的一种或多种症状。
在本发明中,20种常规氨基酸和其缩写遵从常规用法。参见Immunology-ASynthesis(第2版,E.S.Golub和D.R.Gren,Eds.,Sinauer Associates,Sunderland,Mass.(1991)),其通过引用合并入本文。
术语“嵌合抗体”是指这样的抗体,其中可变区序列源自一个物种,恒定区序列源自另一物种,如其中可变区序列源自小鼠抗体及恒定区序列源自人抗体的抗体。
“人源化”抗体是指非人(例如小鼠)抗体形式,其是嵌合的免疫球蛋白、免疫球蛋白链或者其片段(如Fv、Fab、Fab'、F(ab')2或者抗体的其它抗原结合亚序列),含有源自非人免疫球蛋白的最小序列。优选地,人源化抗体是人免疫球蛋白(接受者抗体),其中接受者抗体的互补决定区(CDR)的残基由来自具有希望的特异性、亲和性和能力的非人物种(供体抗体)如小鼠、大鼠或者兔的CDR残基置换。
此外,在人源化中,还可能对VH和/或VL的CDR1、CDR2和/或CDR3区内的氨基酸残基进行突变,由此改善抗体的一或多种结合特性(例如亲和性)。可进行例如PCR介导的突变引入突变,其对抗体结合或其它功能特性的影响可利用本文所述的体外或体内测试评估。通常,引入保守性突变。此类突变可为氨基酸取代、添加或缺失。另外,CDR内的突变通常不超过一个或两个。因此,本发明所述人源化抗体还涵盖CDR内包含1或2两个氨基酸突变的抗体。
下面结合具体实施例对本发明进行进一步的解释说明,但这些实施例并非限制本发明的范围。
实施例1人源化抗体的制备
1、抗紧密连接蛋白18.2单克隆抗体的制备
多种策略同时应用于免疫Balb/c小鼠和筛选,以获得特异性只结合紧密连接蛋白18.2,不结合紧密连接蛋白18不同剪接体紧密连接蛋白18.1的单克隆抗体,具体如下:
1)构建紧密连接蛋白18.2稳转细胞株
合成含人紧密连接蛋白18.1(UniProtKB-P56856)全长序列的质粒基因紧密连接蛋白18.1-puc57-Amp(苏州泓迅生物,SynbioTech)。以该质粒为模板,上游引物5’-ttggcaaagaattgctagatgtccaccaccacatgcc-3’(SEQ ID NO:171),下游引物5’-tgttcgggccctcctcgattacacatagtcgtgcttgg-3’(SEQ ID NO:172),PCR扩增人紧密连接蛋白18.1全长片段(Met1-Val261)。扩增产物经NEBuilder HiFi DNA Assembly Master Mix(NEB,Cat:M0530L)酶连后,克隆到真核表达质粒系统。以此类似,合成含人紧密连接蛋白18.2(UniProtKB-P56856-2)全长序列的质粒基因紧密连接蛋白18.2-puc57-Amp(苏州泓迅生物,SynbioTech)。以该质粒为模板,上游引物5’-ttggcaaagaattgctagatggccgtgactgcctgtc-3’(SEQ ID NO:173),下游引物5’-tgttcgggccctcctcgattacacatagtcgtgcttgg-3’(SEQID NO:174),PCR扩增人紧密连接蛋白18.2全长片段(Met1-Val261)。扩增产物经NEBuilderHiFi DNA Assembly Master Mix(NEB,Cat:M0530L)酶连后,克隆到真核表达质粒系统。以此质粒分别电转NIH3T3和HEK293细胞,使用1-10μg/mL Puromycin(Gibco,Cat:A1113803)进行逐步加压筛选稳定表达细胞系。
得到的HEK293-紧密连接蛋白18.1和HEK293-紧密连接蛋白18.2稳转细胞系首先用RT-PCR方法进行验证。用Trizol RNA提取试剂盒从阳性克隆细胞中提取总RNA,用逆转录试剂盒(SuperScriptTM First-Strand Synthesis System,Cat:18080051),利用Oligo(dT)引物逆转录得到cDNA文库。由于紧密连接蛋白的2个剪接片段紧密连接蛋白18.1和紧密连接蛋白18.2区别在于氮端到第一个胞外区(Loop1),设计引物KNB14(5’-tgtgcgccaccatggccgtg-3’(SEQ ID NO:175)),KNB15(5’-tggaaggataagattgtacc-3’(SEQID NO:176)),可以扩增紧密连接蛋白18.1和紧密连接蛋白18.2的Loop1之后到碳端之间区域(504bp);设计引物KNB16(5’-tgggtgccattggcctcctg-3’(SEQ ID NO:177)),特异性互补结合紧密连接蛋白18.2氮端,不结合紧密连接蛋白18.1氮端区域,只扩增紧密连接蛋白18.2的氮端到碳端之间全长片段(780bp),以表达紧密连接蛋白18.2的KATO III细胞(ATCCHTB-103)作为阳性对照。结果见图1,RT-PCR显示HEK293稳转细胞株分别表达紧密连接蛋白18.1和紧密连接蛋白18.2。HEK293-紧密连接蛋白18.2稳转细胞株和对照KATO III细胞均可扩增出紧密连接蛋白18.2特异性的780bp特征条带,而HEK293-紧密连接蛋白18.1只能扩增出504bp的共同片段。
将构建的稳转细胞株HEK293-紧密连接蛋白18.2细胞和NIH3T3-紧密连接蛋白18.2细胞消化收集,PBS洗2次,每管加入100μL 1:200稀释的一抗兔抗紧密连接蛋白18.2(Abcam,EPR19202,货号:ab222512),4℃孵育60分钟,用0.5%BSA/PBS洗去多余的一抗溶液,再加入50μL二抗山羊抗兔IgGFc-AF647(Jackson ImmunoResearch,货号:111-606-046),4℃孵育45分钟,之后用0.5%BSA/PBS洗去多余的二抗,最后用100μL PBS溶液重悬细胞,立即上流式细胞仪器检测。结果见图2、图3。
图2显示了通过FACS实验,检测转染紧密连接蛋白18.2全长基因的HEK293-紧密连接蛋白18.2稳转细胞株的结果。其中黑色点为未转染的HEK293细胞,灰色点为HEK293-紧密连接蛋白18.2稳转细胞株,HEK293细胞不表达紧密连接蛋白18.2,HEK293-紧密连接蛋白18.2稳转株在细胞膜表面高表达紧密连接蛋白18.2。
图3显示了通过FACS实验,检测紧密连接蛋白18.2在NIH3T3-紧密连接蛋白18.2高表达稳转细胞株的结果。其中黑色的线为阴性对照,灰色的阴影为3T3-紧密连接蛋白18.2稳转细胞株。NO.32-H为紧密连接蛋白18.2高表达的3T3-紧密连接蛋白18.2稳转细胞株,NO.18-M为紧密连接蛋白18.2中表达的3T3-紧密连接蛋白18.2稳转细胞株,NO.6-L为紧密连接蛋白18.2低表达的3T3-紧密连接蛋白18.2稳转细胞株。
将扩增生长的阳性稳转细胞系收集冻存,其中NIH3T3-紧密连接蛋白18.2稳转细胞株用于免疫动物。
2)从杂交瘤制备抗紧密连接蛋白18.2单克隆抗体
取6~8周雌性Balb/c小鼠,以3T3-紧密连接蛋白18.2稳转细胞或编码紧密连接蛋白18.2的质粒分别进行免疫,或交替进行免疫。用细胞进行免疫时,每次取1×106 3T3-紧密连接蛋白18.2稳转细胞与弗氏佐剂或非弗氏佐剂混合后,注射大腿根部和足垫,两周后在不同部位再次免疫。采用DNA进行免疫时,取20μg质粒与1μg CpG混合后,用基因枪(Biorad)40psi直接打入小鼠腹部,每周免疫一次。准备融合前3天,采用HEK293-紧密连接蛋白18.2高表达的稳转细胞株1×106细胞/50μL/只,进行尾静脉注射冲击免疫。三天后处死小鼠,收集腘淋巴结、腹股沟淋巴结、髂淋巴结,在DMEM中研磨得到富含B细胞的悬浮液;取出小鼠脾脏,在DMEM中研磨后离心,得到脾细胞悬浮液。取适量的淋巴结和脾细胞的混悬液和SP2/0混合后,采用电融合仪进行细胞融合。
3)构建抗紧密连接蛋白18.2噬菌体抗体库
将收集的部分小鼠脾脏与外周淋巴结细胞悬液,用Trizol RNA提取试剂盒提取总RNA,用逆转录试剂盒(SuperScript First-Strand Synthesis System,货号18080051),利用轻、重链特异性引物逆转录分别得到抗体轻、重链cDNA文库。以该cDNA为模板,利用轻、重链可变区引物PCR扩增抗体轻、重链可变区片段,酶切克隆到含有人抗体轻链恒定区Ckappa或人IgG1重链恒定区CH1的噬菌体质粒载体,分别形成嵌合体轻链库和重链库。将轻链库中的抗体片段以BspQI和SfiI双酶切后,连接进入重链库,形成基于丝状噬菌体M13的小鼠嵌合体Fab噬菌体展示文库,库容为1.2×1010。取0.8mL噬菌体(滴度约1x1013/mL)与200μL5%BSA/PBS混合后,加入1x107 HEK293-紧密连接蛋白18.1细胞,冰浴1小时;1000rpm离心10分钟,收集上清,将上清与1x106HEK293-紧密连接蛋白18.2细胞混合,冰浴1小时,1000rpm离心3分钟,弃上清;加入1mL 1%BSA/PBS,反复洗涤5-10次;加入1mL 100mM TEA(三乙胺)裂解细胞,室温10分钟,加入0.5mL 1M Tris-HCl,pH7.5中和后,感染10mL处于对数生长期的TG1 E.coli.细胞,37℃静置30分钟。按照分子生物学常规流程,回收噬菌体,检测滴度并进行下一轮筛选。
2、抗紧密连接蛋白18.2特异性抗体的筛选和序列获取
将HEK293-紧密连接蛋白18.1、HEK293-紧密连接蛋白18.2和HEK293分别以5μM、0.5μM和0μM Cell Tracker Green CMFDA Dye(Thermo,货号C2925)按说明进行活细胞预染,洗去染料后,按1:1:1混合,加至96孔板(2x105细胞/孔),并与杂交瘤上清或细菌诱导上清结合,冰浴孵育1小时后,加入AlexaFluro647标记的二抗抗mouse IgG Fc或抗人IgG F(ab)’2(Jackson ImmunoResearch),冰上孵育45分钟。洗涤后,每孔加入100μL PBS重悬细胞,准备流式细胞仪(iQue Screener),根据FL2通道荧光强度区别,分别圈出三种不同的细胞群后,检测FL4通道待测抗体与各细胞群的结合情况。筛选得到的抗体以高亲和力、特异性结合HEK293-紧密连接蛋白18.2稳转细胞,同时不结合HEK293-紧密连接蛋白18.1稳转细胞及HEK293细胞。从杂交瘤细胞中,通过FACS检测,共筛选出320个克隆可以结合紧密连接蛋白18.2,同时不结合紧密连接蛋白18.1;经过3轮panning,从噬菌体Fab库中,筛选得到62个高亲和力结合紧密连接蛋白18.2但不结合紧密连接蛋白18.1的克隆。
从噬菌体库筛选得到的阳性克隆,提取质粒进行测序,可变区序列分别克隆进入重链和轻链恒定区载体进行全长IgG表达。从杂交瘤得到的阳性细胞中,加入1mL TRNzol进行裂解,以异硫氢酸胍法提取总RNA。以此为模板,合成第一链cDNA后,以第一链cDNA为后续模板扩增杂交瘤细胞所对应的可变区DNA序列。将扩增产物测序后,得到候选杂交瘤重链和轻链可变区序列,如下所示。
克隆18D10:
重链
DVQLQESGPGLVKPSQSLSLTCTVTGYSITSNYAWNWIRQFPGNKLEWMGYINYSGNTNYNPSLKSRISITRDTSKNQFFLQLNSVTAEDTATYYCATSYYGNSFIYWGQGTLVTVSA(SEQ ID NO:139)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:140)、CDR2(SEQ ID NO:141)、CDR3(SEQ ID NO:142);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:143)、FR2(SEQ ID NO:144)、FR3(SEQ ID NO:145)、FR4(SEQ ID NO:146)。
核酸序列
GATGTGCAGCTTCAGGAGTCGGGACCTGGCCTGGTGAAACCTTCTCAGTCTCTGTCCCTCACCTGCACTGTCACTGGCTACTCAATCACCAGTAATTATGCCTGGAACTGGATCCGACAGTTTCCAGGAAACAAACTAGAGTGGATGGGCTACATAAACTACAGTGGGAACACTAACTATAACCCATCTCTCAAAAGTCGAATCTCTATCACTCGAGACACATCCAAGAACCAGTTCTTCCTGCAGTTGAATTCTGTGACTGCTGAGGACACAGCCACATATTATTGTGCAACCTCCTATTATGGTAATTCCTTTATTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA(SEQ ID NO:178)。
轻链
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNAYSFPWTFGGGTKLEIK(SEQ ID NO:147)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:148)、CDR2(SEQ ID NO:149)、CDR3(SEQ ID NO:150);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:151)、FR2(SEQ ID NO:152)、FR3(SEQ ID NO:153)、FR4(SEQ ID NO:154)。
核酸序列
GACATTGTGATGACACAGTCTCCATCCTCCCTGACTGTGACAGCAGGAGAGAAGGTCACTATGAGCTGCAAGTCCAGTCAGAGTCTGTTAAACAGTGGAAATCAAAAGAACTACTTGACCTGGTACCAGCAGAAACCAGGGCAGCCTCCTAAACTGTTGATCTACTGGGCATCCACTAGGGAGTCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGGAACAGATTTCACTCTCACCATCAGCAGTGTGCAGGCTGAAGACCTGGCAGTTTATTACTGTCAGAATGCTTATAGTTTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA(SEQ ID NO:179)。
克隆18A9:
重链
QVQLQQSGREVVRPGTSVKVSCKPSGYAFTNYLIDWVKQRPGQGLEWIGGINPGSGDTVYNEKFKAKATLTADKSSMTANMQLSSLTSDDSAVYFCARRVRGNSFDSWGQGTLVTVSA(SEQ ID NO:155)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:156)、CDR2(SEQ ID NO:157)、CDR3(SEQ ID NO:158);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:159)、FR2(SEQ ID NO:160)、FR3(SEQ ID NO:161)、FR4(SEQ ID NO:162)。
核酸序列
CAGGTGCAGCTGCAGCAGTCTGGACGTGAGGTGGTAAGGCCTGGGACTTCAGTGAAGGTGTCCTGCAAGCCTTCTGGATACGCCTTCACTAATTACTTGATAGACTGGGTAAAACAGAGGCCTGGACAGGGCCTTGAGTGGATTGGAGGGATTAATCCTGGAAGTGGTGACACTGTGTACAATGAGAAGTTCAAGGCCAAGGCAACACTGACTGCAGACAAATCCTCCATGACTGCCAACATGCAGCTCAGCAGCCTGACATCTGATGACTCTGCGGTCTATTTCTGCGCAAGAAGGGTCCGTGGTAATTCGTTTGATTCCTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA(SEQ ID NO:180)。
轻链
DIVMSQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGKDFTLTISSVQAEDLALYYCQNNYFYPLTFGAGTKLELK(SEQ ID NO:163)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:164)、CDR2(SEQ ID NO:165)、CDR3(SEQ ID NO:166);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:167)、FR2(SEQ ID NO:168)、FR3(SEQ ID NO:169)、FR4(SEQ ID NO:170)。
核酸序列
GACATTGTGATGTCACAGTCTCCATCCTCCCTGACTGTGACAGCAGGAGAGAAGGTCACTATGAGCTGCAAGTCCAGTCAGAGTCTGTTAAACAGTGGAAATCAAAAGAACTACTTGACCTGGTACCAGCAGAAACCAGGGCAGCCTCCTAAATTGTTGATCTACTGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGGAAAAGATTTCACTCTCACCATCAGCAGTGTGCAGGCTGAAGACCTGGCACTTTATTACTGTCAGAATAATTATTTTTATCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA(SEQ ID NO:181)。
上述重链和轻链可变区序列片段PCR扩增,将重链可变区克隆入含有人重链恒定区的载体,以在哺乳动物细胞中表达完整的IgG1重链。类似地,将轻链可变区克隆入含有人轻链恒定区的载体,以在哺乳动物细胞中表达完整的kappa轻链。经测序正确后转染入HEK293-6E哺乳动物细胞中,IgG1经表达分泌入培养基中,合并收集上清,过滤后纯化。采用Protein A层析纯化IgG,将培养上清液加载于大小合适的Protein A柱子上,用50mM Tris-HCl pH8.0,250mM NaCl洗涤,用0.1M Glycine-HCl,pH3.0将结合的IgG洗脱下来。利用浓缩管(Millipore)将蛋白超滤浓缩,检测OD280,通过分光光度法测定IgG的浓度。采用SDS-PAGE分析IgG的纯度。
取对数生长期的HEK293-紧密连接蛋白18.1细胞、HEK293-紧密连接蛋白18.2细胞和HEK293细胞,消化后以5×104细胞/100μL加入U型96孔板,1100rpm离心3分钟,弃上清,轻轻拍散细胞,每孔加入50μL梯度稀释的抗体(抗体浓度从100nM起,5倍稀释8个梯度),4℃孵育1小时。孵育结束后,每孔加入140μL 0.5%BSA洗3次,加30μL/孔二抗AlexaFluro647抗人IgG(Jackson ImmunoResearch,货号:109-606-170),4℃孵育40分钟。孵育结束后,每孔加入140μL 0.5%BSA洗3次,最后每孔重悬于50μL PBS进行流式细胞仪(iQue Screener)检测。结果如表1所示,结果显示,得到的嵌合体紧密连接蛋白18.2IgG1抗体只识别转染了紧密连接蛋白18.2的HEK293-紧密连接蛋白18.2细胞,但与HEK293和HEK293-紧密连接蛋白18.1无结合。
表1:紧密连接蛋白18.2抗体与稳转细胞株的结合(N.B.表示未检测到结合)
3、抗紧密连接蛋白18.2抗体的人源化
把选择的单克隆抗体可变区序列与人胚系抗体序列进行比对,找出同源性高的序列进行CDR移植;随后同时利用计算机进行同源建模,分析CDR区及其周边的框架氨基酸序列,考察其空间立体结合方式。通过计算静电力,范德华力,亲疏水性和熵值,分析各阳性单克隆抗体基因序列中可能与靶点相互作用以及维护空间构架的关键氨基酸个体,在此基础上设计回复突变位点。分析考察HLA-DR亲和性,选出免疫原性较低的人胚胎系框架序列。分析可能在发酵过程中发生修饰的氨基酸残基,并设计突变以降低发生修饰的可能性。
设计共得到不同的重链衍生物和轻链衍生物,将轻、重链衍生物分别进行全序列合成后,克隆到含有抗体kappa链恒定区Ckappa或人IgG1恒定区CH1-CH3的载体,同样母本来源的轻、重链衍生物质粒进行组合配对后,转染HEK293.6E细胞,表达5-6天,收取上清Protein A柱纯化。
人源化抗体的序列如下:
18D10:
重链可变区:
18D10VHv1:
QVQLQESGPGLVKPSETLSLTCTVSGYSITSNYAWNWIRQPPGKGLEWIGYINYSGNTNYNPSLKSRVTISRDTSKNQFSLKLSSVTAADTAVYYCATSYYGNSFIYWGQGTLVTVSS(SEQ ID NO:1)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:2)、CDR2(SEQ ID NO:3)、CDR3(SEQ ID NO:4);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:5)、FR2(SEQ ID NO:6)、FR3(SEQ ID NO:7)、FR4(SEQ ID NO:8)。
核酸序列
CAGGTTCAGCTGCAAGAGTCTGGACCTGGCCTGGTCAAGCCTAGCGAGACACTGAGCCTGACCTGTACCGTGTCCGGCTACAGCATCACCAGCAACTACGCCTGGAACTGGATCAGACAGCCTCCTGGCAAAGGCCTCGAGTGGATCGGCTACATCAACTACAGCGGCAACACCAACTACAACCCCAGCCTGAAGTCCAGAGTGACCATCAGCAGAGACACCAGCAAGAACCAGTTCTCCCTGAAGCTGAGCAGCGTGACAGCCGCCGATACAGCCGTGTACTACTGTGCCACAAGCTACTACGGCAACAGCTTCATCTACTGGGGCCAGGGCACACTGGTCACCGTTTCTTCT(SEQ ID NO:182)。
18D10VHv2:
