CN115572330A - 一种特异性抗体及其制备方法和应用 - Google Patents
一种特异性抗体及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种特异性抗体及其制备方法和应用。本发明进一步涉及编码这些抗体的核酸分子、能够表达这些抗体的载体或重组细胞、以及包含这些抗体的治疗组合物或诊断组合物、以及使用这些抗体来治疗和诊断疾病的方法。
Description
技术领域
本发明涉及生物技术领域,具体地,本发明涉及CD155的抗体及其制备方法和在治疗肿瘤中的应用;进一步地,本发明还涉及编码这些抗体的核酸分子,能够表达这些抗体的载体或重组细胞,以及包含这些抗体的治疗组合物或诊断组合物,以及使用这些抗体来治疗或诊断疾病,特别是肿瘤的方法。
背景技术
CD155(又称PVR、Necl5或Tage4)是TIGIT的高亲和力配体,主要表达在内皮细胞和中枢神经系统,单核细胞,树突状细胞,成纤维细胞以及破骨细胞上。CD155在神经细胞和上皮细胞以及造血系统来源的肿瘤表达量很高,如黑色素细胞瘤,神经母细胞瘤,宫颈癌细胞,急性髓系和淋巴系的白血病细胞等。作为免疫球蛋白样的粘附分子,CD155参与细胞运动、自然杀伤细胞和T细胞介导的免疫。肿瘤表面高表达的CD155一旦与NK和T细胞表面的TIGIT结合,其对肿瘤细胞的杀伤作用就会被抑制。CD155过表达促进肿瘤细胞侵袭和迁移,并与肿瘤进展和预后不良有关。目前临床上针对实体瘤的抗肿瘤治疗靶点有限,而CD155被认为是治疗具有CD155过度表达的肿瘤的目标。
发明内容
本发明提供一种新型的具有靶向性强、亲和力高及抗肿瘤活性的抗CD155单克隆抗体。这些抗体及其片段的特征在于具有独特的互补决定区(CDR)序列组,作为独立疗法与其他抗癌剂组合在癌症免疫疗法中用于防止肿瘤免疫逃避。
具体地,一方面,本发明提供一种与人脊髓灰质炎病毒受体结合的可分离的抗体或其抗原结合片段,所述的抗体或其抗原结合片段包含选自下组任一所示的CDR序列:
重链可变区的CDR序列选自:SEQ ID NO 1~15;或与SEQ ID NO 1~15具有至少80%同一性的序列;和
轻链可变区的CDR序列选自:SEQ ID NO 16~29;或与SEQ ID NO 16~29具有至少80%同一性的序列。
其中,SEQ ID NO 1~15为:
GYAFSNYW(SEQ ID NO 1);IYPGDGDL(SEQ ID NO 2);ARGTATFDY(SEQ ID NO 3);
GFSLSSNG(SEQ ID NO 4);IWSDGST(SEQ ID NO 5);RNKDYYAMDN(SEQ ID NO 6);
GYTFTDYA(SEQ ID NO 7);ISTYYGDA(SEQ ID NO 8);ARGSDYAGYYFDY(SEQ ID NO9);
GYTFTNYW(SEQ ID NO 10);FYPGGYYT(SEQ ID NO 11);ARWGDTSGTDYAMDY(SEQ IDNO 12);
GYTFTEYS(SEQ ID NO 13);ITPTNGGS(SEQ ID NO 14);ARWVGPMDY(SEQ ID NO15)。
其中,SEQ ID NO 16~29为:
QSISDY(SEQ ID NO 16);YAA(SEQ ID NO 17);QNAHSFPYS(SEQ ID NO 18);
QGVGTA(SEQ ID NO 19);WAS(SEQ ID NO 20);QHFGSYPT(SEQ ID NO 21);
QDVSTA(SEQ ID NO 22);QQHYTTPRT(SEQ ID NO 23);ASSSVSY(SEQ ID NO 24);RTS(SEQ ID NO 25);QQYQSYPWT(SEQ ID NO 26);QQYNTYPLTFGSGTNLEIK(SEQ ID NO 27);SAS(SEQ ID NO 28);QQYNTYPLT(SEQ ID NO 29)。
在一些实施例中,本发明所述的重链可变区CDR序列选自下组任一所示的序列:
重链可变区CDR1序列为:SEQ ID NO 1、SEQ ID NO 4、SEQ ID NO 7、SEQ ID NO 10或SEQ ID NO 13;或与SEQ ID NO 1、SEQ ID NO 4、SEQ ID NO 7、SEQ ID NO 10或SEQ IDNO 13具有至少80%同一性的序列;和
重链可变区CDR2序列为:SEQ ID NO 2、SEQ ID NO 5、SEQ ID NO 8、SEQ ID NO 11或SEQ ID NO 14;或与SEQ ID NO 2、SEQ ID NO 5、SEQ ID NO 8、SEQ ID NO 11或SEQ IDNO 14具有至少80%同一性的序列;和
重链可变区CDR3序列为:SEQ ID NO 3、SEQ ID NO 6、SEQ ID NO 9、SEQ ID NO 12或SEQ ID NO 15;或与SEQ ID NO 3、SEQ ID NO 6、SEQ ID NO 9、SEQ ID NO 12或SEQ IDNO 15具有至少80%同一性的序列。
具体地,一些实施例中,本发明所述的重链可变区的CDR序列选自下组任一所示的序列:
1)重链可变区CDR1序列为:SEQ ID NO 1;或与SEQ ID NO 1具有至少80%同一性的序列;和
重链可变区CDR2序列为:SEQ ID NO 2;或与SEQ ID NO 2具有至少80%同一性的序列;和
重链可变区CDR3序列为:SEQ ID NO 3;或与SEQ ID NO 3具有至少80%同一性的序列;或
2)重链可变区CDR1序列为:SEQ ID NO 4;或与SEQ ID NO 4具有至少80%同一性的序列;和
重链可变区CDR2序列为:SEQ ID NO 5;或与SEQ ID NO 5具有至少80%同一性的序列;和
重链可变区CDR3序列为:SEQ ID NO 6;或与SEQ ID NO 6具有至少80%同一性的序列;或
3)重链可变区CDR1序列为:SEQ ID NO 7;或与SEQ ID NO 7具有至少80%同一性的序列;和
重链可变区CDR2序列为:SEQ ID NO 8;或与SEQ ID NO 8具有至少80%同一性的序列;和
重链可变区CDR3序列为:SEQ ID NO 9;或与SEQ ID NO 9具有至少80%同一性的序列;或
4)重链可变区CDR1序列为:SEQ ID NO 10;或与SEQ ID NO 10具有至少80%同一性的序列;和
重链可变区CDR2序列为:SEQ ID NO 11;或与SEQ ID NO 11具有至少80%同一性的序列;和
重链可变区CDR3序列为:SEQ ID NO 12;或与SEQ ID NO 12具有至少80%同一性的序列;或
5)重链可变区CDR1序列为:SEQ ID NO 13;或与SEQ ID NO 13具有至少80%同一性的序列;和
重链可变区CDR2序列为:SEQ ID NO 14;或与SEQ ID NO 14具有至少80%同一性的序列;和
重链可变区CDR3序列为:SEQ ID NO 15;或与SEQ ID NO 15具有至少80%同一性的序列。
在一些实施例中,本发明所述的轻链可变区的CDR序列选自下组任一所示的序列:
轻链可变区CDR1序列为:SEQ ID NO 16、SEQ ID NO 19、SEQ ID NO 22、SEQ ID NO24或SEQ ID NO 27;或与SEQ ID NO 16、SEQ ID NO 19、SEQ ID NO 22、SEQ ID NO 24或SEQID NO 27具有至少80%同一性的序列;和
轻链可变区CDR2序列为:SEQ ID NO 17、SEQ ID NO 20、SEQ ID NO 25或SEQ IDNO28;或与SEQ ID NO 17、SEQ ID NO 20、SEQ ID NO 25或SEQ ID NO 28具有至少80%同一性的序列;和
轻链可变区CDR3序列为:SEQ ID NO 18、SEQ ID NO 21、SEQ ID NO 23、SEQ ID NO26或SEQ ID NO 29;或与SEQ ID NO 18、SEQ ID NO 21、SEQ ID NO 23、SEQ ID NO 26或SEQID NO 29具有至少80%同一性的序列。
具体地,一些实施例中,本发明所述的轻链可变区的CDR序列选自下组任一所示的序列:
1)轻链可变区CDR1序列为:SEQ ID NO 16;或与SEQ ID NO 16具有至少80%同一性的序列;和
轻链可变区CDR2序列为:SEQ ID NO 17;或与SEQ ID NO 17具有至少80%同一性的序列;和
轻链可变区CDR3序列为:SEQ ID NO 18;或与SEQ ID NO 18具有至少80%同一性的序列;或
2)轻链可变区CDR1序列为:SEQ ID NO 19;或与SEQ ID NO 19具有至少80%同一性的序列;和
轻链可变区CDR2序列为:SEQ ID NO 20;或与SEQ ID NO 20具有至少80%同一性的序列;和
轻链可变区CDR3序列为:SEQ ID NO 21;或与SEQ ID NO 21具有至少80%同一性的序列;或
3)轻链可变区CDR1序列为:SEQ ID NO 22;或与SEQ ID NO 22具有至少80%同一性的序列;和
轻链可变区CDR2序列为:SEQ ID NO 20;或与SEQ ID NO 20具有至少80%同一性的序列;和
轻链可变区CDR3序列为:SEQ ID NO 23;或与SEQ ID NO 23具有至少80%同一性的序列;或
4)轻链可变区CDR1序列为:SEQ ID NO 24;或与SEQ ID NO 24具有至少80%同一性的序列;和
