CN114957469B - 一种抗NKp30抗体及其应用 - Google Patents
一种抗NKp30抗体及其应用 Download PDFInfo
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Abstract
本发明公开了一种抗NKp30单域抗体及其编码抗NKp30单域抗体的核酸,其抗体能够激活NK细胞或γδT细胞释放细胞因子。本发明还公开了包含抗NKp30单域抗体的多功能融合蛋白及其组合物,以及在治疗、预防或诊断疾病的药物中的用途。
Description
技术领域
本发明属于肿瘤免疫疗法和分子免疫学领域,具体涉及一种抗NKp30单域抗体及其应用。
背景技术
肿瘤免疫
肿瘤是目前世界范围内危害人类健康的重大疾病。机体免疫系统的功能异常与肿瘤的发生和发展具有十分密切的关系。CTLA-4和PD-1等T细胞免疫检查点疗法显著改善了多种转移性和难治性癌症患者的预后,然而它们仅对少数患者有效,有效率在20%左右,并且面临耐药性问题。
自然杀伤细胞和γδT细胞
NK细胞是医学界公认的第一道防线,与其他抗癌免疫细胞相比,NK细胞杀灭肿瘤和病毒感染细胞的作用更强、更有效。它的激活不依赖于肿瘤细胞表面抗原,也不需要像T细胞一样,要经过免疫系统的抗原辨识反应才确定“攻击”目标。NK细胞游弋在全身血管行使免疫监视作用,它能在第一时间发现并迅速启动免疫防御和免疫稳定功能,杀死病变、癌变的细胞。NK细胞作用于靶细胞后杀伤作用,在体外1小时、体内4小时即可见到杀伤效应。人类主要NK细胞活化性受体包括CD16、NKG2D和自然细胞毒性受体(NCRs),后者包括NKp30、NKp44和NKp46。
目前NK细胞的激活主要是通过抗体Fc区结合CD16,但Fc与CD16的亲和力低,科学家又开发了CD16激动剂,能更有效的引起NK细胞的活化而发挥抗肿瘤作用,但是CD16的缺失或CD16的多态性限制了CD16激动剂的应用。
γδT细胞是一种既能杀伤癌细胞,肿瘤干细胞,又能识别癌抗原的免疫细胞,它的杀伤性较强,但肿瘤干细胞杀伤不如NK细胞。同时,γδT细胞主要分布于皮肤和黏膜组织上,因此对于黏膜方面的癌症治疗效果突出,比如消化道、呼吸道、生殖系统方面的癌症效果显著。目前还未有γδT细胞的生物制品激动剂相关报道。
NKp30
NKp30(Natural cytotoxicity triggering receptor 3)由NCR3基因编码,属于自然细胞毒性引发受体(NCRs)家族成员,是细胞表面的一种激活型受体。NKp30表达于所有静息与活化的NK细胞、多种效应NKT细胞、γδT细胞、MAIT细胞(黏膜相关恒定的T淋巴细胞),激活NKp30能激活NK细胞、γδT细胞等肿瘤杀伤性细胞。重要的是,NKp30可以在没有CD16A结合的情况下激活NK细胞,且激活后杀伤效果强于anti-CD16A,抗NKp30抗体与抗CD16A抗体有协同放大作用。
单域抗体
骆驼或是羊驼等骆驼科动物能够产生一种天然缺失轻链的重链抗体,其分子只包含一个重链可变区(VHH)和两个常规的CH2与CH3区,但却具有完整的抗原结合功能,而且不像人工改造的单链抗体片段(scFv)那样容易聚集。重链单域抗体因其特殊的结构性质,兼具了传统抗体与小分子药物的优势,克服了传统抗体的开发周期长,稳定性较低,保存条件苛刻等缺陷,代表了新一代抗体治疗开发的方向。
尽管单域抗体比具有两条重链和两条轻链的常见单克隆抗体的尺寸小得多,但其可以与单克隆抗体(mAb)相似的亲和力和特异性结合抗原。单域抗体用作结构单元时,其可融合至IgG Fc域以产生IgG样抗体,包括二价和多价抗体。开发靶向肿瘤相关抗原与NKp30的双特异性抗体,桥接肿瘤细胞与NK细胞。仅激活肿瘤微环境中的NK细胞,有助于减少副作用,避免因全身性NK细胞的高度活化,对丢失MHC分子的异常细胞敏感性降低。