QVQLQESGPGLVKPSETLSLTCTVSGGSISSNYAWNWIRQPPGKGLEWMGYINYSGNTNYNPSLKSRITISRDTSKNQFSLKLSSVTAADTAVYYCATSYYGNSFIYWGQGTLVTVSS(SEQ ID NO:9)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:10)、CDR2(SEQ ID NO:11)、CDR3(SEQ ID NO:12);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:13)、FR2(SEQ ID NO:14)、FR3(SEQ ID NO:15)、FR4(SEQ ID NO:16)。
核酸序列
CAGGTTCAGCTGCAAGAGTCTGGACCTGGCCTGGTCAAGCCTAGCGAGACACTGAGCCTGACCTGTACCGTGTCCGGCGGCAGCATCAGCAGCAACTACGCCTGGAACTGGATCAGACAGCCTCCTGGCAAAGGCCTCGAGTGGATGGGCTACATCAACTACAGCGGCAACACCAACTACAACCCCAGCCTGAAGTCCAGAATCACCATCAGCAGAGACACCAGCAAGAACCAGTTCTCCCTGAAGCTGAGCAGCGTGACAGCCGCCGATACAGCCGTGTACTACTGTGCCACAAGCTACTACGGCAACAGCTTCATCTACTGGGGCCAGGGCACACTGGTCACCGTTTCTTCT(SEQ ID NO:183)。
18D10VHv3:
QVQLQESGPGLVKPSETLSLTCTVSGGSISSNYAWNWIRQPPGKGLEWIGYINYSGNTNYNPSLKSRVTISRDTSKNQFSLKLSSVTAADTAVYYCATSYYGNSFIYWGQGTLVTVSS(SEQ ID NO:17)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:18)、CDR2(SEQ ID NO:19)、CDR3(SEQ ID NO:20);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:21)、FR2(SEQ ID NO:22)、FR3(SEQ ID NO:23)、FR4(SEQ ID NO:24)。
核酸序列
CAGGTTCAGCTGCAAGAGTCTGGACCTGGCCTGGTCAAGCCTAGCGAGACACTGAGCCTGACCTGTACCGTGTCCGGCGGCAGCATCAGCAGCAACTACGCCTGGAACTGGATCAGACAGCCTCCTGGCAAAGGCCTCGAGTGGATCGGCTACATCAACTACAGCGGCAACACCAACTACAACCCCAGCCTGAAGTCCAGAGTGACCATCAGCAGAGACACCAGCAAGAACCAGTTCTCCCTGAAGCTGAGCAGCGTGACAGCCGCCGATACAGCCGTGTACTACTGTGCCACAAGCTACTACGGCAACAGCTTCATCTACTGGGGCCAGGGCACACTGGTCACCGTTTCTTCT(SEQ ID NO:184)。
18D10VHv4:
QVQLQESGPGLVKPSETLSLTCTVSGGSISSNYAWNWIRQPPGKGLEWIGYINYSGYTNYNPSLKSRVTISRDTSKNQFSLKLSSVTAADTAVYYCATSYYGNSFIYWGQGTLVTVSS(SEQ ID NO:25)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:26)、CDR2(SEQ ID NO:27)、CDR3(SEQ ID NO:28);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:29)、FR2(SEQ ID NO:30)、FR3(SEQ ID NO:31)、FR4(SEQ ID NO:32)。
核酸序列
CAGGTTCAGCTGCAAGAGTCTGGACCTGGCCTGGTCAAGCCTAGCGAGACACTGAGCCTGACCTGTACCGTGTCCGGCGGCAGCATCAGCAGCAACTACGCCTGGAACTGGATCAGACAGCCTCCTGGCAAAGGCCTCGAGTGGATCGGCTACATCAACTACAGCGGCTACACCAACTACAACCCCAGCCTGAAGTCCAGAGTGACCATCAGCAGAGACACCAGCAAGAACCAGTTCTCCCTGAAGCTGAGCAGCGTGACAGCCGCCGATACAGCCGTGTACTACTGTGCCACAAGCTACTACGGCAACAGCTTCATCTACTGGGGCCAGGGCACACTGGTCACCGTTTCTTCT(SEQ ID NO:185)。
18D10VHv5:
QVQLQESGPGLVKPSETLSLTCTVSGGSISSNYAWNWIRQPPGKGLEWIGYINYSGNTAYNPSLKSRVTISRDTSKNQFSLKLSSVTAADTAVYYCATSYYGNSFIYWGQGTLVTVSS(SEQ ID NO:33)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:34)、CDR2(SEQ ID NO:35)、CDR3(SEQ ID NO:36);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:37)、FR2(SEQ ID NO:38)、FR3(SEQ ID NO:39)、FR4(SEQ ID NO:40)。
核酸序列
CAGGTTCAGCTGCAAGAGTCTGGACCTGGCCTGGTCAAGCCTAGCGAGACACTGAGCCTGACCTGTACCGTGTCCGGCGGCAGCATCAGCAGCAACTACGCCTGGAACTGGATCAGACAGCCTCCTGGCAAAGGCCTCGAGTGGATCGGCTACATCAACTACAGCGGCAACACCGCCTACAACCCCAGCCTGAAGTCCAGAGTGACCATCAGCAGAGACACCAGCAAGAACCAGTTCTCCCTGAAGCTGAGCAGCGTGACAGCCGCCGATACAGCCGTGTACTACTGTGCCACAAGCTACTACGGCAACAGCTTCATCTACTGGGGCCAGGGCACACTGGTCACCGTTTCTTCT(SEQ ID NO:186)。
18D10VHv6:
QVQLQESGPGLVKPSETLSLTCTVSGGSISSNYAWNWIRQPPGKGLEWIGYIYYSGNTNYNPSLKSRVTISRDTSKNQFSLKLSSVTAADTAVYYCATSYYGNSFIYWGQGTLVTVSS(SEQ ID NO:41)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:42)、CDR2(SEQ ID NO:43)、CDR3(SEQ ID NO:44);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:45)、FR2(SEQ ID NO:46)、FR3(SEQ ID NO:47)、FR4(SEQ ID NO:48)。
核酸序列
CAGGTTCAGCTGCAAGAGTCTGGACCTGGCCTGGTCAAGCCTAGCGAGACACTGAGCCTGACCTGTACCGTGTCCGGCGGCAGCATCAGCAGCAACTACGCCTGGAACTGGATCAGACAGCCTCCTGGCAAAGGCCTCGAGTGGATCGGCTACATCTACTACAGCGGCAACACCAACTACAACCCCAGCCTGAAGTCCAGAGTGACCATCAGCAGAGACACCAGCAAGAACCAGTTCTCCCTGAAGCTGAGCAGCGTGACAGCCGCCGATACAGCCGTGTACTACTGTGCCACAAGCTACTACGGCAACAGCTTCATCTACTGGGGCCAGGGCACACTGGTCACCGTTTCTTCT(SEQ ID NO:187)。
轻链可变区:
18D10VLv1:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNAYSFPWTFGQGTKVEIK(SEQ ID NO:49)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:50)、CDR2(SEQ ID NO:51)、CDR3(SEQ ID NO:52);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:53)、FR2(SEQ ID NO:54)、FR3(SEQ ID NO:55)、FR4(SEQ ID NO:56)。
核酸序列
GACATCGTGATGACACAGAGCCCTGATAGCCTGGCCGTGTCTCTGGGAGAGAGAGCCACCATCAACTGCAAGAGCAGCCAGAGCCTGCTGAACAGCGGCAACCAGAAGAACTACCTGACCTGGTATCAGCAGAAGCCCGGCCAGCCTCCTAAGCTGCTGATCTACTGGGCCAGCACCAGAGAAAGCGGCGTGCCAGATAGATTCAGCGGCAGCGGCTCTGGAACCGACTTCACCCTGACAATCAGCTCCCTGCAGGCCGAGGATGTGGCCGTGTACTACTGTCAGAACGCCTACAGCTTCCCCTGGACATTCGGCCAGGGCACCAAGGTGGAAATCAAG(SEQ ID NO:188)。
18D10VLv2:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQAYSFPWTFGQGTKVEIK(SEQ ID NO:57)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:58)、CDR2(SEQ ID NO:59)、CDR3(SEQ ID NO:60);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:61)、FR2(SEQ ID NO:62)、FR3(SEQ ID NO:63)、FR4(SEQ ID NO:64)。
核酸序列
GACATCGTGATGACACAGAGCCCTGATAGCCTGGCCGTGTCTCTGGGAGAGAGAGCCACCATCAACTGCAAGAGCAGCCAGAGCCTGCTGAACAGCGGCAACCAGAAGAACTACCTGGCCTGGTATCAGCAGAAGCCCGGCCAGCCTCCTAAGCTGCTGATCTACTGGGCCAGCACCAGAGAAAGCGGCGTGCCAGATAGATTCAGCGGCAGCGGCTCTGGAACCGACTTCACCCTGACAATCAGCTCCCTGCAGGCCGAGGATGTGGCCGTGTACTACTGTCAGCAGGCCTACAGCTTCCCCTGGACATTCGGCCAGGGCACCAAGGTGGAAATCAAG(SEQ ID NO:189)。
优选的人源化抗体的序列如下:
重链氨基酸序列:
QVQLQESGPGLVKPSETLSLTCTVSGGSISSNYAWNWIRQPPGKGLEWIGYIYYSGNTNYNPSLKSRVTISRDTSKNQFSLKLSSVTAADTAVYYCATSYYGNSFIYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:65)。
重链核酸序列
CAGGTTCAGCTGCAAGAGTCTGGACCTGGCCTGGTCAAGCCTAGCGAGACACTGAGCCTGACCTGTACCGTGTCCGGCGGCAGCATCAGCAGCAACTACGCCTGGAACTGGATCAGACAGCCTCCTGGCAAAGGCCTCGAGTGGATCGGCTACATCTACTACAGCGGCAACACCAACTACAACCCCAGCCTGAAGTCCAGAGTGACCATCAGCAGAGACACCAGCAAGAACCAGTTCTCCCTGAAGCTGAGCAGCGTGACAGCCGCCGATACAGCCGTGTACTACTGTGCCACAAGCTACTACGGCAACAGCTTCATCTACTGGGGCCAGGGCACACTGGTCACCGTTTCTTCTGCTAGCACCAAGGGCCCATCCGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGTCCCTCTCCCTGTCTCCGGGTAAATGA(SEQ ID NO:190)。
轻链氨基酸序列:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNAYSFPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:66)。
轻链核酸序列
GACATCGTGATGACACAGAGCCCTGATAGCCTGGCCGTGTCTCTGGGAGAGAGAGCCACCATCAACTGCAAGAGCAGCCAGAGCCTGCTGAACAGCGGCAACCAGAAGAACTACCTGACCTGGTATCAGCAGAAGCCCGGCCAGCCTCCTAAGCTGCTGATCTACTGGGCCAGCACCAGAGAAAGCGGCGTGCCAGATAGATTCAGCGGCAGCGGCTCTGGAACCGACTTCACCCTGACAATCAGCTCCCTGCAGGCCGAGGATGTGGCCGTGTACTACTGTCAGAACGCCTACAGCTTCCCCTGGACATTCGGCCAGGGCACCAAGGTGGAAATCAAGCGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG(SEQ ID NO:191)。
18A9:
重链可变区:
18A9VHv1:
QVQLVQSGAEVKKPGSSVKVSCKPSGYAFTNYLIDWVRQAPGQGLEWMGGINPGSGDTVYNEKFQGRVTLTADKSSMTAYMELSSLRSEDTAVYFCARRVRGNSFDSWGQGTLVTVSS(SEQ ID NO:67)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:68)、CDR2(SEQ ID NO:69)、CDR3(SEQ ID NO:70);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:71)、FR2(SEQ ID NO:72)、FR3(SEQ ID NO:73)、FR4(SEQ ID NO:74)。
核酸序列
CAGGTTCAGCTGGTTCAGTCTGGCGCCGAAGTGAAGAAACCTGGCAGCAGCGTGAAGGTGTCCTGCAAGCCTTCTGGCTACGCCTTCACCAACTACCTGATCGACTGGGTCCGACAGGCTCCTGGACAGGGACTTGAATGGATGGGCGGCATCAACCCTGGCAGCGGCGATACAGTGTACAACGAGAAGTTCCAGGGCAGAGTGACCCTGACCGCCGACAAGTCTAGCATGACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGATACCGCCGTGTACTTCTGTGCCAGAAGAGTGCGGGGCAACAGCTTCGATTCTTGGGGCCAGGGAACCCTGGTCACCGTTTCTTCT(SEQ ID NO:192)。
18A9VHv2:
QVQLVQSGAEVKKPGSSVKVSCKPSGYTFTNYLIDWVRQAPGQGLEWMGGINPGSGDTVYNEKFQGRVTLTADESTSTAYMELSSLRSEDTAVYFCARRVRGNSFDSWGQGTLVTVSS(SEQ ID NO:75)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:76)、CDR2(SEQ ID NO:77)、CDR3(SEQ ID NO:78);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:79)、FR2(SEQ ID NO:80)、FR3(SEQ ID NO:81)、FR4(SEQ ID NO:82)。
核酸序列
CAGGTTCAGCTGGTTCAGTCTGGCGCCGAAGTGAAGAAACCTGGCAGCAGCGTGAAGGTGTCCTGCAAGCCTTCTGGCTACACCTTCACCAACTACCTGATCGACTGGGTCCGACAGGCTCCTGGACAGGGACTTGAATGGATGGGCGGCATCAACCCTGGCAGCGGCGATACAGTGTACAACGAGAAGTTCCAGGGCAGAGTGACCCTGACCGCCGACGAGTCTACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGATACCGCCGTGTACTTCTGTGCCAGAAGAGTGCGGGGCAACAGCTTCGATTCTTGGGGCCAGGGAACCCTGGTCACCGTTTCTTCT(SEQ ID NO:193)。
18A9VHv3:
QVQLVQSGAEVKKPGSSVKVSCKPSGYTFTNYLIDWVRQAPGQGLEWMGGINPGSGDTVYNEKFQGRVTLTADKSSMTAYMELSSLRSEDTAVYYCARRVRGNSFDSWGQGTLVTVSS(SEQ ID NO:83)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:84)、CDR2(SEQ ID NO:85)、CDR3(SEQ ID NO:86);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:87)、FR2(SEQ ID NO:88)、FR3(SEQ ID NO:89)、FR4(SEQ ID NO:90)。
核酸序列
CAGGTTCAGCTGGTTCAGTCTGGCGCCGAAGTGAAGAAACCTGGCAGCAGCGTGAAGGTGTCCTGCAAGCCTTCTGGCTACACCTTCACCAACTACCTGATCGACTGGGTCCGACAGGCTCCTGGACAGGGACTTGAATGGATGGGCGGCATCAACCCTGGCAGCGGCGATACAGTGTACAACGAGAAGTTCCAGGGCAGAGTGACCCTGACCGCCGACAAGTCTAGCATGACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGATACCGCCGTGTACTACTGTGCCAGAAGAGTGCGGGGCAACAGCTTCGATTCTTGGGGCCAGGGAACCCTGGTCACCGTTTCTTCT(SEQ ID NO:194)。
18A9VHv4:
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYLIDWVRQAPGQGLEWMGGINPGSGDTVYNEKFQGRVTLTADKSSMTAYMELSSLRSEDTAVYFCARRVRGNSFDSWGQGTLVTVSS(SEQ ID NO:91)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:92)、CDR2(SEQ ID NO:93)、CDR3(SEQ ID NO:94);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:95)、FR2(SEQ ID NO:96)、FR3(SEQ ID NO:97)、FR4(SEQ ID NO:98)。
核酸序列
CAGGTTCAGCTGGTTCAGTCTGGCGCCGAAGTGAAGAAACCTGGCAGCAGCGTGAAGGTGTCCTGCAAGGCTTCTGGCTACACCTTCACCAACTACCTGATCGACTGGGTCCGACAGGCTCCTGGACAGGGACTTGAATGGATGGGCGGCATCAACCCTGGCAGCGGCGATACAGTGTACAACGAGAAGTTCCAGGGCAGAGTGACCCTGACCGCCGACAAGTCTAGCATGACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGATACCGCCGTGTACTTCTGTGCCAGAAGAGTGCGGGGCAACAGCTTCGATTCTTGGGGCCAGGGAACCCTGGTCACCGTTTCTTCT(SEQ ID NO:195)。
18A9VHv5:
QVQLVQSGAEVKKPGSSVKVSCKPSGYTFTNYLIDWVRQAPGQGLEWMGGINPGSGDTVYNEKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARRVRGNSFDSWGQGTLVTVSS(SEQ ID NO:99)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:100)、CDR2(SEQ ID NO:101)、CDR3(SEQ ID NO:102);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:103)、FR2(SEQ ID NO:104)、FR3(SEQ ID NO:105)、FR4(SEQ ID NO:106)。
核酸序列