轻链可变区CDR2序列为:SEQ ID NO 25;或与SEQ ID NO 25具有至少80%同一性的序列;和
轻链可变区CDR3序列为:SEQ ID NO 26;或与SEQ ID NO 26具有至少80%同一性的序列;或
5)轻链可变区CDR1序列为:SEQ ID NO 27;或与SEQ ID NO 27具有至少80%同一性的序列;和
轻链可变区CDR2序列为:SEQ ID NO 28;或与SEQ ID NO 28具有至少80%同一性的序列;和
轻链可变区CDR3序列为:SEQ ID NO 29;或与SEQ ID NO 29具有至少80%同一性的序列。
一些实施例中,本发明提供一种与人脊髓灰质炎病毒受体结合的可分离的抗体或其抗原结合片段,所述的抗体或其抗原结合片段包含选自下组任一所示的CDR序列:
具体地,
1)重链可变区CDR1序列为:SEQ ID NO 1;和
重链可变区CDR2序列为:SEQ ID NO 2;和
重链可变区CDR3序列为:SEQ ID NO 3;和
轻链可变区CDR1序列为:SEQ ID NO 16;和
轻链可变区CDR2序列为:SEQ ID NO 17;和
轻链可变区CDR3序列为:SEQ ID NO 18;或
2)重链可变区CDR1序列为:SEQ ID NO 4;和
重链可变区CDR2序列为:SEQ ID NO 5;和
重链可变区CDR3序列为:SEQ ID NO 6;和
轻链可变区CDR1序列为:SEQ ID NO 19;和
轻链可变区CDR2序列为:SEQ ID NO 20;和
轻链可变区CDR3序列为:SEQ ID NO 21;或
3)重链可变区CDR1序列为:SEQ ID NO 7;和
重链可变区CDR2序列为:SEQ ID NO 8;和
重链可变区CDR3序列为:SEQ ID NO 9;和
轻链可变区CDR1序列为:SEQ ID NO 22;和
轻链可变区CDR2序列为:SEQ ID NO 20;和
轻链可变区CDR3序列为:SEQ ID NO 23;或
4)重链可变区CDR1序列为:SEQ ID NO 10;和
重链可变区CDR2序列为:SEQ ID NO 11;和
重链可变区CDR3序列为:SEQ ID NO 12;和
轻链可变区CDR1序列为:SEQ ID NO 24;和
轻链可变区CDR2序列为:SEQ ID NO 25;和
轻链可变区CDR3序列为:SEQ ID NO 26;或
5)重链可变区CDR1序列为:SEQ ID NO 13;和
重链可变区CDR2序列为:SEQ ID NO 14;和
重链可变区CDR3序列为:SEQ ID NO 15;和
轻链可变区CDR1序列为:SEQ ID NO 27;和
轻链可变区CDR2序列为:SEQ ID NO 28;和
轻链可变区CDR3序列为:SEQ ID NO 29。
一些实施例中,本发明提供一种与人脊髓灰质炎病毒受体结合的可分离的抗体或其抗原结合片段,所述的抗体或其抗原结合片段的重链可变区的框架区序列和轻链可变区的框架区序列的至少之一的至少一部分来自于啮齿动物、人、鸡、骆驼、鸵鸟、绵羊、牛、非人灵长类动物或鲨鱼。
其中,本发明所述的重链可变区的框架区序列和轻链可变区的框架区序列来自于啮齿动物;具体地,本发明所述的重链可变区的框架区序列和轻链可变区的框架区序列来自于鼠源。
具体地,一些实施例中,本发明所述的重链可变区具有如SEQ ID NO 30~34所示的氨基酸序列;或与SEQ ID NO 30~34所示的氨基酸序列具有至少95%同一性的序列。
其中,SEQ ID NO 30~34所示的氨基酸序列为:
EVQLQESGAELVRPGSSVKISCKASGYAFSNYWMNWVKQRPGQGLEWVGQIYPGDGDLNYNGNFRGKATLTVDKSSTTVYMQLSSLTSEDSAVYFCARGTATFDYWGQGTTLTVSS(SEQ ID NO 30);
QVQLQQSGPGLVAPSQSLSITCTVSGFSLSSNGVHWVRQPPGKGLEWLAVIWSDGSTTHNSALKSRLTLSKDNSKSQVFLKVNSLQTDDTAMYYCARNKDYYAMDNWGPGTSVTVSS(SEQ ID NO 31);
QVQLQQSGAELVRPGVSVKISCKGSGYTFTDYAMHWVKQSHAKSLEWIGVISTYYGDANYNQKFKDKATMTVDKSSSTAYMELARLASEDSAIYYCARGSDYAGYYFDYWGQGTTLTVSS(SEQ ID NO 32);
EVQLQQSGAELVRPGTSVKMSCKAAGYTFTNYWISWLKQRPGHGLEWIGDFYPGGYYTNYNEKFKDKATLTADTSSSTAYMQLSSLTSEDSAIYYCARWGDTSGTDYAMDYWGQGTSVTVSS(SEQ ID NO 33);
EVQLQQSGPELVKPGASVKISCKTSGYTFTEYSMHWVKQSHGKSLEWIGGITPTNGGSSYNQKFKDKATLTVDKSSSTVYMELRSLTSEDSAVYSCARWVGPMDYWGQGVSVTVSS(SEQ ID NO 34)。
具体地,一些实施例中,本发明所述的轻链可变区具有如SEQ ID NO 35~39所示的氨基酸序列;或与SEQ ID NO 35~39所示的氨基酸序列具有至少95%同一性的序列。
其中,SEQ ID NO 35~39所示的氨基酸序列为:
DIVMTQSPATLSVTPGDRVSLSCRASQSISDYLHWYQQKSHESPRLLLKYAAHSISGIPSRFSGSGSGSDFTLSINSVEPEDVGVYYCQNAHSFPYSFGGGTKLEIK(SEQ ID NO 35);
DIVMTQSHKFMSTSVGDRVSITCKASQGVGTAVAWYQQKPGQSPKLLIHWASTRHTGVPDRFTGSGSGTDFTLTITNVQSEDLADYFCQHFGSYPTFGGGTKLEIK(SEQ ID NO 36);
DIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDYTLTISSVQAEDLALYYCQQHYTTPRTFGGGTELEIK(SEQ ID NO 37);
DIVLTQSPAIMSASPGEKVTISCSASSSVSYMYWYQQKPGSSPKPWIYRTSNLASGVPARFSGSGSGTSYSLTINSMEAEDVATYYCQQYQSYPWTFGGGTKLEIK(SEQ ID NO 38);
DIVLTQSQKFMSTSVGDRVSVTCKASQQYNTYPLTFGSGTNLEIKVAWYQQKPGQSPKVLIYSASYRFSGVPDRFTGSGSGTDFTLTINNVQSEDLAEYFCQQYNTYPLTFGSGTNLEIK(SEQ ID NO 39)。
一些实施例中,本发明提供一种与人脊髓灰质炎病毒受体结合的可分离的抗体或其抗原结合片段,所述的重链恒定区序列和轻链恒定区序列的至少之一的至少一部分来自于啮齿动物、人、鸡、骆驼、鸵鸟、绵羊、牛、非人灵长类动物或鲨鱼。
一些实施例中,重链恒定区选自IgG1亚型、IgG2亚型、IgG3亚型或IgG4亚型。
一些实施例中,轻链恒定区选自κ亚型或λ亚型。
具体地,一些实施例中,重链恒定区和轻链恒定区均来自于人源IgG1。
其中,重链恒定区来自于人IgG1抗体https://www.ncbi.nlm.nih.gov/protein/AWK57454.1。
重链恒定区的全长序列如SEQ ID NO 40所示;
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO 40)。
轻链恒定区来自于人IgG1抗体https://www.ncbi.nlm.nih.gov/protein/P01834.2?report=genbank&log$=protalign&blast_rank=1&RID=17HAJPNW013。
轻链恒定区的全长序列如SEQ ID NO 41所示;
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO 41)。
上述SEQ ID NO 40所示的重链恒定区的全长序列包括重链CH1区、铰链区和Fc区;其中,CH1区序列为ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV;铰链区序列为EPKSCDKTHTCP;Fc区序列为PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK。
上述SEQ ID NO:41所示的抗体恒定区的全长序列为Kappa轻链恒定区。
一些实施例中,本发明提供一种与人脊髓灰质炎病毒受体结合的可分离的抗体或其抗原结合片段,所述的抗体或其抗原结合片段的重链具有如SEQ ID NO 42~46所示的氨基酸序列;和
轻链具有如SEQ ID NO 47~51所示的氨基酸序列。
其中,SEQ ID NO 42~46具有如下所示的氨基酸序列:
EVQLQESGAELVRPGSSVKISCKASGYAFSNYWMNWVKQRPGQGLEWVGQIYPGDGDLNYNGNFRGKA TLTVDKSSTTVYMQLSSLTSEDSAVYFCARGTATFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO 42);
QVQLQQSGPGLVAPSQSLSITCTVSGFSLSSNGVHWVRQPPGKGLEWLAVIWSDGSTTHNSALKSRLT LSKDNSKSQVFLKVNSLQTDDTAMYYCARNKDYYAMDNWGPGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO 43);