本发明将NKp30作为免疫治疗的靶点,开发了新的抗NKp30单域抗体,用于双功能抗体、多功能抗体或多功能融合蛋白的开发。
发明内容
本发明提供了一种抗NKp30单域抗体,其能够激活NK细胞或γδT细胞释放细胞因子。
在可选的实施方案中,所述细胞因子为淋巴因子,优选为IL2、IL3、IL4、IL5、IL6、IL9、IL10、IFN-γ或TNF-α,更优选为IFN-γ、TNF-α或IL2。
在可选的实施方案中,所述抗NKp30单域抗体包含免疫球蛋白单一可变结构域,其免疫球蛋白单一可变结构域包含互补决定区CDR1、CDR2和CDR3,其中,
(a)CDR1,选自SEQ ID NO:47-69的任一氨基酸序列,或与SEQ ID NO:47-69的任一氨基酸序列具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或以上同一性的序列,或与SEQ ID NO:47-69的任一氨基酸序列相比具有一个或多个(优选2个或3个)保守氨基酸突变(优选置换、插入或缺失)的氨基酸序列;
(b)CDR2,选自SEQ ID NO:70-92的任一氨基酸序列,或与SEQ ID NO:70-92的任一氨基酸序列具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或以上同一性的序列,或与SEQ ID NO:70-92的任一氨基酸序列相比具有一个或多个(优选2个或3个)保守氨基酸突变(优选置换、插入或缺失)的氨基酸序列;
(c)CDR3,选自SEQ ID NO:93-115的任一氨基酸序列,或与SEQ ID NO:93-115的任一氨基酸序列具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或以上同一性的序列,或与SEQ ID NO:93-115的任一氨基酸序列相比具有一个或多个(优选2个或3个)保守氨基酸突变(优选置换、插入或缺失)的氨基酸序列。
在可选的实施方案中,所述抗NKp30单域抗体的单一可变结构域包含选自以下的CDR1、CDR2和CDR3:
(1)SEQ ID NO:47所示的CDR1,SEQ ID NO:70所示的CDR2,SEQ ID NO:93所示的CDR3;
(2)SEQ ID NO:48所示的CDR1,SEQ ID NO:71所示的CDR2,SEQ ID NO:94所示的CDR3;
(3)SEQ ID NO:49所示的CDR1,SEQ ID NO:72所示的CDR2,SEQ ID NO:95所示的CDR3;
(4)SEQ ID NO:50所示的CDR1,SEQ ID NO:73所示的CDR2,SEQ ID NO:96所示的CDR3;
(5)SEQ ID NO:51所示的CDR1,SEQ ID NO:74所示的CDR2,SEQ ID NO:97所示的CDR3;
(6)SEQ ID NO:52所示的CDR1,SEQ ID NO:75所示的CDR2,SEQ ID NO:98所示的CDR3;
(7)SEQ ID NO:53所示的CDR1,SEQ ID NO:76所示的CDR2,SEQ ID NO:99所示的CDR3;
(8)SEQ ID NO:54所示的CDR1,SEQ ID NO:77所示的CDR2,SEQ ID NO:100所示的CDR3;
(9)SEQ ID NO:55所示的CDR1,SEQ ID NO:78所示的CDR2,SEQ ID NO:101所示的CDR3;
(10)SEQ ID NO:56所示的CDR1,SEQ ID NO:79所示的CDR2,SEQ ID NO:102所示的CDR3;
(11)SEQ ID NO:57所示的CDR1,SEQ ID NO:80所示的CDR2,SEQ ID NO:103所示的CDR3;