CAGGTTCAGCTGGTTCAGTCTGGCGCCGAAGTGAAGAAACCTGGCAGCAGCGTGAAGGTGTCCTGCAAGCCTTCTGGCTACACCTTCACCAACTACCTGATCGACTGGGTCCGACAGGCTCCTGGACAGGGACTTGAATGGATGGGCGGCATCAACCCTGGCAGCGGCGATACAGTGTACAACGAGAAGTTCCAGGGCAGAGTGACCATCACCGCCGACGAGTCTACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGATACCGCCGTGTACTTCTGTGCCAGAAGAGTGCGGGGCAACAGCTTCGATTCTTGGGGCCAGGGAACCCTGGTCACCGTTTCTTCT(SEQ ID NO:196)。
18A9VHv6:
QVQLVQSGAEVKKPGASVKVSCKPSGYAFTNYLIDWVRQAPGQGLEWMGGINPGSGDTVYNEKFQGRVTLTADKSSSTAYMELSSLRSEDTAVYFCARRVRGNSFDSWGQGTLVTVSS(SEQ ID NO:107)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:108)、CDR2(SEQ ID NO:109)、CDR3(SEQ ID NO:110);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:111)、FR2(SEQ ID NO:112)、FR3(SEQ ID NO:113)、FR4(SEQ ID NO:114)。
核酸序列
CAGGTTCAGCTGGTTCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCAGCGTGAAGGTGTCCTGCAAGCCTTCTGGCTACGCCTTCACCAACTACCTGATCGACTGGGTCCGACAGGCTCCTGGACAGGGACTTGAATGGATGGGCGGCATCAACCCTGGCAGCGGCGATACAGTGTACAACGAGAAGTTCCAGGGCAGAGTGACCCTGACCGCCGACAAGTCTAGCAGCACCGCCTACATGGAACTGAGCAGCCTGAGAAGCGAGGATACCGCCGTGTACTTCTGTGCCAGAAGAGTGCGGGGCAACAGCTTCGATTCTTGGGGCCAGGGAACCCTGGTCACCGTTTCTTCT(SEQ ID NO:197)。
18A9VHv7:
QVQLVQSGAEVKKPGASVKVSCKPSGYTFTNYLIDWVRQAPGQGLEWMGGINPGSGDTVYNEKFQGRVTLTADTSTSTVYMELSSLRSEDTAVYFCARRVRGNSFDSWGQGTLVTVSS(SEQ ID NO:115)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:116)、CDR2(SEQ ID NO:117)、CDR3(SEQ ID NO:118);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:119)、FR2(SEQ ID NO:120)、FR3(SEQ ID NO:121)、FR4(SEQ ID NO:122)。
核酸序列
CAGGTTCAGCTGGTTCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCAGCGTGAAGGTGTCCTGCAAGCCTTCTGGCTACACCTTCACCAACTACCTGATCGACTGGGTCCGACAGGCTCCTGGACAGGGACTTGAATGGATGGGCGGCATCAACCCTGGCAGCGGCGATACAGTGTACAACGAGAAGTTCCAGGGCAGAGTGACCCTGACCGCCGACACCTCTACCAGCACCGTCTACATGGAACTGAGCAGCCTGAGAAGCGAGGATACCGCCGTGTACTTCTGTGCCAGAAGAGTGCGGGGCAACAGCTTCGATTCTTGGGGCCAGGGAACCCTGGTCACCGTTTCTTCT(SEQ ID NO:198)。
轻链可变区:
18A9VLv1:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGKDFTLTISSLQAEDVAVYYCQNNYFYPLTFGGGTKVEIK(SEQ ID NO:123)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:124)、CDR2(SEQ ID NO:125)、CDR3(SEQ ID NO:126);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:127)、FR2(SEQ ID NO:128)、FR3(SEQ ID NO:129)、FR4(SEQ ID NO:130)。
核酸序列
GACATCGTGATGACACAGAGCCCTGATAGCCTGGCCGTGTCTCTGGGAGAGAGAGCCACCATCAACTGCAAGAGCAGCCAGAGCCTGCTGAACAGCGGCAACCAGAAGAACTACCTGACCTGGTATCAGCAGAAGCCCGGCCAGCCTCCTAAGCTGCTGATCTACTGGGCCAGCACCAGAGAAAGCGGCGTGCCAGATAGATTCAGCGGCAGCGGCTCTGGAAAGGACTTCACCCTGACAATCAGCTCCCTGCAGGCCGAGGATGTGGCCGTGTACTACTGCCAGAACAACTACTTCTACCCTCTGACCTTCGGCGGAGGCACCAAGGTGGAAATCAAG(SEQ ID NO:199)。
18A9VLv2:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQNYFYPLTFGGGTKVEIK(SEQ ID NO:131)。
其中下划线部分从左向右依次分别为CDR1(SEQ ID NO:132)、CDR2(SEQ ID NO:133)、CDR3(SEQ ID NO:134);
无下划线部分从左向右依次分别为FR1(SEQ ID NO:135)、FR2(SEQ ID NO:136)、FR3(SEQ ID NO:137)、FR4(SEQ ID NO:138)。
核酸序列
GACATCGTGATGACACAGAGCCCTGATAGCCTGGCCGTGTCTCTGGGAGAGAGAGCCACCATCAACTGCAAGAGCAGCCAGAGCCTGCTGAACAGCGGCAACCAGAAGAACTACCTGGCCTGGTATCAGCAGAAGCCCGGCCAGCCTCCTAAGCTGCTGATCTACTGGGCCAGCACCAGAGAAAGCGGCGTGCCAGATAGATTCAGCGGCAGCGGCTCTGGAACCGACTTCACCCTGACAATCAGCTCCCTGCAGGCCGAGGATGTGGCCGTGTACTACTGCCAGCAGAACTACTTCTACCCTCTGACCTTCGGCGGAGGCACCAAGGTGGAAATCAAG(SEQ ID NO:200)。
实施例2人源化抗体药理学研究
1、人源化抗体的亲和力测定(EC50)
取对数生长期的细胞,3%BSA封闭30分钟以5×104细胞/100μL铺U型96孔板,1100rpm离心3分钟,弃上清,轻轻拍散细胞,每孔加入50μL梯度稀释的抗体(抗体浓度从100nM起,5倍稀释8个梯度),4℃孵育1小时。孵育结束后,每孔加入140μL0.5%BSA洗3次,加30μL/孔AF 647APC抗人二抗4℃孵育40分钟。孵育结束后,每孔加入140μL 0.5%BSA洗3次,最后每孔重悬于50μL PBS进行iQue(Intellicyt,USA)检测(见表2)。
表2:人源化抗体的亲和力测定结果
2、CM311抗体对肿瘤细胞的ADCC杀伤活性
取30mL鲜血至50mL离心管中,加入15mL 1×PBS,混和均匀,缓慢加入至已加入20mL Ficoll.Paque Plu的离心管中,使血液铺于Ficoll.Paque Plu表面。20℃,2000rpm离心30分钟,弃最上层血清,吸取白膜层(即PBMC),分装至50mL离心管,每管10mL。每管加入不低于30mL的1×PBS,混合均匀。4℃,1300rpm离心10分钟,弃上清,加入10mL 1×PBS清洗并计数。
FBS/RPMI 1640培养基重悬细胞,37℃,5%CO2培养2小时。1300rpm离心10分钟,弃上清,FBS/RPMI 1640培养基重悬,接种细胞于U型96孔板中,4*105个/孔,50μL/孔。加入前述18D10嵌合体,18A9嵌合体,抗紧密连接蛋白18.2人源化抗体18D10、18A9(即CM311,CM311为人源化抗体18D10或18A9的统称)以及对照抗体anti-KLH的稀释液(40、20、10、5、2.5、1.25μg/mL),25μL/孔。37℃,5%CO2孵育30分钟。取出孔板,加入Kato III细胞,8×103个/孔,25μL/孔。37℃5%CO2孵育3.5小时,向靶细胞最大释放孔加入2μL 10*裂解液,37℃5%CO2继续孵育30分钟。取出孔板,1000rpm离心3分钟,取上清至黑色酶标板,50μL/孔。加入LDH检测底物50μL/孔,室温孵育10分钟,加入终止液25μL/孔,终止反应。酶标仪(Biotek)检测。
结果计算如下:
结果如图4所示,抗紧密连接蛋白18.2人源化抗体18D10、18A9具有较强的ADCC活性。
3、CM311抗体对肿瘤细胞的CDC细胞杀伤活性
取对数生长期的Kato III细胞重悬至1×107个/mL。加入CFSE(Sigma,87444-5MG-F),终浓度为1μM。室温孵育10分钟,加入3倍体积培养基终止反应。4℃1000rpm离心5分钟,弃上清,培养基重悬,接种细胞至96孔板,1*105个/孔,50μL/孔。加入已稀释的前述18D10嵌合体,18A9嵌合体,抗紧密连接蛋白18.2人源化抗体18D10、18A9(CM311)以及对照抗体anti-KLH(稀释后浓度为30、10、3.33、1.11、0.37μg/mL),50μL/孔。用培养基稀释补体至30%,加入孔板,50μL/孔。37℃,5%CO2孵育2小时,1000rpm离心3分钟,弃上清。1:200稀释PI染液,与Sulfate latex(Invitrogen,S37227)混匀后加入96孔板中,100μL/孔。冰上孵育10分钟,FACS检测。结果如图5所示,抗紧密连接蛋白18.2人源化抗体18D10、18A9具有较强的CDC效应。
实施例3抗体药物偶联物的制备和检测
1、抗体药物偶联物的制备
取10毫克的CM311抗体,使用15mL的30KD超滤装置置换到还原缓冲液(25mM硼酸钠,pH8.0,25mM NaCl,5mM EDTA)中,共三次置换;终体积约为1mL,转移至新的Eppendorf离心管(称重)中,并称重;检测蛋白浓度,计算蛋白总量。向抗体中加入2.5倍摩尔数的DTT,室温保温2小时,连续混匀;使用15mL的30KD超滤装置置换到偶联缓冲液(50mM Tris,pH7.2,150mM NaCl,5mM EDTA)中,共三次置换。取样以A280测定蛋白浓度,并称重,计算蛋白总量;取10μL样品,以Ellman’s方法测定自由巯基数;
并以下列公式计算其自由巯基的摩尔浓度:
b:比色皿光路长度(通常1cm)
根据自由巯基的摩尔浓度和总蛋白溶液体积计算自由巯基摩尔数。
向还原后的抗体中加入1.1倍于自由巯基摩尔数的vc-MMAE即MC-vc-PAB-MMAE(溶于DMSO),混匀后室温反应2小时,间断混匀。向反应体系中加入20倍于所投入之vc-MMAE(即MC-vc-PAB-MMAE)摩尔数的N-乙酰半胱氨酸于反应液中,混匀,静置5分钟。使用15mL的30KD超滤装置置换到偶联物储存液(20mM组氨酸(Histidine),3%蔗糖(Sucrose),0.03%Tween-80,pH5.5)中,共三次置换,即得到抗体药物偶联物产物Anti-Claudin-18.2-ADC(人源化抗体18D10或18A9制备的抗体药物偶联物的统称)于4℃保存。
2、抗体药物偶联物的DAR测定
抗体药物偶联物的载药量(DAR)是用疏水作用色谱法(HIC-HPLC)检测而得的。
典型的抗体药物偶联物CM311-18D10-VH6/VL1-ADC的图谱见图6。根据该图谱峰面积计算得到平均载药数DAR为3.8。
类似地可得,抗体药物偶联物CM311-18D10-VH3/VL2-ADC的平均载药数DAR为3.5。
抗体药物偶联物CM311-18D10-VH6/VL2-ADC的平均载药数DAR为3.4。
抗体药物偶联物CM311-18A9-VH7/VL2-ADC的平均载药数DAR为3.0。
需要说明的是,以上抗体药物偶联物的名称如CM311-18D10-VH6/VL1-ADC,其表示制备该抗体药物偶联物时使用的抗体为CM311-18D10-VH6/VL1。进一步地,该抗体名称CM311-18D10-VH6/VL1表示制备前述抗体药物偶联物时使用的抗体为18D10这一类中重链可变区为VHv6且轻链可变区为VLv1的抗体,对应上表2可知,制备前述抗体药物偶联物时使用的具体抗体为h18D10.v16。其余三种抗体药物偶联物CM311-18D10-VH3/VL2-ADC、CM311-18D10-VH6/VL2-ADC、CM311-18A9-VH7/VL2-ADC的名称可参照前述进行理解。具体地,制备抗体药物偶联物CM311-18D10-VH3/VL2-ADC时使用的具体抗体为表2中的h18D10.v23;制备抗体药物偶联物CM311-18D10-VH6/VL2-ADC时使用的具体抗体为表2中的h18D10.v26;制备抗体药物偶联物CM311-18A9-VH7/VL2-ADC时使用的具体抗体为表2中的h18A9.v27。
实施例4抗体药物偶联物体外药效学研究
复苏后的细胞株经过1-2代细胞传代之后,先吸取上清液至15mL离心管内,离心机离心,弃上清;用5mL PBS润洗细胞培养瓶,再用2mL胰蛋白酶消化细胞,用培养基重悬至之前的15mL离心管内,离心机离心,弃上清,再用培养基再次重悬,取出0.5mL用细胞计数仪计数。在96孔细胞培养板上进行铺板(LT-1C8细胞以5000或10000个细胞/孔,LT-M11细胞以5000个细胞/孔,BxPC-3以3000个细胞/孔),培养24小时后,加入系列稀释浓度的抗体药物偶联物CM311ADC(由不同CM311单抗偶联而成)保温96小时,之后每孔加入CCK-8或者Presto-Blue显色试剂,用酶标仪检测并进行四参数拟合。
实验试剂及来源:
受试药物
抗体药物偶联物名称 | 浓度 | 保存条件 |
CM311-18D10-VH3/VL2-ADC | 1.0mg/mL | 2-8℃ |
CM311-18D10-VH6/VL1-ADC | 1.2mg/mL | 2-8℃ |
CM311-18D10-VH6/VL2-ADC | 0.9mg/mL | 2-8℃ |
CM311-18A9-VH7/VL2-ADC | 0.7mg/mL | 2-8℃ |
细胞株
实验结果:
各CM311ADC的IC50的平均值见表3。图7为不同CM311ADC对LT-M11细胞杀伤的代表性图。
表3:不同CM311ADC在所筛选的细胞株中的IC50值
注:图7中:
Sample 1:CM311-18D10-VH3/VL2-ADC
Sample 2:CM311-18D10-VH6/VL1-ADC
Sample 3:CM311-18D10-VH6/VL2-ADC
Sample 4:CM311-18A9-VH7/VL2-ADC
从表3和图7的结果可以看出,不同CM311ADC在Claudin18.2中、高度表达的细胞株中均表现出显著的细胞杀伤活性,在Claudin18.2阴性的BxPC-3细胞株中无显著细胞杀伤活性。
实施例5抗体药物偶联物体内药效学研究
CM311ADC的抗肿瘤活性在STO#025和STO#523两个胃癌PDX模型中进行了测试。这两个胃癌模型都有较高的Claudin 18mRNA水平。
人胃癌裸小鼠PDX模型的建立过程为:将体积大小约为15-30mm3的肿瘤组织移植于BALB/c裸小鼠背部皮下。当肿瘤体积达到150-260mm3时,用随机区组法分组,每组5只小鼠,保证各组间肿瘤体积均一并兼顾体重,共4组,包括溶媒组、1mg/kg CM311-ADC-1给药组、3mg/kg CM311-ADC-1给药组和3mg/kg CM311-ADC-2(非结合对照ADC)给药组。其中,CM311-ADC-1指的是抗体药物偶联物CM311-18D10-VH6/VL1-ADC;CM311-ADC-2相比于CM311-ADC-1,抗体是人IgG1同型对照,与肿瘤细胞表面的靶点无结合。
数据分析:实验期间,每周测定两次肿瘤体积。肿瘤体积(Tumor Volume,TV)的计算公式为:TV=l×w2/2。其中l、w分别代表肿瘤测量长和宽。根据测量结果计算出相对肿瘤体积(relative tumor volume,RTV),RTV=Vf/V0。其中V0为分组给药时(即Day 0)测量所得肿瘤体积,Vf为最后一天测量的肿瘤体积。相对肿瘤增殖率T/C(%)=(给药组RTV/Vehicle组RTV)×100%。肿瘤生长抑制率TGI%=(Vehicle组平均肿瘤体积-给药组平均肿瘤体积)/Vehicle组平均肿瘤体积×100%。当T/C(%)≤40%,且P<0.05时认为供试品对肿瘤生长有显著抑制作用。
实验结果:
1)CM311ADC在Claudin 18mRNA高表达水平的人胃癌PDX模型STO#025中的疗效研究
实验结果如图8和图9所示。CM311-ADC-1按1和3mg/kg剂量给药后,Day 28的相对肿瘤增殖率T/C(%)分别为29.86%和0%,肿瘤生长抑制率TGI%分别为70.13%和100%,分别有0/5和5/5的肿瘤完全消退,以及2/5和0/5的肿瘤部分消退;CM311-ADC-2(3mg/kg)组T/C(%)为67.24%,TGI%为32.76%,实验结果表明,CM311-ADC-1(3mg/kg)和CM311-ADC-1(1mg/kg)均具有显著抑制肿瘤生长的活性,CM311-ADC-2(3mg/kg)无显著抗肿瘤活性。荷瘤小鼠对CM311-ADC-1和CM311-ADC-2均有很好的耐受性。
2)CM311ADC在Claudin 18mRNA高表达水平的人胃癌PDX模型STO#523中的疗效研究
实验结果如图10和图11所示。CM311-ADC-1按1和3mg/kg剂量给药后,Day 28的相对肿瘤增殖率T/C(%)分别为35.60%和6.79%,肿瘤生长抑制率TGI%分别为64.40%和93.21%;CM311-ADC-2(3mg/kg)组T/C(%)为114.81%,TGI%为-14.81%,实验结果表明,CM311-ADC-1(3mg/kg)和CM311-ADC-1(1mg/kg)均具有显著抑制肿瘤生长的活性,CM311-ADC-2(3mg/kg)无显著抗肿瘤活性。荷瘤小鼠对CM311-ADC-1和CM311-ADC-2均有很好的耐受性。
实施例6抗体与抗体药物偶联物的体外细胞活性比较
测试方法:
KATO III细胞株以5000cells/孔铺板,24小时后加入待测样品。待测样品均以终浓度1000ng/mL 2.4倍稀释9次,作用96小时,Presto-Blue显色60min后使用酶标仪读取荧光值。
待测样品如下:
Sample1:CM311,具体为CM311-18D10-VH6/VL1;
Sample2:Anti-Claudin-18.2-ADC,具体为CM311-18D10-VH6/VL1-ADC;
Sample3:非结合对照ADC,具体为IgG-L1D1(IgG-L1D1即IgG抗体偶联了L1D1小分子(即vcMMAE,也就是MC-vc-PAB-MMAE)药物的ADC)。
测试结果如图12和表4所示。从图12中可以看出,Anti-Claudin-18.2-ADC(例如CM311-18D10-VH6/VL1-ADC)显示很强的细胞杀伤作用,EC50值为16.37ng/mL;而CM311(例如CM311-18D10-VH6/VL1)和IgG-L1D1均未显示明显的细胞杀伤作用。
表4:抗体与抗体药物偶联物的体外细胞活性比较结果(4参数拟合结果)
SEQUENCE LISTING
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康诺亚生物医药科技(成都)有限公司
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<213> Artificial
<220>
<223> 18D10VHv3 FR2
<400> 22
Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
1 5 10
<210> 23
<211> 32
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv3 FR3
<400> 23
Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys
1 5 10 15
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Thr
20 25 30
<210> 24
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv3 FR4
<400> 24
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 25
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv4
<400> 25
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 Asn
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Asn Tyr Ser Gly Tyr Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Ser Tyr Tyr Gly Asn Ser Phe Ile Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 26