QVQLQQSGAELVRPGVSVKISCKGSGYTFTDYAMHWVKQSHAKSLEWIGVISTYYGDANYNQKFKDKA TMTVDKSSSTAYMELARLASEDSAIYYCARGSDYAGYYFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO 44);
EVQLQQSGAELVRPGTSVKMSCKAAGYTFTNYWISWLKQRPGHGLEWIGDFYPGGYYTNYNEKFKDKA TLTADTSSSTAYMQLSSLTSEDSAIYYCARWGDTSGTDYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO 45);
EVQLQQSGPELVKPGASVKISCKTSGYTFTEYSMHWVKQSHGKSLEWIGGITPTNGGSSYNQKFKDKA TLTVDKSSSTVYMELRSLTSEDSAVYSCARWVGPMDYWGQGVSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO 46)。
其中,SEQ ID NO 42~46所示的氨基酸序列中,“__”部分为重链可变区序列,无“__”部分为重链恒定区序列。
其中,SEQ ID NO 47~51具有如下所示的氨基酸序列:
DIVMTQSPATLSVTPGDRVSLSCRASQSISDYLHWYQQKSHESPRLLLKYAAHSISGIPSRFSGSGSG SDFTLSINSVEPEDVGVYYCQNAHSFPYSFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO 47);
DIVMTQSHKFMSTSVGDRVSITCKASQGVGTAVAWYQQKPGQSPKLLIHWASTRHTGVPDRFTGSGSG TDFTLTITNVQSEDLADYFCQHFGSYPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO 48);
DIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSG TDYTLTISSVQAEDLALYYCQQHYTTPRTFGGGTELEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO 49);
DIVLTQSPAIMSASPGEKVTISCSASSSVSYMYWYQQKPGSSPKPWIYRTSNLASGVPARFSGSGSGT SYSLTINSMEAEDVATYYCQQYQSYPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO 50);
DIVLTQSQKFMSTSVGDRVSVTCKASQQYNTYPLTFGSGTNLEIKVAWYQQKPGQSPKVLIYSASYRF SGVPDRFTGSGSGTDFTLTINNVQSEDLAEYFCQQYNTYPLTFGSGTNLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO 51)。
其中,SEQ ID NO 47~51所示的氨基酸序列中,“__”部分为轻链可变区序列,无“__”部分为轻链恒定区序列。
具体地,本发明提供一种与人脊髓灰质炎病毒受体结合的可分离的抗体或其抗原结合片段,所述的抗体或其抗原结合片段的重链和轻链选自下组任一所示的序列:
1)重链具有如SEQ ID NO 42所示的氨基酸序列;和
轻链具有如SEQ ID NO 47所示的氨基酸序列;或
2)重链具有如SEQ ID NO 43所示的氨基酸序列;和
轻链具有如SEQ ID NO 48所示的氨基酸序列;或
3)重链具有如SEQ ID NO 44所示的氨基酸序列;和
轻链具有如SEQ ID NO 49所示的氨基酸序列;或
4)重链具有如SEQ ID NO 45所示的氨基酸序列;和
轻链具有如SEQ ID NO 50所示的氨基酸序列;或
5)重链具有如SEQ ID NO 46所示的氨基酸序列;和
轻链具有如SEQ ID NO 51所示的氨基酸序列。
其中,本发明所述的抗体为单克隆抗体;具体地,本发明所述的单克隆抗体的恒定区包含人恒定区,本发明的抗体为嵌合单克隆抗体;所述的嵌合单克隆抗体包含人IgG1恒定区。
其中,本发明所述的抗体或其抗原结合片段为全抗体、单链抗体、多聚体抗体、CDR移植抗体、融合蛋白、多价抗体、Fab片段、Fv片段、单域抗体或最小识别单位的至少之一。
另一方面,本发明提供一种核酸分子,所述的核酸分子编码本发明所述的抗体或其抗原结合片段。其中,所述的核酸分子编码的抗体或抗原结合片段可特异性靶向结合CD155。
另一方面,本发明提供一种表达载体,所述表达载体携带本发明所述的核酸分子。将本发明所述的表达载体导入宿主细胞后,在调控系统的介导下,实现本发明所述的抗体或其抗原结合片段的表达,从而实现本发明所述抗体或其抗原结合片段的体外大量获得。
其中,所述的表达载体为真核表达载体,如CHO细胞表达载体。
其中,所述的真核表达载体包含常见真核表达启动子原件的载体,包括CMVpromoter、SV40 promoter等。
又另一方面,本发明提供一种重组细胞,所述的重组细胞携带本发明所述的核酸分子或表达本发明所述的抗体或其抗原结合片段。
其中,所述的重组细胞通过将本发明所述的表达载体引入至宿主细胞中而获得。
其中,所述重组细胞为真核细胞。
其中,所述重组细胞为哺乳动物细胞。
又另一方面,本发明提供一种制备所述抗体或其抗原结合片段的方法,包括以下步骤:
步骤1:在所述的重组细胞中表达所述抗体或其抗原结合片段;和
步骤2:从所述的重组细胞培养物中分离所述的抗体或其抗原结合片段。
又另一方面,本发明提供一种药物组合物,其含有本发明所述的抗体或其抗原结合片段、本发明所述的核苷酸序列、本发明所述的表达载体或本发明所述的重组细胞。
其中,本发明所述的药物组合物还包括药学上可接受的载体。
又另一方面,本发明提供本发明所述的抗体或其抗原结合片段、本发明所述的核苷酸序列、本发明所述的表达载体、本发明所述的重组细胞或本发明所述的药物组合物在制备药物中的用途。
其中,所述药物用于治疗或者预防肿瘤、感染以及增强免疫力。
其中,所述肿瘤为表达PVR的任何肿瘤;所述的肿瘤为血液瘤或实体瘤,其中,实体瘤选自黑素瘤、乳腺癌、卵巢癌、胰腺癌、结肠直肠癌、结肠癌、宫颈癌、肾癌、肺癌、甲状腺癌、前列腺癌、脑癌、咽喉癌、喉癌、膀胱癌、肝癌、纤维肉瘤、子宫内膜细胞癌、成胶质细胞癌、肉瘤、骨髓瘤、白血病或淋巴瘤;血液瘤选自髓样白血病、急性成淋巴细胞白血病、慢性淋巴细胞白血病、骨髓增生性疾病、多发性骨髓瘤或骨髓增生异常综合征。
其中,所述的感染选自病毒感染;所述病毒经由被感染细胞表面上的PVR与靶细胞结合。
又另一方面,本发明提供一种试剂盒,所述试剂盒包括本发明所述的抗体或其抗原结合片段、本发明所述的核苷酸序列、本发明所述的表达载体、本发明所述的重组细胞或本发明所述的药物组合物。
又另一方面,本发明提供本发明所述的抗体或其抗原结合片段、本发明所述的核苷酸序列、本发明所述的表达载体、本发明所述的重组细胞或本发明所述的药物组合物在制备试剂盒中的用途,所述试剂盒用于检测或诊断CD155相关指标。
在对本发明描述的过程中,对于本发明中的术语进行了解释和说明,这些解释和说明仅仅是为了方便对于方案的理解,并不能看做是对本发明保护方案的限制。
本发明所用氨基酸三字母代码和单字母代码如J.biol.chem,243,p3558(1968)中所述。
术语“抗体”是能够与特异性抗原结合的免疫球蛋白分子,通常包括两条相同的分子量较轻的轻链和两条相同的分子量较重的重链,重链(H链)和轻链(L链)由二硫键连接形成一个四肽链分子。免疫球蛋白重链恒定区的氨基酸组成和排列顺序不同,故其抗原性也不同。据此,可将免疫球蛋白分为5类,或称为免疫球蛋白的不同亚型,即IgM、IgD、IgG、IgA、IgE,其相应的重链分别为μ链、δ链、γ链、α链、ε链。同一类Ig根据其铰链区氨基酸组成和重链二硫键的数目和位置的差别,又可分为不同的亚类,如IgG1、IgG2、IgG3、IgG4。轻链通过恒定区的不同分为κ链和λ链。5类Ig中每类Ig都可以有κ链和λ链。
抗体重链和轻链靠近N端的约110个氨基酸的序列变化很大,为可变区(Fv区);靠近C端的其余氨基酸序列相对稳定,为恒定区。可变区包括3个高变区(Hypervariableregion,HVR)和4个序列相对保守的框架区(framework region,FR)。3个高变区决定抗体的特异性,又称为互补决定区(complementarity-determining region,CDR)。每条轻链可变区(LCVR)和重链可变区(HCVR)由3个CDR区和4个FR区组成,从氨基端到羧基端依次排列顺序为:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。轻链的3个CDR区指LCDR1、LCDR2、LCDR3;重链的3个CDR区指HCDR1、HCDR2、HCDR3。
在可变区中某些区域氨基酸组成和排列顺序具有更高的变化程度,称为高变区(Hypervariable region,HVR),高变区为抗原和抗体结合的位置,因此也称为决定簇互补区(complementarity-determining region,CDR)。重链可变区和轻链可变区上均有三个CDR区。CDR区序列可以由IMGT、Kabat、Chothia和AbM方法来定义或本领域熟知的任何CDR区序列确定方法而鉴定的可变区内的氨基酸残基。