(12)SEQ ID NO:58所示的CDR1,SEQ ID NO:81所示的CDR2,SEQ ID NO:104所示的CDR3;
(13)SEQ ID NO:59所示的CDR1,SEQ ID NO:82所示的CDR2,SEQ ID NO:105所示的CDR3;
(14)SEQ ID NO:60所示的CDR1,SEQ ID NO:83所示的CDR2,SEQ ID NO:106所示的CDR3;
(15)SEQ ID NO:61所示的CDR1,SEQ ID NO:84所示的CDR2,SEQ ID NO:107所示的CDR3;
(16)SEQ ID NO:62所示的CDR1,SEQ ID NO:85所示的CDR2,SEQ ID NO:108所示的CDR3;
(17)SEQ ID NO:63所示的CDR1,SEQ ID NO:86所示的CDR2,SEQ ID NO:109所示的CDR3;
(18)SEQ ID NO:64所示的CDR1,SEQ ID NO:87所示的CDR2,SEQ ID NO:110所示的CDR3;
(19)SEQ ID NO:65所示的CDR1,SEQ ID NO:88所示的CDR2,SEQ ID NO:111所示的CDR3;
(20)SEQ ID NO:66所示的CDR1,SEQ ID NO:89所示的CDR2,SEQ ID NO:112所示的CDR3;
(21)SEQ ID NO:67所示的CDR1,SEQ ID NO:90所示的CDR2,SEQ ID NO:113所示的CDR3;
(22)SEQ ID NO:68所示的CDR1,SEQ ID NO:91所示的CDR2,SEQ ID NO:114所示的CDR3;或
(23)SEQ ID NO:69所示的CDR1,SEQ ID NO:92所示的CDR2,SEQ ID NO:115所示的CDR3。
在可选的实施方案中,所述免疫球蛋白单一可变结构域是VHH。
在可选的实施方案中,所述VHH包含与SEQ ID NO:1-23中任一所述的氨基酸序列具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或以上同一性的序列。
在可选的实施方案中,所述VHH选自SEQ ID NO:1-23中任一所述的氨基酸序列。
在可选的实施方案中,所述抗体以20.1nM或更小的KD结合NKp30。
在可选的实施方案中,所述抗体还包含免疫球蛋白Fc区,所述免疫球蛋白Fc区选自IgG1、IgG2、IgG3和/或IgG4。
在可选的实施方案中,所述免疫球蛋白Fc区的氨基酸序列如SEQ ID NO:116所示。
本发明还提供了核酸分子,其编码上述任一所述的抗NKp30单域抗体。
在可选的实施方案中,所述核酸分子包含选自SEQ ID NO:24-46的编码抗体单一可变结构域的核苷酸序列。
本发明还提供了表达载体,其包含与表达调控原件可操作地连接的上述核酸分子。
本发明还提供了重组细胞,其包含上述核酸分子或上述的表达载体转化,并能够表达所述抗NKp30单域抗体。
本发明还提供了一种多功能融合蛋白,其包含上述任一所述的抗NKp30单域抗体。
在可选的实施方案中,其多功能融合蛋白还包含一个或多个与其他抗原特异性结合的第二抗体或其抗原结合部分。
在可选的实施方案中,其中所述结合第二抗体或其抗原结合部分的抗原选自肿瘤相关抗原(TAA)或免疫检查点。
在可选的实施方案中,其多功能融合蛋白还包含细胞因子。
在可选的实施方案中,所述细胞因子选自IL8、IL10、IL15、IL18、TGF、VEGF、IFNγ、IFNα或GM-CSF。
本发明还提供了上述任一所述的抗NKp30单域抗体、多功能融合蛋白在制备用于治疗和/或预防和/或诊断疾病的药物中的用途。
在可选的实施方案中,所述用途通过肿瘤免疫疗法、细胞疗法和基因疗法中的一种或多种来实现。
本发明还提供了上述任一所述的抗NKp30单域抗体、多功能融合蛋白在治疗癌症的药物中的用途。