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv4 CDR1
<400> 26
Gly Gly Ser Ile Ser Ser Asn Tyr Ala Trp Asn
1 5 10
<210> 27
<211> 16
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv4 CDR2
<400> 27
Tyr Ile Asn Tyr Ser Gly Tyr Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 28
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv4 CDR3
<400> 28
Ser Tyr Tyr Gly Asn Ser Phe Ile Tyr
1 5
<210> 29
<211> 25
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv4 FR1
<400> 29
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
20 25
<210> 30
<211> 14
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv4 FR2
<400> 30
Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
1 5 10
<210> 31
<211> 32
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv4 FR3
<400> 31
Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys
1 5 10 15
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Thr
20 25 30
<210> 32
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv4 FR4
<400> 32
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 33
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv5
<400> 33
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 Asn
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Asn Tyr Ser Gly Asn Thr Ala Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Ser Tyr Tyr Gly Asn Ser Phe Ile Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 34
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv5 CDR1
<400> 34
Gly Gly Ser Ile Ser Ser Asn Tyr Ala Trp Asn
1 5 10
<210> 35
<211> 16
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv5 CDR2
<400> 35
Tyr Ile Asn Tyr Ser Gly Asn Thr Ala Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 36
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv5 CDR3
<400> 36
Ser Tyr Tyr Gly Asn Ser Phe Ile Tyr
1 5
<210> 37
<211> 25
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv5 FR1
<400> 37
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
20 25
<210> 38
<211> 14
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv5 FR2
<400> 38
Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
1 5 10
<210> 39
<211> 32
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv5 FR3
<400> 39
Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys
1 5 10 15
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Thr
20 25 30
<210> 40
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv5 FR4
<400> 40
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 41
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv6
<400> 41
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 Asn
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Ser Tyr Tyr Gly Asn Ser Phe Ile Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 42
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv6 CDR1
<400> 42
Gly Gly Ser Ile Ser Ser Asn Tyr Ala Trp Asn
1 5 10
<210> 43
<211> 16
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv6 CDR2
<400> 43
Tyr Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 44
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv6 CDR3
<400> 44
Ser Tyr Tyr Gly Asn Ser Phe Ile Tyr
1 5
<210> 45
<211> 25
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv6 FR1
<400> 45
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
20 25
<210> 46
<211> 14
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv6 FR2
<400> 46
Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
1 5 10
<210> 47
<211> 32
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv6 FR3
<400> 47
Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys
1 5 10 15
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Thr
20 25 30
<210> 48
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 18D10VHv6 FR4
<400> 48
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 49
<211> 113
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv1
<400> 49
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Ser Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 50
<211> 17
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv1 CDR1
<400> 50
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 51
<211> 7
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv1 CDR2
<400> 51
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 52
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv1 CDR3
<400> 52
Gln Asn Ala Tyr Ser Phe Pro Trp Thr
1 5
<210> 53
<211> 23
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv1 FR1
<400> 53
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys
20
<210> 54
<211> 15
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv1 FR2
<400> 54
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 55
<211> 32
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv1 FR3
<400> 55
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys
20 25 30
<210> 56
<211> 10
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv1 FR4
<400> 56
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 57
<211> 113
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv2
<400> 57
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Ala Tyr Ser Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 58
<211> 17
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv2 CDR1
<400> 58
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 59
<211> 7
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv2 CDR2
<400> 59
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 60
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv2 CDR3
<400> 60
Gln Gln Ala Tyr Ser Phe Pro Trp Thr
1 5
<210> 61
<211> 23
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv2 FR1
<400> 61
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys
20
<210> 62
<211> 15
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv2 FR2
<400> 62
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 63
<211> 32
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv2 FR3
<400> 63
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys
20 25 30
<210> 64
<211> 10
<212> PRT
<213> Artificial
<220>
<223> 18D10VLv2 FR4
<400> 64
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 65
<211> 448
<212> PRT
<213> Artificial
<220>
<223> 重链
<400> 65
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 Asn
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Ser Tyr Tyr Gly Asn Ser Phe Ile Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 66
<211> 220
<212> PRT
<213> Artificial
<220>
<223> 轻链
<400> 66
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Ser Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 67
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv1
<400> 67
Gln 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 Pro Ser Gly Tyr Ala Phe Thr Asn Tyr
20 25 30
Leu Ile Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Ser Met Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Arg Val Arg Gly Asn Ser Phe Asp Ser Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 68
<211> 10
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv1 CDR1
<400> 68
Gly Tyr Ala Phe Thr Asn Tyr Leu Ile Asp
1 5 10
<210> 69
<211> 16
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv1 CDR2
<400> 69
Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe Gln
1 5 10 15
<210> 70
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv1 CDR3
<400> 70
Arg Val Arg Gly Asn Ser Phe Asp Ser
1 5
<210> 71
<211> 25
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv1 FR1
<400> 71
Gln 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 Pro Ser
20 25
<210> 72
<211> 14
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv1 FR2
<400> 72
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 73
<211> 33
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv1 FR3
<400> 73
Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Ser Met Thr Ala Tyr Met
1 5 10 15
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys Ala
20 25 30
Arg
<210> 74
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv1 FR4
<400> 74
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 75
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv2
<400> 75
Gln 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 Pro Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Leu Ile Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Arg Val Arg Gly Asn Ser Phe Asp Ser Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 76
<211> 10
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv2 CDR1
<400> 76
Gly Tyr Thr Phe Thr Asn Tyr Leu Ile Asp
1 5 10
<210> 77
<211> 16
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv2 CDR2
<400> 77
Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe Gln
1 5 10 15
<210> 78
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv2 CDR3
<400> 78
Arg Val Arg Gly Asn Ser Phe Asp Ser
1 5
<210> 79
<211> 25
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv2 FR1
<400> 79
Gln 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 Pro Ser
20 25
<210> 80
<211> 14
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv2 FR2
<400> 80
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 81
<211> 33
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv2 FR3
<400> 81
Gly Arg Val Thr Leu Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met
1 5 10 15
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys Ala
20 25 30
Arg
<210> 82
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv2 FR4
<400> 82
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 83
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv3
<400> 83
Gln 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 Pro Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Leu Ile Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Ser Met 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 Arg Val Arg Gly Asn Ser Phe Asp Ser Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 84