术语“Fc区”或“Fc”是指免疫球蛋白重链的C端区,其含有铰链区的至少一部分、CH2结构域和CH3结构域,其介导免疫球蛋白与宿主组织或因子的结合,包括与位于免疫系统的各种细胞(例如,效应细胞)上的Fc受体结合或与经典补体系统的第一组分(例如C1q)结合,包括天然序列Fc区和变异Fc区。
术语“全长抗体”、“完整抗体”可互换使用,指基本上完整形式的抗体,与抗原结合片段不同。具体而言,完整抗体包括那些具有重链和轻链(包括Fc区)的。恒定区可以是天然序列恒定区(例如人天然序列恒定区)或其氨基酸序列变体。在有些情况中,完整抗体可具有一项或多项效应器功能。
术语“抗体片段”或“抗原结合片段”是指保留与抗原特异性结合能力的抗体片段及抗体类似物,其通常包括至少部分母体抗体(Parental Antibody)的抗原结合区或可变区。抗原结合片段包括但不限于:Fab片段(由VL、VH、CL和CH1结构域组成的单价片段)、F(ab’)2片段(通过铰链区上的二硫键连接的两个Fab片段的二价片段)、Fab’片段(通过切割F(ab’)2的铰链区的二硫键而获得)、Fv片段(VH和VL通过非共价键结合的最小功能片段)、Fd片段(Fab片段的重链部分)、互补决定区(CDR)片段、二硫键稳定性蛋白(dsFv)等;线性抗体(Linear Antibody)、单链抗体(例如ScFv单抗体)(技术来自Genmab)、二价单链抗体、单链噬菌体抗体、单域抗体(Single Domain Antibody)(例如VH结构域抗体)、结构域抗体(技术来自AbIynx);由抗体片段形成的多特异性抗体(例如三链抗体、四链抗体等);和工程改造抗体如嵌合抗体(Chimeric Antibody)(例如人源化鼠抗体)、异缀合抗体(Heteroconjugate Antibody)等。这些抗原结合片段用本领域技术人员已知的常规技术获得,并用与完整抗体相同的方法对这些片段的实用性进行筛选。
术语“单链抗体(或scFv抗体)”是指包含抗体的重链可变区(VH)和轻链可变区(VL)结构域的抗体片段,其中这些结构域存在于单个多肽链中。其中所述重链可变区的C端通过连接肽linker与所述轻链可变区的N端相连,可表示为VH-Link-VL,或所述轻链可变区的C端通过连接肽linker与所述重链可变区的N端相连,可表示为VL-Link-VH。
术语“单域抗体”用基因工程方法获得,主要有3类,第一类是从骆驼科动物HCAb获得的重链可变区,为单一的折叠单元,保留了完整的抗原结合活性,是最小的天然抗体片段。第二类是从鲨鱼等软骨鱼IgNAR获得的重链可变区,用VNAR表示。第三类是从人源或鼠源单抗获得的重链或轻链可变区,保留了抗原结合活性,但亲和性和可溶性大为下降。
术语“单克隆抗体(mAb)”指获自基本均一抗体群体的抗体,即除了少数出现可能的天然产生突变外,群体包含的单独抗体是相同的,对特定表位显示单一结合特异性和亲和力。修饰语“单克隆”表示从实质上一致的抗体组中获得的抗体的性质,不需要通过特定方法生产抗体。单克隆抗体由本领域技术人员所知晓的方法产生,例如通过将骨髓瘤细胞和免疫脾细胞融合制备杂合的抗体产生细胞。通过培养杂交瘤合成,不会污染任何其他抗体。单克隆抗体也可以用如重组技术、噬菌体展示技术、合成技术,或其他现有技术进行重组得到。
术语“嵌合抗体”是将鼠源性抗体的可变区与人抗体的恒定区融合而成的抗体,可以减轻鼠源性抗体诱发的免疫应答反应。
术语“特异性结合”是指,两分子间的非随机的结合反应,如抗体和其所针对的抗原之间的反应。
术语“同一性”用于指两个多肽之间或两个核酸之间的序列相似程度。当两个进行比较的序列中的某个位置都被相同的碱基或氨基酸单体亚单元占据时(例如,两个DNA分子的每一个中的某个位置都被腺嘌呤占据,或两个多肽的每一个中的某个位置都被赖氨酸占据),那么各分子在该位置上是同一的。两个序列之间的“百分数同一性”是由这两个序列共有的匹配位置数目除以进行比较的位置数目×100的函数。例如,如果两个序列的10个位置中有6个匹配,那么这两个序列具有60%的同一性。
术语“核酸分子”包括DNA分子和RNA分子。核酸分子可以是单链或双链的,并且可以是cDNA。
术语“载体”是指任何重组多核苷酸构建体,其可用于转化的目的,即将异源DNA引入到宿主细胞中,可以为质粒(例如Plasmid-X质粒)、病毒(例如,复制缺陷型逆转录病毒,腺病毒和腺伴随病毒)、噬菌体等。
术语“表达载体”是指在转化、转染或转导至宿主细胞中时能够复制及表达感兴趣基因的核苷酸序列。表达载体包含一个或多个表型选择标志及复制起点,以确保维持载体及以在需要的情况下于宿主内提供扩增。表达载体进一步包含启动子,以驱动细胞内多肽的表达。
术语“重组细胞”是指经表达载体引入其中的细胞。重组细胞可包括微生物(例如细菌)、植物或动物细胞。易于转化的细菌包括肠杆菌科(enterobacteriaceae)的成员,例如大肠杆菌(Escherichia coli)或沙门氏菌(Salmonella)的菌株;芽孢杆菌科(Bacillaceae)例如枯草芽孢杆菌(Bacillus subtilis);肺炎球菌(Pneumococcus);链球菌(Streptococcus)和流感嗜血菌(Haemophilus influenzae)。适当的微生物包括酿酒酵母(Saccharomyces cerevisiae)和毕赤酵母(Pichia pastoris)。适当的动物宿主细胞包括CHO、HEK293和NS0细胞。
在制备或者获取这些抗体的过程中,可以利用表达这些抗体的核苷酸序列,与不同的载体连接,然后在不同细胞中表达,来获得相应抗体。
本发明还提供了一种表达载体,所述表达载体包含上述分离的核苷酸序列。在将上述分离的多核苷酸连接到载体上时,可以将多核苷酸与载体上的控制组件直接或者间接相连,只要这些控制组件能够控制多核苷酸的翻译和表达等即可。当然这些控制组件可以直接来自于载体本身,也可以是外源性的,即并非来自于载体本身。当然,多核苷酸与控制组件进行可操作地连接即可。本文中“可操作地连接”是指将外源基因连接到载体上,使得载体内的控制组件,例如转录控制序列和翻译控制序列等等,能够发挥其预期的调节外源基因的转录和翻译的功能。当然用来编码抗体重链和轻链的多核苷酸,可以分别独立的插入到不同的载体上,常见的是插入到同一载体上。
术语“药学上可接受的载体”可以包括生理学上兼容的任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和延迟吸收剂等等。具体实例可以是水、盐水、磷酸盐缓冲盐水、葡萄糖、甘油、乙醇等以及它们的组合物中的一种或多种。有许多情况下,药物组合物中包括等渗剂,例如糖类、多元醇(如甘露醇、山梨醇)或氯化钠等。当然药学上可接受的载体还可包括微量的辅助物质,例如润湿剂或乳化剂、防腐剂或缓冲剂,用来延长抗体的保存限期或效力。
其中,本发明的抗体可掺入适用于胃肠外施用(例如静脉内、皮下、腹膜内、肌肉内)的药物组合物中。这些药物组合物可以被制备成各种形式。例如液体、半固体和固体剂型等,包括但不限于液体溶液(例如,注射溶液和输注溶液)、分散剂或悬浮剂、片剂、丸剂、粉末、脂质体和栓剂。典型的药物组合物为注射溶液或输注溶液形式。所述抗体可通过静脉输注或注射或肌肉内或皮下注射来施用。
除此之外,本发明提供了治疗有需要的受试者的癌症的方法,包括向所述受试者施用治疗有效量的本发明所述的抗体或抗体片段。
术语“有效量”是指当施用于受试者时将会具有预期治疗作用的足够量的单克隆抗体或抗体片段。达到治疗最终结果所需的有效量可取决于许多因素,包括例如,肿瘤的具体类型和患者病况的严重程度,以及该组合是否进一步与放射共同施用。本发明中,抗体的有效量应当足以影响受试者随时间的有益治疗反应,该有益的治疗反应包括但并不限抑制肿瘤生长、降低肿瘤生长速率、防止肿瘤和转移生长以及增强存活率。
除此之外,根据本发明的分子的治疗有效量将取决于施用方案、所施用分子的单位剂量、该分子是否与其他治疗剂联合施用、患者的免疫状态和健康、所施用分子的治疗活性、其在血液循环中的持久性和治疗医生的判断。
术语“治疗有效量”指对治疗哺乳动物疾病或病症有效的药物的量。在癌症的情况下,治疗有效量的药物可减少癌细胞的数量;减小肿瘤大小;抑制(即在一定程度上放慢并优选停止)癌细胞浸润到外周器官;抑制(即在一定程度上放慢并优选停止)肿瘤转移;在一定程度上抑制肿瘤生长;和/或在一定程度上缓解与病症相关的一种或多种症状。在药物可防止现有癌细胞生长和/或杀伤现有癌细胞的程度上,该药物可以是抑制细胞生长的和/或细胞毒性的。对于癌症疗法,可通过例如评估存活持续时间、疾病进展时间、应答率、应答持续时间和/或生活质量来测量体内功效。
附图说明
图1SDS-PAGE电泳图谱
图2Daudi--hCD155细胞模型嵌合抗体亲和力曲线
图3 152、161、143嵌合抗体hPBMC模型ADCC活性
图4 33、149嵌合抗体hPBMC模型ADCC活性
具体实施方式
下面详细描述本发明的实施例,所述实施例的示例在附图中示出,其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施例是示例性的,旨在用于解释本发明,而不能理解为对本发明的限制。
实施例1杂交瘤技术筛选抗CD155单克隆抗体