在可选的实施方案中,所述癌为肺癌、肝癌、黑色素瘤、恶性胶质瘤、头颈癌、结肠直肠癌、胃癌、前列腺癌、卵巢癌、膀胱癌、胰腺癌、胃癌、结肠癌、宫颈癌或相关肿瘤。
本发明还提供了一种药物组合物,其包含上述任一所述的抗NKp30单域抗体和可接受的载体、稀释剂或赋形剂。
本发明还提供了一种药物组合物,其包含上述任一所述的多功能融合蛋白和可接受的载体、稀释剂或赋形剂。
因此,本发明涉及以下实施方案:
1、一种抗NKp30单域抗体,其特征在于,其能够激活NK细胞或γδT细胞释放细胞因子。
2、根据方案1所述的抗NKp30单域抗体,其特征在于,所述细胞因子为淋巴因子,优选为IL2、IL3、IL4、IL5、IL6、IL9、IL10、IFN-γ或TNF-α,更优选为IFN-γ、TNF-α或IL2。
3、根据方案1或2所述的抗NKp30单域抗体,其包含免疫球蛋白单一可变结构域,其特征在于,其免疫球蛋白单一可变结构域包含互补决定区CDR1、CDR2和CDR3,其中,
(a)CDR1,选自SEQ ID NO:47-69的任一氨基酸序列,或与SEQ ID NO:47-69的任一氨基酸序列具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或以上同一性的序列,或与SEQ ID NO:47-69的任一氨基酸序列相比具有一个或多个(优选2个或3个)保守氨基酸突变(优选置换、插入或缺失)的氨基酸序列;
(b)CDR2,选自SEQ ID NO:70-92的任一氨基酸序列,或与SEQ ID NO:70-92的任一氨基酸序列具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或以上同一性的序列,或与SEQ ID NO:70-92的任一氨基酸序列相比具有一个或多个(优选2个或3个)保守氨基酸突变(优选置换、插入或缺失)的氨基酸序列;
(c)CDR3,选自SEQ ID NO:93-115的任一氨基酸序列,或与SEQ ID NO:93-115的任一氨基酸序列具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或以上同一性的序列,或与SEQ ID NO:93-115的任一氨基酸序列相比具有一个或多个(优选2个或3个)保守氨基酸突变(优选置换、插入或缺失)的氨基酸序列。
4、根据方案3所述的抗NKp30单域抗体,其中所述单一可变结构域包含选自以下的CDR1、CDR2和CDR3:
(1)SEQ ID NO:47所示的CDR1,SEQ ID NO:70所示的CDR2,SEQ ID NO:93所示的CDR3;
(2)SEQ ID NO:48所示的CDR1,SEQ ID NO:71所示的CDR2,SEQ ID NO:94所示的CDR3;
(3)SEQ ID NO:49所示的CDR1,SEQ ID NO:72所示的CDR2,SEQ ID NO:95所示的CDR3;
(4)SEQ ID NO:50所示的CDR1,SEQ ID NO:73所示的CDR2,SEQ ID NO:96所示的CDR3;
(5)SEQ ID NO:51所示的CDR1,SEQ ID NO:74所示的CDR2,SEQ ID NO:97所示的CDR3;
(6)SEQ ID NO:52所示的CDR1,SEQ ID NO:75所示的CDR2,SEQ ID NO:98所示的CDR3;
(7)SEQ ID NO:53所示的CDR1,SEQ ID NO:76所示的CDR2,SEQ ID NO:99所示的CDR3;
(8)SEQ ID NO:54所示的CDR1,SEQ ID NO:77所示的CDR2,SEQ ID NO:100所示的CDR3;
(9)SEQ ID NO:55所示的CDR1,SEQ ID NO:78所示的CDR2,SEQ ID NO:101所示的CDR3;