<211> 10
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv3 CDR1
<400> 84
Gly Tyr Thr Phe Thr Asn Tyr Leu Ile Asp
1 5 10
<210> 85
<211> 16
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv3 CDR2
<400> 85
Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe Gln
1 5 10 15
<210> 86
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv3 CDR3
<400> 86
Arg Val Arg Gly Asn Ser Phe Asp Ser
1 5
<210> 87
<211> 25
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv3 FR1
<400> 87
Gln 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 Pro Ser
20 25
<210> 88
<211> 14
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv3 FR2
<400> 88
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 89
<211> 33
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv3 FR3
<400> 89
Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Ser Met Thr Ala Tyr Met
1 5 10 15
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
20 25 30
Arg
<210> 90
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv3 FR4
<400> 90
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 91
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv4
<400> 91
Gln 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
Leu Ile Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Ser Met Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Arg Val Arg Gly Asn Ser Phe Asp Ser Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 92
<211> 10
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv4 CDR1
<400> 92
Gly Tyr Thr Phe Thr Asn Tyr Leu Ile Asp
1 5 10
<210> 93
<211> 16
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv4 CDR2
<400> 93
Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe Gln
1 5 10 15
<210> 94
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv4 CDR3
<400> 94
Arg Val Arg Gly Asn Ser Phe Asp Ser
1 5
<210> 95
<211> 25
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv4 FR1
<400> 95
Gln 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
20 25
<210> 96
<211> 14
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv4 FR2
<400> 96
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 97
<211> 33
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv4 FR3
<400> 97
Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Ser Met Thr Ala Tyr Met
1 5 10 15
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys Ala
20 25 30
Arg
<210> 98
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv4 FR4
<400> 98
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 99
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv5
<400> 99
Gln 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 Pro Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Leu Ile Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Arg Val Arg Gly Asn Ser Phe Asp Ser Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 100
<211> 10
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv5 CDR1
<400> 100
Gly Tyr Thr Phe Thr Asn Tyr Leu Ile Asp
1 5 10
<210> 101
<211> 16
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv5 CDR2
<400> 101
Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe Gln
1 5 10 15
<210> 102
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv5 CDR3
<400> 102
Arg Val Arg Gly Asn Ser Phe Asp Ser
1 5
<210> 103
<211> 25
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv5 FR1
<400> 103
Gln 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 Pro Ser
20 25
<210> 104
<211> 14
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv5 FR2
<400> 104
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 105
<211> 33
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv5 FR3
<400> 105
Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met
1 5 10 15
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys Ala
20 25 30
Arg
<210> 106
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv5 FR4
<400> 106
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 107
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv6
<400> 107
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Pro Ser Gly Tyr Ala Phe Thr Asn Tyr
20 25 30
Leu Ile Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Arg Val Arg Gly Asn Ser Phe Asp Ser Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 108
<211> 10
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv6 CDR1
<400> 108
Gly Tyr Ala Phe Thr Asn Tyr Leu Ile Asp
1 5 10
<210> 109
<211> 16
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv6 CDR2
<400> 109
Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe Gln
1 5 10 15
<210> 110
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv6 CDR3
<400> 110
Arg Val Arg Gly Asn Ser Phe Asp Ser
1 5
<210> 111
<211> 25
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv6 FR1
<400> 111
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Pro Ser
20 25
<210> 112
<211> 14
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv6 FR2
<400> 112
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 113
<211> 33
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv6 FR3
<400> 113
Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met
1 5 10 15
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys Ala
20 25 30
Arg
<210> 114
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv6 FR4
<400> 114
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 115
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv7
<400> 115
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Pro Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Leu Ile Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Ala 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 Phe Cys
85 90 95
Ala Arg Arg Val Arg Gly Asn Ser Phe Asp Ser Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 116
<211> 10
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv7 CDR1
<400> 116
Gly Tyr Thr Phe Thr Asn Tyr Leu Ile Asp
1 5 10
<210> 117
<211> 16
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv7 CDR2
<400> 117
Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe Gln
1 5 10 15
<210> 118
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv7 CDR3
<400> 118
Arg Val Arg Gly Asn Ser Phe Asp Ser
1 5
<210> 119
<211> 25
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv7 FR1
<400> 119
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Pro Ser
20 25
<210> 120
<211> 14
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv7 FR2
<400> 120
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 121
<211> 33
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv7 FR3
<400> 121
Gly Arg Val Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr Met
1 5 10 15
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys Ala
20 25 30
Arg
<210> 122
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 18A9VHv7 FR4
<400> 122
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 123
<211> 113
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv1
<400> 123
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Lys Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asn Tyr Phe Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 124
<211> 17
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv1 CDR1
<400> 124
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 125
<211> 7
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv1 CDR2
<400> 125
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 126
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv1 CDR3
<400> 126
Gln Asn Asn Tyr Phe Tyr Pro Leu Thr
1 5
<210> 127
<211> 23
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv1 FR1
<400> 127
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys
20
<210> 128
<211> 15
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv1 FR2
<400> 128
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 129
<211> 32
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv1 FR3
<400> 129
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Lys Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys
20 25 30
<210> 130
<211> 10
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv1 FR4
<400> 130
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 131
<211> 113
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv2
<400> 131
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Asn Tyr Phe Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 132
<211> 17
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv2 CDR1
<400> 132
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 133
<211> 7
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv2 CDR2
<400> 133
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 134
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv2 CDR3
<400> 134
Gln Gln Asn Tyr Phe Tyr Pro Leu Thr
1 5
<210> 135
<211> 23
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv2 FR1
<400> 135
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys
20
<210> 136
<211> 15
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv2 FR2
<400> 136
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 137
<211> 32
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv2 FR3
<400> 137
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys
20 25 30
<210> 138
<211> 10
<212> PRT
<213> Artificial
<220>
<223> 18A9VLv2 FR4
<400> 138
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 139
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 重链
<400> 139
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asn
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Asn Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Ala Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Thr Ser Tyr Tyr Gly Asn Ser Phe Ile Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 140