通过杂交瘤技术和流式细胞术方法筛选可以产生分子水平与CD155结合的高亲和力抗CD155单克隆抗体的杂交瘤细胞株。采用Uniprot数据库设计出CD155受体编码基因,构建到慢病毒表达载体上,通过慢病毒感染构建Daudi-hCD155细胞株,用于抗CD155单克隆抗体筛选。免疫原人源CD155胞外区蛋白(SinoBiological,Cat.10109-H08H),Balb/C小鼠三次皮下注射免疫后,流式细胞术方法测定免疫小鼠血清抗体滴度,达到105级。脾脏注射加强免疫后,与骨髓瘤细胞融合。采用HAT选择培养基和HT选择培养基选择性培养筛选融合的杂交瘤细胞株,采用流式细胞术方法筛选能产生抗CD155抗体的阳性杂交瘤细胞株,采用有限稀释法进行阳性杂交瘤细胞的克隆化培养,筛选稳定的能产生抗CD155单克隆抗体的杂交瘤细胞株。经三次克隆化培养,四次流式细胞术检测后,共筛选得到5株阳性杂交瘤细胞株,命名为152、161、143、33、149。
实施例2杂交瘤测序及嵌合抗体表达载体的构建
采用RNA提取试剂盒(Invitrogen,Cat.12183018A),提取152、161、143、33、149杂交瘤单克隆细胞株RNA,经反转录试剂盒(Invitrogen,Cat.11755250)将RNA反转录成cDNA,后利用引物将抗体轻重链可变区序列通过PCR反应调取出来,委托金唯智生物科技有限公司测序。采用分子克隆的方法构建一系列(152、161、143、33、149)嵌合抗体表达载体,在CHO-S表达系统中,重组表达嵌合抗体。编码一系列(152、161、143、33、149)嵌合单克隆抗体轻重链的核苷酸序列是委托金唯智生物科技有限公司通过化学合成获得的,所获得的序列经双酶切后,插入到真核表达载体的相同酶切位点间,构建一系列(152、161、143、33、149)嵌合抗体表达载体。然后采用质粒提取试剂盒(Invitrogen,Cat.A31231)提取一系列经验证正确的表达载体,-80℃保藏。其中,嵌合抗体序列如表1所示:
表1
实施例3编码一系列嵌合抗体载体转染并在细胞中表达
将CHO-S宿主细胞用ExpiCHOTM Expression Medium(Gibco,Cat.A2910002)复苏培养后,当细胞密度约6*106cell/mL时收集细胞,采用ExpiFectamineTM CHO TransfectionKit(Gibco,Cat.A29129)进行瞬时转染。每个嵌合抗体转染100mL体系,轻重链表达质粒各50ug,转染当天为DAY-0,细胞置于37℃、130rpm培养,DAY-1补加300ul ExpiFectamineTMCHO Enhancer和8mL ExpiCHOTM Feed,细胞至于32℃、130rpm培养,DAY-5不加8mLExpiCHOTM Feed,细胞至于32℃、130rpm培养,DAY-10收集细胞悬液,200g离心5min后收集上清细胞发酵液,细胞发酵液再置于4℃、8000rpm离心30min,再次收集上清细胞发酵液。
实施例4上清细胞发酵液纯化嵌合抗体
采用Protein A层析柱对收集的细胞培养液进行纯化,并收集吸收峰,对收集的样品经还原与非还原后通过10%SDS-PAGE电泳检测,还原型SDS-PAGE电泳图谱显示二条带,分别在25KD和50KD左右,非还原型SDS-PAGE电泳图谱显示单一条带,在150KD左右,电泳图谱条带大小与理论一致。纯化后样品采用pH7.4的0.01M PBS缓冲液在4℃透析过夜。
结论:由图1可以看出,嵌合抗体SDS-PAGE电泳图非还原条件下,全长抗体电泳图条带在150KD左右,还原条件下,抗体电泳图谱条带在25KD和50KD左右,抗体表达正确,分子量与理论一致。
实施例5嵌合抗体亲和力测定
采用流式细胞术方法测定嵌合抗体亲和力。利用慢病毒技术构建的Daudi--hCD155细胞模型评估嵌合抗体与阳性对照Rituximab的亲和力。将抗体从最高浓度20ug/mL两倍两倍稀释,稀释20个梯度,与Daudi-hCD155细胞在4℃孵育30min后,用冷的PBS洗涤细胞三次,细胞再与Goat Anti-Human IgG Fc(FITC)二抗(abcam,Cat.ab97224)在4℃孵育30min后,用冷的PBS洗涤细胞三次,BD FACSVerse分析流式检测荧光值,计算EC50。试验结果如图2所示。EC50值如表2所示,数据分析显示,152、161、33、149嵌合抗体亲和力均比阳性对照Rituximab高。
表2
152 | 161 | 33 | 149 | Rituximab | |
EC50 | 0.008602 | 0.01528 | 0.008679 | 0.01417 | 0.06140 |
其中,152嵌合抗体亲和力EC50为0.008602nM、161嵌合抗体亲和力EC50为0.01528nM、33嵌合抗体亲和力EC50为0.008679nM、149嵌合抗体亲和力EC50为0.01417nM,阳性对照Rituximab嵌合抗体亲和力EC50为0.06140nM,其中152、161、33、149嵌合抗体亲和力均比阳性对照Rituximab高。
实施例6嵌合抗体种属交叉反应测定
采用ELISA方法测定嵌合抗体种属交叉反应。用人CD155胞外区蛋白(SinoBiological,Cat.10109-H08H)、猴CD155胞外区蛋白(SinoBiological,Cat.90005-C08H)、大鼠CD155胞外区蛋白(SinoBiological,Cat.80007-R08H)、小鼠CD155胞外区蛋白(SinoBiological,Cat.50259-M08H)包被酶标板,将嵌合抗体从最高浓度20ug/mL两倍两倍稀释,稀释20个梯度,按每孔100ul体积加入酶标板中,37℃孵育30min后,用PBST洗涤酶标板三次,再按每孔100ul体积加入Goat Anti-Human IgG H&L(HRP)二抗(abcam,Cat.ab6858),37℃孵育30min后,用PBST洗涤酶标板三次,每孔加入100ul显色液,37℃孵育5min后,每孔加入50ul终止液,Bioteck 800-TS酶标仪读数。嵌合抗体种属交叉反应测定如表3显示。
表3
抗体 | 人CD155 | 猴CD155 | 大鼠CD155 | 小鼠CD155 |
152 | ++ | ++ | - | - |
161 | ++ | ++ | - | - |
143 | ++ | + | - | - |
33 | ++ | ++ | - | - |
149 | ++ | ++ | - | - |
由表3的结果可知,所有嵌合抗体均与人/猴CD155反应,与大鼠/小鼠CD155无反应。其中,表3中“++”表示强结合,“+”表示弱结合,“-”表示无结合。
实施例7嵌合抗体hPBMC模型测定ADCC活性
采用慢病毒转染方式构建过表达CD155的Daudi-hCD155细胞系,以无酚红1640+4%FBS+1%双抗培养基重悬细胞,并测定细胞活力,保证活力>95%。调整细胞密度为8*105/mL,以每孔50μL体积加入96孔板中。实验设置空白孔、靶细胞最大释放孔、靶细胞自发释放孔、效应细胞自发释放孔、单抗孔。
152、161、143、33、149抗体及阳性对照Rituximab以50μg/mL或10μg/mL为初始浓度,用无酚红1640完全培养基五倍稀释10个浓度梯度。加入Daudi-hCD155靶细胞中孵育10min。
采集人全血,按照密度梯度离心法提取人外周血单核细胞PBMC,测定细胞活力>95%。调整PBMC细胞密度为1*107/mL,以每孔100μL的体积加入到靶细胞Daudi-hCD155中共孵育4h,效靶比为25:1。收集上清前30min,向靶细胞最大释放孔加入9%triton 100x裂解液。所有孔孵育结束后,250g,5min室温离心,取上清50μl按照LDH试剂盒说明书测定OD值。
并按照说明书中公式计算杀伤率:
如图3、图4所示,在hPBMC模型中,嵌合抗体ADCC活性均比阳性对照Rituximab强。嵌合抗体ADCC活性如表4、表5所示。
表4
152 | 161 | 143 | Rituximab | |
IC50 | 7.727 | 11.22 | 60.80 | 533.5 |
表4数据分析显示,152抗体ADCC活性IC50为7.727ng/mL,161抗体ADCC活性IC50为11.22ng/mL,143抗体IC50为60.80ng/mL,阳性对照RituximabADCC活性IC50为533.5ng/mL,IC50数值越小活性越强,在hPBMC模型中,152、161、143嵌合抗体ADCC活性均比阳性对照Rituximab强。
表5
33 | 149 | Rituximab | |
IC50 | 109.7 | 72.86 | 895.7 |
表5数据分析显示,33抗体ADCC活性IC50为109.7ng/mL,149抗体ADCC活性IC50为72.86ng/mL,阳性对照RituximabADCC活性IC50为895.7ng/mL,IC50数值越小活性越强,在hPBMC模型中,33、149嵌合抗体ADCC活性均比阳性对照Rituximab强。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外,在不相互矛盾的情况下,本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
SEQUENCE LISTING
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<220>
<223> 轻链可变区CDR序列
<400> 17
Tyr Ala Ala
1
<210> 18
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区CDR序列
<400> 18
Gln Asn Ala His Ser Phe Pro Tyr Ser
1 5
<210> 19
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区CDR序列
<400> 19
Gln Gly Val Gly Thr Ala
1 5
<210> 20
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区CDR序列
<400> 20
Trp Ala Ser
1
<210> 21
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区CDR序列
<400> 21
Gln His Phe Gly Ser Tyr Pro Thr
1 5
<210> 22
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区CDR序列
<400> 22
Gln Asp Val Ser Thr Ala
1 5
<210> 23
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区CDR序列
<400> 23
Gln Gln His Tyr Thr Thr Pro Arg Thr
1 5
<210> 24
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区CDR序列
<400> 24
Ala Ser Ser Ser Val Ser Tyr
1 5
<210> 25
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区CDR序列
<400> 25
Arg Thr Ser
1
<210> 26
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区CDR序列
<400> 26
Gln Gln Tyr Gln Ser Tyr Pro Trp Thr
1 5
<210> 27
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区CDR序列
<400> 27
Gln Gln Tyr Asn Thr Tyr Pro Leu Thr Phe Gly Ser Gly Thr Asn Leu
1 5 10 15
Glu Ile Lys
<210> 28
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区CDR序列
<400> 28
Ser Ala Ser
1
<210> 29
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区CDR序列
<400> 29
Gln Gln Tyr Asn Thr Tyr Pro Leu Thr
1 5
<210> 30
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> 重链可变区
<400> 30
Glu Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Val
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Asp Leu Asn Tyr Asn Gly Asn Phe
50 55 60
Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Val Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gly Thr Ala Thr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu
100 105 110
Thr Val Ser Ser
115
<210> 31
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> 重链可变区
<400> 31
Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Asn
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ala Val Ile Trp Ser Asp Gly Ser Thr Thr His Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Leu Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Val Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Asn Lys Asp Tyr Tyr Ala Met Asp Asn Trp Gly Pro Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 32
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> 重链可变区
<400> 32
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ala Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ala Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Leu Ala Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Gly Ser Asp Tyr Ala Gly Tyr Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 33
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> 重链可变区
<400> 33
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ala Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile Ser Trp Leu Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile
35 40 45
Gly Asp Phe Tyr Pro Gly Gly Tyr Tyr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Trp Gly Asp Thr Ser Gly Thr Asp Tyr Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 34
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> 重链可变区
<400> 34
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Ser Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Gly Ile Thr Pro Thr Asn Gly Gly Ser Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys
85 90 95
Ala Arg Trp Val Gly Pro Met Asp Tyr Trp Gly Gln Gly Val Ser Val
100 105 110
Thr Val Ser Ser
115
<210> 35
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区
<400> 35
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Arg Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr
20 25 30
Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Leu
35 40 45
Lys Tyr Ala Ala His Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Pro
65 70 75 80
Glu Asp Val Gly Val Tyr Tyr Cys Gln Asn Ala His Ser Phe Pro Tyr
85 90 95
Ser Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 36
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区
<400> 36
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Gly Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
His Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln His Phe Gly Ser Tyr Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 37