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 重链 CDR1
<400> 140
Gly Tyr Ser Ile Thr Ser Asn Tyr Ala Trp Asn
1 5 10
<210> 141
<211> 16
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 重链 CDR2
<400> 141
Tyr Ile Asn Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 142
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 重链 CDR3
<400> 142
Ser Tyr Tyr Gly Asn Ser Phe Ile Tyr
1 5
<210> 143
<211> 25
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 重链 FR1
<400> 143
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr
20 25
<210> 144
<211> 14
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 重链 FR2
<400> 144
Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met Gly
1 5 10
<210> 145
<211> 32
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 重链 FR3
<400> 145
Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu Gln
1 5 10 15
Leu Asn Ser Val Thr Ala Glu Asp Thr Ala Thr Tyr Tyr Cys Ala Thr
20 25 30
<210> 146
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 重链 FR4
<400> 146
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
1 5 10
<210> 147
<211> 113
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 轻链
<400> 147
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Ser Phe Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 148
<211> 17
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 轻链 CDR1
<400> 148
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 149
<211> 7
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 轻链 CDR2
<400> 149
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 150
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 轻链 CDR3
<400> 150
Gln Asn Ala Tyr Ser Phe Pro Trp Thr
1 5
<210> 151
<211> 23
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 轻链 FR1
<400> 151
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys
20
<210> 152
<211> 15
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 轻链 FR2
<400> 152
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 153
<211> 32
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 轻链 FR3
<400> 153
Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys
20 25 30
<210> 154
<211> 10
<212> PRT
<213> Artificial
<220>
<223> 克隆18D10 轻链 FR4
<400> 154
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 155
<211> 118
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 重链
<400> 155
Gln Val Gln Leu Gln Gln Ser Gly Arg Glu Val Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Val Ser Cys Lys Pro Ser Gly Tyr Ala Phe Thr Asn Tyr
20 25 30
Leu Ile Asp Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe
50 55 60
Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Met Thr Ala Asn
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Arg Val Arg Gly Asn Ser Phe Asp Ser Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 156
<211> 10
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 重链 CDR1
<400> 156
Gly Tyr Ala Phe Thr Asn Tyr Leu Ile Asp
1 5 10
<210> 157
<211> 16
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 重链 CDR2
<400> 157
Gly Ile Asn Pro Gly Ser Gly Asp Thr Val Tyr Asn Glu Lys Phe Lys
1 5 10 15
<210> 158
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 重链 CDR3
<400> 158
Arg Val Arg Gly Asn Ser Phe Asp Ser
1 5
<210> 159
<211> 25
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 重链 FR1
<400> 159
Gln Val Gln Leu Gln Gln Ser Gly Arg Glu Val Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Val Ser Cys Lys Pro Ser
20 25
<210> 160
<211> 14
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 重链 FR2
<400> 160
Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 161
<211> 33
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 重链 FR3
<400> 161
Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Met Thr Ala Asn Met
1 5 10 15
Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys Ala
20 25 30
Arg
<210> 162
<211> 11
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 重链 FR4
<400> 162
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
1 5 10
<210> 163
<211> 113
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 轻链
<400> 163
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Lys Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Asn
85 90 95
Asn Tyr Phe Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
100 105 110
Lys
<210> 164
<211> 17
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 轻链 CDR1
<400> 164
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 165
<211> 7
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 轻链 CDR2
<400> 165
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 166
<211> 9
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 轻链 CDR3
<400> 166
Gln Asn Asn Tyr Phe Tyr Pro Leu Thr
1 5
<210> 167
<211> 23
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 轻链 FR1
<400> 167
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys
20
<210> 168
<211> 15
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 轻链 FR2
<400> 168
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 169
<211> 32
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 轻链 FR3
<400> 169
Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Lys Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr Tyr Cys
20 25 30
<210> 170
<211> 10
<212> PRT
<213> Artificial
<220>
<223> 克隆18A9 轻链 FR4
<400> 170
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
1 5 10
<210> 171
<211> 37
<212> DNA
<213> Artificial
<220>
<223> 引物
<400> 171
ttggcaaaga attgctagat gtccaccacc acatgcc 37
<210> 172
<211> 38
<212> DNA
<213> Artificial
<220>
<223> 引物
<400> 172
tgttcgggcc ctcctcgatt acacatagtc gtgcttgg 38
<210> 173
<211> 37
<212> DNA
<213> Artificial
<220>
<223> 引物
<400> 173
ttggcaaaga attgctagat ggccgtgact gcctgtc 37
<210> 174
<211> 38
<212> DNA
<213> Artificial
<220>
<223> 引物
<400> 174
tgttcgggcc ctcctcgatt acacatagtc gtgcttgg 38
<210> 175
<211> 20
<212> DNA
<213> Artificial
<220>
<223> 引物
<400> 175
tgtgcgccac catggccgtg 20
<210> 176
<211> 20
<212> DNA
<213> Artificial
<220>
<223> 引物
<400> 176
tggaaggata agattgtacc 20
<210> 177
<211> 20
<212> DNA
<213> Artificial
<220>
<223> 引物
<400> 177
tgggtgccat tggcctcctg 20
<210> 178
<211> 354
<212> DNA
<213> Artificial
<220>
<223> 克隆18D10 重链
<400> 178
gatgtgcagc ttcaggagtc gggacctggc ctggtgaaac cttctcagtc tctgtccctc 60
acctgcactg tcactggcta ctcaatcacc agtaattatg cctggaactg gatccgacag 120
tttccaggaa acaaactaga gtggatgggc tacataaact acagtgggaa cactaactat 180
aacccatctc tcaaaagtcg aatctctatc actcgagaca catccaagaa ccagttcttc 240
ctgcagttga attctgtgac tgctgaggac acagccacat attattgtgc aacctcctat 300
tatggtaatt cctttattta ctggggccaa gggactctgg tcactgtctc tgca 354
<210> 179
<211> 339
<212> DNA
<213> Artificial
<220>
<223> 克隆18D10 轻链
<400> 179
gacattgtga tgacacagtc tccatcctcc ctgactgtga cagcaggaga gaaggtcact 60
atgagctgca agtccagtca gagtctgtta aacagtggaa atcaaaagaa ctacttgacc 120
tggtaccagc agaaaccagg gcagcctcct aaactgttga tctactgggc atccactagg 180
gagtctgggg tccctgatcg cttcacaggc agtggatctg gaacagattt cactctcacc 240
atcagcagtg tgcaggctga agacctggca gtttattact gtcagaatgc ttatagtttt 300
ccgtggacgt tcggtggagg caccaagctg gaaatcaaa 339
<210> 180
<211> 354
<212> DNA
<213> Artificial
<220>
<223> 克隆18A9 重链
<400> 180
caggtgcagc tgcagcagtc tggacgtgag gtggtaaggc ctgggacttc agtgaaggtg 60
tcctgcaagc cttctggata cgccttcact aattacttga tagactgggt aaaacagagg 120
cctggacagg gccttgagtg gattggaggg attaatcctg gaagtggtga cactgtgtac 180
aatgagaagt tcaaggccaa ggcaacactg actgcagaca aatcctccat gactgccaac 240
atgcagctca gcagcctgac atctgatgac tctgcggtct atttctgcgc aagaagggtc 300
cgtggtaatt cgtttgattc ctggggccaa gggactctgg tcactgtctc tgca 354
<210> 181
<211> 339
<212> DNA
<213> Artificial
<220>
<223> 克隆18A9 轻链
<400> 181
gacattgtga tgtcacagtc tccatcctcc ctgactgtga cagcaggaga gaaggtcact 60
atgagctgca agtccagtca gagtctgtta aacagtggaa atcaaaagaa ctacttgacc 120
tggtaccagc agaaaccagg gcagcctcct aaattgttga tctactgggc atccactagg 180
gaatctgggg tccctgatcg cttcacaggc agtggatctg gaaaagattt cactctcacc 240
atcagcagtg tgcaggctga agacctggca ctttattact gtcagaataa ttatttttat 300
ccgctcacgt tcggtgctgg gaccaagctg gagctgaaa 339
<210> 182
<211> 354
<212> DNA
<213> Artificial
<220>
<223> 18D10VHv1
<400> 182
caggttcagc tgcaagagtc tggacctggc ctggtcaagc ctagcgagac actgagcctg 60
acctgtaccg tgtccggcta cagcatcacc agcaactacg cctggaactg gatcagacag 120
cctcctggca aaggcctcga gtggatcggc tacatcaact acagcggcaa caccaactac 180
aaccccagcc tgaagtccag agtgaccatc agcagagaca ccagcaagaa ccagttctcc 240
ctgaagctga gcagcgtgac agccgccgat acagccgtgt actactgtgc cacaagctac 300
tacggcaaca gcttcatcta ctggggccag ggcacactgg tcaccgtttc ttct 354
<210> 183
<211> 354
<212> DNA
<213> Artificial
<220>
<223> 18D10VHv2
<400> 183
caggttcagc tgcaagagtc tggacctggc ctggtcaagc ctagcgagac actgagcctg 60
acctgtaccg tgtccggcgg cagcatcagc agcaactacg cctggaactg gatcagacag 120
cctcctggca aaggcctcga gtggatgggc tacatcaact acagcggcaa caccaactac 180
aaccccagcc tgaagtccag aatcaccatc agcagagaca ccagcaagaa ccagttctcc 240
ctgaagctga gcagcgtgac agccgccgat acagccgtgt actactgtgc cacaagctac 300
tacggcaaca gcttcatcta ctggggccag ggcacactgg tcaccgtttc ttct 354
<210> 184
<211> 354
<212> DNA
<213> Artificial
<220>
<223> 18D10VHv3
<400> 184
caggttcagc tgcaagagtc tggacctggc ctggtcaagc ctagcgagac actgagcctg 60
acctgtaccg tgtccggcgg cagcatcagc agcaactacg cctggaactg gatcagacag 120
cctcctggca aaggcctcga gtggatcggc tacatcaact acagcggcaa caccaactac 180
aaccccagcc tgaagtccag agtgaccatc agcagagaca ccagcaagaa ccagttctcc 240
ctgaagctga gcagcgtgac agccgccgat acagccgtgt actactgtgc cacaagctac 300
tacggcaaca gcttcatcta ctggggccag ggcacactgg tcaccgtttc ttct 354
<210> 185
<211> 354
<212> DNA
<213> Artificial
<220>
<223> 18D10VHv4
<400> 185
caggttcagc tgcaagagtc tggacctggc ctggtcaagc ctagcgagac actgagcctg 60
acctgtaccg tgtccggcgg cagcatcagc agcaactacg cctggaactg gatcagacag 120
cctcctggca aaggcctcga gtggatcggc tacatcaact acagcggcta caccaactac 180
aaccccagcc tgaagtccag agtgaccatc agcagagaca ccagcaagaa ccagttctcc 240
ctgaagctga gcagcgtgac agccgccgat acagccgtgt actactgtgc cacaagctac 300
tacggcaaca gcttcatcta ctggggccag ggcacactgg tcaccgtttc ttct 354
<210> 186
<211> 354
<212> DNA
<213> Artificial
<220>
<223> 18D10VHv5
<400> 186
caggttcagc tgcaagagtc tggacctggc ctggtcaagc ctagcgagac actgagcctg 60
acctgtaccg tgtccggcgg cagcatcagc agcaactacg cctggaactg gatcagacag 120
cctcctggca aaggcctcga gtggatcggc tacatcaact acagcggcaa caccgcctac 180
aaccccagcc tgaagtccag agtgaccatc agcagagaca ccagcaagaa ccagttctcc 240
ctgaagctga gcagcgtgac agccgccgat acagccgtgt actactgtgc cacaagctac 300
tacggcaaca gcttcatcta ctggggccag ggcacactgg tcaccgtttc ttct 354
<210> 187
<211> 354
<212> DNA
<213> Artificial
<220>
<223> 18D10VHv6
<400> 187
caggttcagc tgcaagagtc tggacctggc ctggtcaagc ctagcgagac actgagcctg 60
acctgtaccg tgtccggcgg cagcatcagc agcaactacg cctggaactg gatcagacag 120
cctcctggca aaggcctcga gtggatcggc tacatctact acagcggcaa caccaactac 180
aaccccagcc tgaagtccag agtgaccatc agcagagaca ccagcaagaa ccagttctcc 240
ctgaagctga gcagcgtgac agccgccgat acagccgtgt actactgtgc cacaagctac 300
tacggcaaca gcttcatcta ctggggccag ggcacactgg tcaccgtttc ttct 354
<210> 188
<211> 339
<212> DNA
<213> Artificial
<220>
<223> 18D10VLv1
<400> 188
gacatcgtga tgacacagag ccctgatagc ctggccgtgt ctctgggaga gagagccacc 60
atcaactgca agagcagcca gagcctgctg aacagcggca accagaagaa ctacctgacc 120
tggtatcagc agaagcccgg ccagcctcct aagctgctga tctactgggc cagcaccaga 180
gaaagcggcg tgccagatag attcagcggc agcggctctg gaaccgactt caccctgaca 240
atcagctccc tgcaggccga ggatgtggcc gtgtactact gtcagaacgc ctacagcttc 300
ccctggacat tcggccaggg caccaaggtg gaaatcaag 339
<210> 189
<211> 339
<212> DNA
<213> Artificial
<220>
<223> 18D10VLv2
<400> 189
gacatcgtga tgacacagag ccctgatagc ctggccgtgt ctctgggaga gagagccacc 60
atcaactgca agagcagcca gagcctgctg aacagcggca accagaagaa ctacctggcc 120
tggtatcagc agaagcccgg ccagcctcct aagctgctga tctactgggc cagcaccaga 180
gaaagcggcg tgccagatag attcagcggc agcggctctg gaaccgactt caccctgaca 240
atcagctccc tgcaggccga ggatgtggcc gtgtactact gtcagcaggc ctacagcttc 300
ccctggacat tcggccaggg caccaaggtg gaaatcaag 339
<210> 190
<211> 1347
<212> DNA
<213> Artificial
<220>
<223> 重链核酸序列
<400> 190
caggttcagc tgcaagagtc tggacctggc ctggtcaagc ctagcgagac actgagcctg 60
acctgtaccg tgtccggcgg cagcatcagc agcaactacg cctggaactg gatcagacag 120
cctcctggca aaggcctcga gtggatcggc tacatctact acagcggcaa caccaactac 180
aaccccagcc tgaagtccag agtgaccatc agcagagaca ccagcaagaa ccagttctcc 240
ctgaagctga gcagcgtgac agccgccgat acagccgtgt actactgtgc cacaagctac 300
tacggcaaca gcttcatcta ctggggccag ggcacactgg tcaccgtttc ttctgctagc 360
accaagggcc catccgtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca 720
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga ggagatgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctatagcaag ctcaccgtgg acaagagcag gtggcagcag 1260
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320
tccctctccc tgtctccggg taaatga 1347
<210> 191
<211> 663
<212> DNA
<213> Artificial
<220>
<223> 轻链核酸序列
<400> 191
gacatcgtga tgacacagag ccctgatagc ctggccgtgt ctctgggaga gagagccacc 60
atcaactgca agagcagcca gagcctgctg aacagcggca accagaagaa ctacctgacc 120
tggtatcagc agaagcccgg ccagcctcct aagctgctga tctactgggc cagcaccaga 180
gaaagcggcg tgccagatag attcagcggc agcggctctg gaaccgactt caccctgaca 240
atcagctccc tgcaggccga ggatgtggcc gtgtactact gtcagaacgc ctacagcttc 300
ccctggacat tcggccaggg caccaaggtg gaaatcaagc gaactgtggc tgcaccatct 360
gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420
ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480
caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540
ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600
gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt 660
tag 663
<210> 192
<211> 354
<212> DNA
<213> Artificial
<220>
<223> 18A9VHv1
<400> 192
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcagcag cgtgaaggtg 60
tcctgcaagc cttctggcta cgccttcacc aactacctga tcgactgggt ccgacaggct 120
cctggacagg gacttgaatg gatgggcggc atcaaccctg gcagcggcga tacagtgtac 180
aacgagaagt tccagggcag agtgaccctg accgccgaca agtctagcat gaccgcctac 240
atggaactga gcagcctgag aagcgaggat accgccgtgt acttctgtgc cagaagagtg 300
cggggcaaca gcttcgattc ttggggccag ggaaccctgg tcaccgtttc ttct 354
<210> 193
<211> 354
<212> DNA
<213> Artificial
<220>
<223> 18A9VHv2
<400> 193
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcagcag cgtgaaggtg 60
tcctgcaagc cttctggcta caccttcacc aactacctga tcgactgggt ccgacaggct 120
cctggacagg gacttgaatg gatgggcggc atcaaccctg gcagcggcga tacagtgtac 180
aacgagaagt tccagggcag agtgaccctg accgccgacg agtctaccag caccgcctac 240
atggaactga gcagcctgag aagcgaggat accgccgtgt acttctgtgc cagaagagtg 300
cggggcaaca gcttcgattc ttggggccag ggaaccctgg tcaccgtttc ttct 354
<210> 194
<211> 354
<212> DNA
<213> Artificial
<220>
<223> 18A9VHv3
<400> 194
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcagcag cgtgaaggtg 60
tcctgcaagc cttctggcta caccttcacc aactacctga tcgactgggt ccgacaggct 120
cctggacagg gacttgaatg gatgggcggc atcaaccctg gcagcggcga tacagtgtac 180
aacgagaagt tccagggcag agtgaccctg accgccgaca agtctagcat gaccgcctac 240
atggaactga gcagcctgag aagcgaggat accgccgtgt actactgtgc cagaagagtg 300
cggggcaaca gcttcgattc ttggggccag ggaaccctgg tcaccgtttc ttct 354
<210> 195
<211> 354
<212> DNA
<213> Artificial
<220>
<223> 18A9VHv4
<400> 195
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcagcag cgtgaaggtg 60
tcctgcaagg cttctggcta caccttcacc aactacctga tcgactgggt ccgacaggct 120
cctggacagg gacttgaatg gatgggcggc atcaaccctg gcagcggcga tacagtgtac 180
aacgagaagt tccagggcag agtgaccctg accgccgaca agtctagcat gaccgcctac 240
atggaactga gcagcctgag aagcgaggat accgccgtgt acttctgtgc cagaagagtg 300
cggggcaaca gcttcgattc ttggggccag ggaaccctgg tcaccgtttc ttct 354
<210> 196
<211> 354
<212> DNA
<213> Artificial
<220>
<223> 18A9VHv5
<400> 196
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcagcag cgtgaaggtg 60
tcctgcaagc cttctggcta caccttcacc aactacctga tcgactgggt ccgacaggct 120
cctggacagg gacttgaatg gatgggcggc atcaaccctg gcagcggcga tacagtgtac 180
aacgagaagt tccagggcag agtgaccatc accgccgacg agtctaccag caccgcctac 240
atggaactga gcagcctgag aagcgaggat accgccgtgt acttctgtgc cagaagagtg 300
cggggcaaca gcttcgattc ttggggccag ggaaccctgg tcaccgtttc ttct 354
<210> 197
<211> 354
<212> DNA
<213> Artificial
<220>
<223> 18A9VHv6
<400> 197
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgccag cgtgaaggtg 60
tcctgcaagc cttctggcta cgccttcacc aactacctga tcgactgggt ccgacaggct 120
cctggacagg gacttgaatg gatgggcggc atcaaccctg gcagcggcga tacagtgtac 180
aacgagaagt tccagggcag agtgaccctg accgccgaca agtctagcag caccgcctac 240
atggaactga gcagcctgag aagcgaggat accgccgtgt acttctgtgc cagaagagtg 300
cggggcaaca gcttcgattc ttggggccag ggaaccctgg tcaccgtttc ttct 354
<210> 198
<211> 354
<212> DNA
<213> Artificial
<220>
<223> 18A9VHv7
<400> 198
caggttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcgccag cgtgaaggtg 60
tcctgcaagc cttctggcta caccttcacc aactacctga tcgactgggt ccgacaggct 120
cctggacagg gacttgaatg gatgggcggc atcaaccctg gcagcggcga tacagtgtac 180
aacgagaagt tccagggcag agtgaccctg accgccgaca cctctaccag caccgtctac 240
atggaactga gcagcctgag aagcgaggat accgccgtgt acttctgtgc cagaagagtg 300
cggggcaaca gcttcgattc ttggggccag ggaaccctgg tcaccgtttc ttct 354
<210> 199
<211> 339
<212> DNA
<213> Artificial
<220>
<223> 18A9VLv1
<400> 199
gacatcgtga tgacacagag ccctgatagc ctggccgtgt ctctgggaga gagagccacc 60
atcaactgca agagcagcca gagcctgctg aacagcggca accagaagaa ctacctgacc 120
tggtatcagc agaagcccgg ccagcctcct aagctgctga tctactgggc cagcaccaga 180
gaaagcggcg tgccagatag attcagcggc agcggctctg gaaaggactt caccctgaca 240
atcagctccc tgcaggccga ggatgtggcc gtgtactact gccagaacaa ctacttctac 300
cctctgacct tcggcggagg caccaaggtg gaaatcaag 339
<210> 200
<211> 339
<212> DNA
<213> Artificial
<220>
<223> 18A9VLv2
<400> 200
gacatcgtga tgacacagag ccctgatagc ctggccgtgt ctctgggaga gagagccacc 60
atcaactgca agagcagcca gagcctgctg aacagcggca accagaagaa ctacctggcc 120
tggtatcagc agaagcccgg ccagcctcct aagctgctga tctactgggc cagcaccaga 180
gaaagcggcg tgccagatag attcagcggc agcggctctg gaaccgactt caccctgaca 240
atcagctccc tgcaggccga ggatgtggcc gtgtactact gccagcagaa ctacttctac 300
cctctgacct tcggcggagg caccaaggtg gaaatcaag 339
Claims (15)
1.抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,所述抗体药物偶联物具有式Ⅰ所示的结构,
Ab-(L-D)p
式Ⅰ
其中:
Ab为抗Claudin 18.2抗体,所述抗Claudin 18.2抗体包含重链和轻链,重链可变区CDR1包含选自SEQ ID NO:2、10、18、26、34、42、68、76、84、92、100、108或116所示的序列或其突变体,重链可变区CDR2包含选自SEQ ID NO:3、11、19、27、35、43、69、77、85、93、101、109或117所示的序列或其突变体,重链可变区CDR3包含选自SEQ ID NO:4、12、20、28、36、44、70、78、86、94、102、110或118所示的序列或其突变体,轻链可变区CDR1包含选自SEQ ID NO:50、58、124或132所示的序列或其突变体,轻链可变区CDR2包含选自SEQ ID NO:51、59、125或133所示的序列或其突变体,轻链可变区CDR3包含选自SEQ ID NO:52、60、126或134所示的序列或其突变体;
D为细胞毒剂;
L为接头,用于连接所述抗Claudin 18.2抗体和所述细胞毒剂;
p为2.0-8.0。
2.权利要求1的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,其中:
所述抗Claudin 18.2抗体的重链可变区CDR1包含选自SEQ ID NO:2、10、18、26、34或42所示的序列或其突变体,重链可变区CDR2包含选自SEQ ID NO:3、11、19、27、35或43所示的序列或其突变体,重链可变区CDR3包含选自SEQ ID NO:4、12、20、28、36或44所示的序列或其突变体,轻链可变区CDR1包含选自SEQ ID NO:50或58所示的序列或其突变体,轻链可变区CDR2包含选自SEQ ID NO:51或59所示的序列或其突变体,轻链可变区CDR3包含选自SEQID NO:52或60所示的序列或其突变体;
或者,所述抗Claudin 18.2抗体的重链可变区CDR1包含选自SEQ ID NO:68、76、84、92、100、108或116所示的序列或其突变体,重链可变区CDR2包含选自SEQ ID NO:69、77、85、93、101、109或117所示的序列或其突变体,重链可变区CDR3包含选自SEQ ID NO:70、78、86、94、102、110或118所示的序列或其突变体,轻链可变区CDR1包含选自SEQ ID NO:124或132所示的序列或其突变体,轻链可变区CDR2包含选自SEQ ID NO:125或133所示的序列或其突变体,轻链可变区CDR3包含选自SEQ ID NO:126或134所示的序列或其突变体;
或者,所述抗Claudin 18.2抗体的重链可变区CDR1、CDR2、CDR3选自如下序列组合:
(1)SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4,
(2)SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12,
(3)SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20,