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区
<400> 37
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Glu Leu Glu Ile Lys
100 105
<210> 38
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区
<400> 38
Asp Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Ile Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Asn Ser Met Glu Ala Glu
65 70 75 80
Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Gln Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 39
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链可变区
<400> 39
Asp Ile Val Leu Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Gln Tyr Asn Thr Tyr
20 25 30
Pro Leu Thr Phe Gly Ser Gly Thr Asn Leu Glu Ile Lys Val Ala Trp
35 40 45
Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Val Leu Ile Tyr Ser Ala
50 55 60
Ser Tyr Arg Phe Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser
65 70 75 80
Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Val Gln Ser Glu Asp Leu
85 90 95
Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Thr Tyr Pro Leu Thr Phe Gly
100 105 110
Ser Gly Thr Asn Leu Glu Ile Lys
115 120
<210> 40
<211> 330
<212> PRT
<213> Artificial Sequence
<220>
<223> 重链恒定区全长序列
<400> 40
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 41
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链恒定区全长序列
<400> 41
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 42
<211> 446
<212> PRT
<213> Artificial Sequence
<220>
<223> 重链
<400> 42
Glu Val Gln Leu Gln Glu Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Val
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Asp Leu Asn Tyr Asn Gly Asn Phe
50 55 60
Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Val Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gly Thr Ala Thr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 43
<211> 447
<212> PRT
<213> Artificial Sequence
<220>
<223> 重链
<400> 43
Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Asn
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ala Val Ile Trp Ser Asp Gly Ser Thr Thr His Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Leu Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Val Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Asn Lys Asp Tyr Tyr Ala Met Asp Asn Trp Gly Pro Gly Thr Ser
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 44
<211> 450
<212> PRT
<213> Artificial Sequence
<220>
<223> 重链
<400> 44
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Val
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ala Met His Trp Val Lys Gln Ser His Ala Lys Ser Leu Glu Trp Ile
35 40 45
Gly Val Ile Ser Thr Tyr Tyr Gly Asp Ala Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Met Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ala Arg Leu Ala Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Gly Ser Asp Tyr Ala Gly Tyr Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 45
<211> 452
<212> PRT
<213> Artificial Sequence
<220>
<223> 重链
<400> 45
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ala Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile Ser Trp Leu Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile
35 40 45
Gly Asp Phe Tyr Pro Gly Gly Tyr Tyr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Trp Gly Asp Thr Ser Gly Thr Asp Tyr Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 46
<211> 446
<212> PRT
<213> Artificial Sequence
<220>
<223> 重链
<400> 46
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Ser Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Gly Ile Thr Pro Thr Asn Gly Gly Ser Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys
85 90 95
Ala Arg Trp Val Gly Pro Met Asp Tyr Trp Gly Gln Gly Val Ser Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 47
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链
<400> 47
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Arg Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr
20 25 30
Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Leu
35 40 45
Lys Tyr Ala Ala His Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Pro
65 70 75 80
Glu Asp Val Gly Val Tyr Tyr Cys Gln Asn Ala His Ser Phe Pro Tyr
85 90 95
Ser Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 48
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链
<400> 48
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Gly Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
His Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln His Phe Gly Ser Tyr Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 49
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链
<400> 49
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Glu Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 50
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链
<400> 50
Asp Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Ile Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Asn Ser Met Glu Ala Glu
65 70 75 80
Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Gln Ser Tyr Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 51
<211> 227
<212> PRT
<213> Artificial Sequence
<220>
<223> 轻链
<400> 51
Asp Ile Val Leu Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Gln Tyr Asn Thr Tyr
20 25 30
Pro Leu Thr Phe Gly Ser Gly Thr Asn Leu Glu Ile Lys Val Ala Trp
35 40 45
Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Val Leu Ile Tyr Ser Ala
50 55 60
Ser Tyr Arg Phe Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser
65 70 75 80
Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Val Gln Ser Glu Asp Leu
85 90 95
Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Thr Tyr Pro Leu Thr Phe Gly
100 105 110
Ser Gly Thr Asn Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val
115 120 125
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser
130 135 140
Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln
145 150 155 160
Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val
165 170 175
Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu
180 185 190
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu
195 200 205
Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
210 215 220
Gly Glu Cys
225
Claims (10)
1.一种与人脊髓灰质炎病毒受体结合的可分离的抗体或其抗原结合片段,其特征在于,所述的抗体或其抗原结合片段包含选自下组任一所示的CDR序列:
重链可变区CDR1序列为:SEQ ID NO 1、SEQ ID NO 4、SEQ ID NO 7、SEQ ID NO 10或SEQ ID NO 13;或与SEQ ID NO 1、SEQ ID NO 4、SEQ ID NO 7、SEQ ID NO 10或SEQ ID NO13具有至少80%同一性的序列;和
重链可变区CDR2序列为:SEQ ID NO 2、SEQ ID NO 5、SEQ ID NO 8、SEQ ID NO 11或SEQ ID NO 14;或与SEQ ID NO 2、SEQ ID NO 5、SEQ ID NO 8、SEQ ID NO 11或SEQ ID NO14具有至少80%同一性的序列;和
重链可变区CDR3序列为:SEQ ID NO 3、SEQ ID NO 6、SEQ ID NO 9、SEQ ID NO 12或SEQ ID NO 15;或与SEQ ID NO 3、SEQ ID NO 6、SEQ ID NO 9、SEQ ID NO 12或SEQ ID NO15具有至少80%同一性的序列;和
轻链可变区CDR1序列为:SEQ ID NO 16、SEQ ID NO 19、SEQ ID NO 22、SEQ ID NO 24或SEQ ID NO 27;或与SEQ ID NO 16、SEQ ID NO 19、SEQ ID NO 22、SEQ ID NO 24或SEQID NO 27具有至少80%同一性的序列;和
轻链可变区CDR2序列为:SEQ ID NO 17、SEQ ID NO 20、SEQ ID NO 25或SEQ ID NO28;或与SEQ ID NO 17、SEQ ID NO 20、SEQ ID NO 25或SEQ ID NO 28具有至少80%同一性的序列;和
轻链可变区CDR3序列为:SEQ ID NO 18、SEQ ID NO 21、SEQ ID NO 23、SEQ ID NO 26或SEQ ID NO 29;或与SEQ ID NO 18、SEQ ID NO 21、SEQ ID NO 23、SEQ ID NO 26或SEQID NO 29具有至少80%同一性的序列。
2.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段的重链可变区具有如SEQ ID NO 30~34所示的氨基酸序列;或与SEQ ID NO 30~34所示的氨基酸序列具有至少95%同一性的序列;和
所述抗体或其抗原结合片段的轻链可变区具有如SEQ ID NO 35~39所示的氨基酸序列;或与SEQ ID NO 35~39所示的氨基酸序列具有至少95%同一性的序列。
3.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段的重链恒定区序列和轻链恒定区序列的至少之一的至少一部分来自于啮齿动物、人、鸡、骆驼、鸵鸟、绵羊、牛、非人灵长类动物或鲨鱼;
所述重链恒定区选自IgG1亚型、IgG2亚型、IgG3亚型或IgG4亚型;所述轻链的恒定区选自κ亚型或λ亚型;
所述重链恒定区、轻链恒定区均来自于人源抗体或其突变体;任选地,所述重链恒定区、轻链恒定区均来自于人源IgG1;
所述重链恒定区的全长序列如SEQ ID NO 40所示;所述轻链恒定区的全长序列如SEQID NO 41所示。
4.根据权利要求1所述的抗体或其抗原结合片段,其特征在于,所述的抗体或其抗原结合片段的重链具有如SEQ ID NO 42~46所示的氨基酸序列;和
轻链具有如SEQ ID NO 47~51所示的氨基酸序列。
5.一种核酸分子,其特征在于,所述核酸分子编码权利要求1-4任意一项所述的抗体或其抗原结合片段。
6.一种表达载体,其特征在于,所述表达载体携带权利要求5所述的核酸分子。
7.一种重组细胞,其特征在于,所述重组细胞携带权利要求5所述的核酸分子和权利要求6所述的表达载体或表达权利要求1-4任意一项所述的抗体或其抗原结合片段。
8.一种药物组合物,其特征在于,含有权利要求1-4任意一项所述的抗体或其抗原结合片段、权利要求5所述的核酸分子、权利要求6所述的表达载体或权利要求7所述的重组细胞。
9.权利要求1-4任意一项所述的抗体或其抗原结合片段、权利要求5所述的核酸分子、权利要求6所述的表达载体、权利要求7所述的重组细胞或权利要求8所述的药物组合物在制备药物中的用途。
10.根据权利要求9所述的用途,其特征在于,所述药物用于治疗或者预防肿瘤、感染以及增强免疫力;所述肿瘤为表达PVR的任何肿瘤;所述的肿瘤为血液瘤或实体瘤,其中,实体瘤选自黑素瘤、乳腺癌、卵巢癌、胰腺癌、结肠直肠癌、结肠癌、宫颈癌、肾癌、肺癌、甲状腺癌、前列腺癌、脑癌、咽喉癌、喉癌、膀胱癌、肝癌、纤维肉瘤、子宫内膜细胞癌、成胶质细胞癌、肉瘤、骨髓瘤、白血病或淋巴瘤;血液瘤选自髓样白血病、急性成淋巴细胞白血病、慢性淋巴细胞白血病、骨髓增生性疾病、多发性骨髓瘤或骨髓增生异常综合征。
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