(4)SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28,
(5)SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36,
(6)SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44,
(7)SEQ ID NO:68、SEQ ID NO:69、SEQ ID NO:70,
(8)SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78,
(9)SEQ ID NO:84、SEQ ID NO:85、SEQ ID NO:86,
(10)SEQ ID NO:92、SEQ ID NO:93、SEQ ID NO:94,
(11)SEQ ID NO:100、SEQ ID NO:101、SEQ ID NO:102,
(12)SEQ ID NO:108、SEQ ID NO:109、SEQ ID NO:110,
(13)SEQ ID NO:116、SEQ ID NO:117、SEQ ID NO:118,
所述抗Claudin 18.2抗体的轻链可变区CDR1、CDR2、CDR3选自如下序列组合:
(1)SEQ ID NO:50、SEQ ID NO:51、SEQ ID NO:52,
(2)SEQ ID NO:58、SEQ ID NO:59、SEQ ID NO:60,
(3)SEQ ID NO:124、SEQ ID NO:125、SEQ ID NO:126,
(4)SEQ ID NO:132、SEQ ID NO:133、SEQ ID NO:134;
优选地,所述抗Claudin 18.2抗体的重链可变区CDR1、CDR2、CDR3选自如下序列组合:
(1)SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4,
(2)SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12,
(3)SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20,
(4)SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28,
(5)SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36,
(6)SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44,
所述抗Claudin 18.2抗体的轻链可变区CDR1、CDR2、CDR3选自如下序列组合:
(1)SEQ ID NO:50、SEQ ID NO:51、SEQ ID NO:52,
(2)SEQ ID NO:58、SEQ ID NO:59、SEQ ID NO:60;
或者优选地,所述抗Claudin 18.2抗体的重链可变区CDR1、CDR2、CDR3选自如下序列组合:
(1)SEQ ID NO:68、SEQ ID NO:69、SEQ ID NO:70,
(2)SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78,
(9)SEQ ID NO:84、SEQ ID NO:85、SEQ ID NO:86,
(4)SEQ ID NO:92、SEQ ID NO:93、SEQ ID NO:94,
(5)SEQ ID NO:100、SEQ ID NO:101、SEQ ID NO:102,
(6)SEQ ID NO:108、SEQ ID NO:109、SEQ ID NO:110,
(7)SEQ ID NO:116、SEQ ID NO:117、SEQ ID NO:118,
所述抗Claudin 18.2抗体的轻链可变区CDR1、CDR2、CDR3选自如下序列组合:
(1)SEQ ID NO:124、SEQ ID NO:125、SEQ ID NO:126,
(2)SEQ ID NO:132、SEQ ID NO:133、SEQ ID NO:134。
3.权利要求1的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,其中:
所述抗Claudin 18.2抗体的重链可变区FR1包含选自SEQ ID NO:5、13、21、29、37、45、71、79、87、95、103、111或119所示的序列或其突变体,重链可变区FR2包含选自SEQ ID NO:6、14、22、30、38、46、72、80、88、96、104、112或120所示的序列或其突变体,重链可变区FR3包含选自SEQ ID NO:7、15、23、31、39、47、73、81、89、97、105、113或121所示的序列或其突变体,重链可变区FR4包含选自SEQ ID NO:8、16、24、32、40、48、74、82、90、98、106、114或122所示的序列或其突变体,轻链可变区FR1包含选自SEQ ID NO:53、61、127或135所示的序列或其突变体,轻链可变区FR2包含选自SEQ ID NO:54、62、128或136所示的序列或其突变体,轻链可变区FR3包含选自SEQ ID NO:55、63、129或137所示的序列或其突变体,轻链可变区FR4包含选自SEQ ID NO:56、64、130或138所示的序列或其突变体;
优选地,所述抗Claudin 18.2抗体的重链可变区FR1包含选自SEQ ID NO:5、13、21、29、37或45所示的序列或其突变体,重链可变区FR2包含选自SEQ ID NO:6、14、22、30、38或46所示的序列或其突变体,重链可变区FR3包含选自SEQ ID NO:7、15、23、31、39或47所示的序列或其突变体,重链可变区FR4包含选自SEQ ID NO:8、16、24、32、40或48所示的序列或其突变体,轻链可变区FR1包含选自SEQ ID NO:53或61、所示的序列或其突变体,轻链可变区FR2包含选自SEQ ID NO:54或62所示的序列或其突变体,轻链可变区FR3包含选自SEQ ID NO:55或63所示的序列或其突变体,轻链可变区FR4包含选自SEQ ID NO:56或64所示的序列或其突变体;
或者优选地,所述抗Claudin 18.2抗体的重链可变区FR1包含选自SEQ ID NO:71、79、87、95、103、111或119所示的序列或其突变体,重链可变区FR2包含选自SEQ ID NO:72、80、88、96、104、112或120所示的序列或其突变体,重链可变区FR3包含选自SEQ ID NO:73、81、89、97、105、113或121所示的序列或其突变体,重链可变区FR4包含选自SEQ ID NO:74、82、90、98、106、114或122所示的序列或其突变体,轻链可变区FR1包含选自SEQ ID NO:127或135所示的序列或其突变体,轻链可变区FR2包含选自SEQ ID NO:128或136所示的序列或其突变体,轻链可变区FR3包含选自SEQ ID NO:129或137所示的序列或其突变体,轻链可变区FR4包含选自SEQ ID NO:130或138所示的序列或其突变体;
或者优选地,所述抗Claudin 18.2抗体的重链可变区FR1、FR2、FR3、FR4选自如下序列组合:
(1)SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8,
(2)SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16,
(3)SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24,
(4)SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ ID NO:32,
(5)SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、SEQ ID NO:40,
(6)SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48,
(7)SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74,
(8)SEQ ID NO:79、SEQ ID NO:80、SEQ ID NO:81、SEQ ID NO:82,
(9)SEQ ID NO:87、SEQ ID NO:88、SEQ ID NO:89、SEQ ID NO:90,
(10)SEQ ID NO:95、SEQ ID NO:96、SEQ ID NO:97、SEQ ID NO:98,
(11)SEQ ID NO:103、SEQ ID NO:104、SEQ ID NO:105、SEQ ID NO:106,
(12)SEQ ID NO:111、SEQ ID NO:112、SEQ ID NO:113、SEQ ID NO:114,
(13)SEQ ID NO:119、SEQ ID NO:120、SEQ ID NO:121、SEQ ID NO:122,
所述抗Claudin 18.2抗体的轻链可变区FR1、FR2、FR3、FR4选自如下序列组合:
(1)SEQ ID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56,
(2)SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64,
(3)SEQ ID NO:127、SEQ ID NO:128、SEQ ID NO:129、SEQ ID NO:130,
(4)SEQ ID NO:135、SEQ ID NO:136、SEQ ID NO:137、SEQ ID NO:138;
更优选地,所述抗Claudin 18.2抗体的重链可变区FR1、FR2、FR3、FR4选自如下序列组合:
(1)SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8,
(2)SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16,
(3)SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24,
(4)SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ ID NO:32,
(5)SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、SEQ ID NO:40,
(6)SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48,
所述抗Claudin 18.2抗体的轻链可变区FR1、FR2、FR3、FR4选自如下序列组合:
(1)SEQ ID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56,
(2)SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64;
或者更优选地,所述抗Claudin 18.2抗体的重链可变区FR1、FR2、FR3、FR4选自如下序列组合:
(1)SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73、SEQ ID NO:74,
(2)SEQ ID NO:79、SEQ ID NO:80、SEQ ID NO:81、SEQ ID NO:82,
(3)SEQ ID NO:87、SEQ ID NO:88、SEQ ID NO:89、SEQ ID NO:90,
(4)SEQ ID NO:95、SEQ ID NO:96、SEQ ID NO:97、SEQ ID NO:98,
(5)SEQ ID NO:103、SEQ ID NO:104、SEQ ID NO:105、SEQ ID NO:106,
(6)SEQ ID NO:111、SEQ ID NO:112、SEQ ID NO:113、SEQ ID NO:114,
(7)SEQ ID NO:119、SEQ ID NO:120、SEQ ID NO:121、SEQ ID NO:122,
所述抗Claudin 18.2抗体的轻链可变区FR1、FR2、FR3、FR4选自如下序列组合:
(1)SEQ ID NO:127、SEQ ID NO:128、SEQ ID NO:129、SEQ ID NO:130,
(2)SEQ ID NO:135、SEQ ID NO:136、SEQ ID NO:137、SEQ ID NO:138。
4.权利要求1的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,其中:
所述抗Claudin 18.2抗体的重链可变区选自SEQ ID NO:1、9、17、25、33、41、67、75、83、91、99、107或115所示的序列,
所述抗Claudin 18.2抗体的轻链可变区选自SEQ ID NO:49、57、123或131所示的序列;
优选地,所述抗Claudin 18.2抗体的重链可变区选自SEQ ID NO:1、9、17、25、33或41所示的序列,
所述抗Claudin 18.2抗体的轻链可变区选自SEQ ID NO:49或57所示的序列;
或者优选地,所述抗Claudin 18.2抗体的重链可变区选自SEQ ID NO:67、75、83、91、99、107或115所示的序列,
所述抗Claudin 18.2抗体的轻链可变区选自SEQ ID NO:123或131所示的序列。
5.权利要求1的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,其中:
所述抗Claudin 18.2抗体的重链可变区、轻链可变区选自如下序列组合:
(1)SEQ ID NO:17和SEQ ID NO:57;
(2)SEQ ID NO:41和SEQ ID NO:49;
(3)SEQ ID NO:41和SEQ ID NO:57;
(4)SEQ ID NO:115和SEQ ID NO:131;
优选地,所述抗Claudin 18.2抗体的重链可变区、轻链可变区的序列分别为SEQ IDNO:41和SEQ ID NO:49。
6.权利要求1的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,其中:
所述抗Claudin 18.2抗体的重链恒定区选自人源性IgG(如IgG1、IgG2、IgG3或IgG4)、IgM、IgA、IgD、IgA恒定区或上述恒定区的突变体,优选为人源性IgG1;
所述抗Claudin 18.2抗体的轻链恒定区选自人源性lambda恒定区、kappa恒定区或上述恒定区的突变体,优选为人源性kappa恒定区。
7.权利要求1的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,其中:
所述抗Claudin 18.2抗体的重链的氨基酸序列包含如SEQ ID NO:65所示的序列,或者包含与SEQ ID NO:65所示序列的同一性大于70%,例如大于75%、80%、85%、90%、95%、99%的序列;
所述抗Claudin 18.2抗体的轻链的氨基酸序列包含如SEQ ID NO:66所示的序列,或者包含与SEQ ID NO:66所示序列的同一性大于70%,例如大于75%、80%、85%、90%、95%、99%的序列。
8.权利要求1的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,其中,p为2.0-7.0、2.0-6.0、2.0-5.0、2.0-4.0、3.0-7.0、3.0-6.0、3.0-5.0或3.0-4.0,优选地,p为3.0-4.0,例如p为3.0-3.8,优选为3.0、3.4、3.5或3.8,更优选为3.8。
9.权利要求1的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,其中,所述细胞毒剂选自SN-38、吉西他滨(Gemcitabine)、Monomethyl auristatin E(MMAE)、Monomethyl auristatin F(MMAF)、美登木素生物碱(例如Maytansine DM1、Maytansine DM4)、卡奇霉素(calicheamicin)、MGBA(如duocarmycin)、阿霉素(doxorubicin)、蓖麻毒素、白喉毒素等毒素、I131、白介素类、肿瘤坏死因子、趋化因子和纳米颗粒;
优选地,所述细胞毒剂为MMAE。
10.权利要求1的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,其中,所述接头选自6-马来酰亚氨基己酰基(MC)、马来酰亚氨基丙酰基(MP)、N-琥珀酰亚氨基4-(2-吡啶基硫代)戊酸酯(SPP)、4-(N-马来酰亚氨基甲基)-环己烷-1-甲酰基(MCC)、N-琥珀酰亚氨基(4-碘-乙酰基)氨基苯甲酸酯(SIAB)、和6-马来酰亚氨基己酰基-缬氨酸-瓜氨酸-对氨基苄氧羰基(MC-vc-PAB);
优选地,所述接头为6-马来酰亚氨基己酰基-缬氨酸-瓜氨酸-对氨基苄氧羰基(MC-vc-PAB)。
11.权利要求1的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,其中:
Ab包括:
(a)重链可变区CDR1、CDR2、CDR3和轻链可变区CDR1、CDR2、CDR3,其中,重链可变区CDR1的序列如SEQ ID NO:42所示,重链可变区CDR2的序列如SEQ ID NO:43所示,重链可变区CDR3的序列如SEQ ID NO:44所示,轻链可变区CDR1的序列如SEQ ID NO:50所示,轻链可变区CDR2的序列如SEQ ID NO:51所示,轻链可变区CDR3的序列如SEQ ID NO:52所示;
(b)重链可变区和轻链可变区,其中,重链可变区的序列如SEQ ID NO:41所示,轻链可变区的序列如SEQ ID NO:49所示;和/或
(c)重链和轻链,其中,重链的序列如SEQ ID NO:65所示,轻链的序列如SEQ ID NO:66所示;
L为MC-vc-PAB;和
D为MMAE。
12.组合物,其包含权利要求1-11任一项所述的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物;任选地,还包含已知的用于治疗肿瘤的化疗药物、免疫治疗药物和免疫抑制剂中的至少一种;或者任选地,还包含至少一种药学上可接受的载体、稀释剂或赋形剂。
13.权利要求1-11任一项所述的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物或者权利要求12所述的组合物在制备药物中的用途,所述药物用于预防和/或治疗与Claudin 18.2相关的疾病;
优选地,所述与Claudin 18.2相关的疾病为胃癌、胃食管交界腺癌、胰腺癌;
更优选地,所述与Claudin 18.2相关的疾病为胃癌。
14.预防和/或治疗与Claudin 18.2相关的疾病的方法,其包括:给予有需要的受试者预防和/或治疗有效量的权利要求1-11任一项所述的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,或者权利要求12所述的组合物;
优选地,所述与Claudin 18.2相关的疾病为胃癌、胃食管交界腺癌、胰腺癌;
更优选地,所述与Claudin 18.2相关的疾病为胃癌。
15.权利要求1-11任一项所述的抗体药物偶联物,其药学上可接受的盐、溶剂合物或所述盐的溶剂合物,或者权利要求12所述的组合物,其用于预防和/或治疗与Claudin18.2相关的疾病;
优选地,所述与Claudin 18.2相关的疾病为胃癌、胃食管交界腺癌、胰腺癌;
更优选地,所述与Claudin 18.2相关的疾病为胃癌。
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WO2024061173A1 (zh) * | 2022-09-19 | 2024-03-28 | 上海美雅珂生物技术有限责任公司 | 用靶向egfr的抗体偶联物治疗鼻咽癌 |
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WO2016165762A1 (en) * | 2015-04-15 | 2016-10-20 | Ganymed Pharmaceuticals Ag | Drug conjugates comprising antibodies against claudin 18.2 |
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CN111110862A (zh) * | 2018-11-01 | 2020-05-08 | 上海健信生物医药科技有限公司 | 抗cldn18.2抗体的药物偶联体及其制备方法和用途 |
US20220372112A1 (en) * | 2019-04-19 | 2022-11-24 | Keymed Biosciences Co., Ltd. | Tumor therapeutic agent and use thereof |
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CR20230207A (es) | 2023-10-26 |
WO2022078523A1 (zh) | 2022-04-21 |
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CA3198667A1 (en) | 2022-04-21 |
EP4230225A1 (en) | 2023-08-23 |
CO2023005979A2 (es) | 2023-05-29 |
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