(10)SEQ ID NO:56所示的CDR1,SEQ ID NO:79所示的CDR2,SEQ ID NO:102所示的CDR3;
(11)SEQ ID NO:57所示的CDR1,SEQ ID NO:80所示的CDR2,SEQ ID NO:103所示的CDR3;
(12)SEQ ID NO:58所示的CDR1,SEQ ID NO:81所示的CDR2,SEQ ID NO:104所示的CDR3;
(13)SEQ ID NO:59所示的CDR1,SEQ ID NO:82所示的CDR2,SEQ ID NO:105所示的CDR3;
(14)SEQ ID NO:60所示的CDR1,SEQ ID NO:83所示的CDR2,SEQ ID NO:106所示的CDR3;
(15)SEQ ID NO:61所示的CDR1,SEQ ID NO:84所示的CDR2,SEQ ID NO:107所示的CDR3;
(16)SEQ ID NO:62所示的CDR1,SEQ ID NO:85所示的CDR2,SEQ ID NO:108所示的CDR3;
(17)SEQ ID NO:63所示的CDR1,SEQ ID NO:86所示的CDR2,SEQ ID NO:109所示的CDR3;
(18)SEQ ID NO:64所示的CDR1,SEQ ID NO:87所示的CDR2,SEQ ID NO:110所示的CDR3;
(19)SEQ ID NO:65所示的CDR1,SEQ ID NO:88所示的CDR2,SEQ ID NO:111所示的CDR3;
(20)SEQ ID NO:66所示的CDR1,SEQ ID NO:89所示的CDR2,SEQ ID NO:112所示的CDR3;
(21)SEQ ID NO:67所示的CDR1,SEQ ID NO:90所示的CDR2,SEQ ID NO:113所示的CDR3;
(22)SEQ ID NO:68所示的CDR1,SEQ ID NO:91所示的CDR2,SEQ ID NO:114所示的CDR3;或
(23)SEQ ID NO:69所示的CDR1,SEQ ID NO:92所示的CDR2,SEQ ID NO:115所示的CDR3。
5、根据方案3或4所述的抗NKp30单域抗体,其中所述免疫球蛋白单一可变结构域是VHH。
6、根据方案5所述的抗NKp30单域抗体,其中所述VHH包含与SEQ ID NO:1-23中任一氨基酸序列具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或以上同一性的序列。
7、根据方案6所述的抗NKp30单域抗体,其中所述VHH选自SEQ ID NO:1-23中任一氨基酸序列。
8、根据方案1-7任一所述的抗NKp30单域抗体,其中所述抗体以20.1nM或更小的KD结合NKp30。
9、根据方案1-8任一所述的抗NKp30单域抗体,其还包含免疫球蛋白Fc区,所述免疫球蛋白Fc区选自IgG1、IgG2、IgG3和/或IgG4。
10、根据方案9所述的抗NKp30单域抗体,所述免疫球蛋白Fc区的氨基酸序列如SEQID NO:116所示。
11、核酸分子,其编码方案1-10任一所述的抗NKp30单域抗体。
12、根据方案11所述的核酸分子,其中所述核酸分子包含选自SEQ ID NO:24-46的编码抗体单一可变结构域的核苷酸序列。
13、表达载体,其包含与表达调控原件可操作地连接的方案12的核酸分子。
14、重组细胞,其包含方案12的核酸分子或以方案13的表达载体转化,并能够表达所述抗NKp30单域抗体。
15、一种多功能融合蛋白,其包含方案1-10任一所述的抗NKp30单域抗体。
16、根据方案15所述的多功能融合蛋白,其还包含一个或多个与其他抗原特异性结合的第二抗体或其抗原结合部分。
17、根据方案16所述的多功能融合蛋白,其中所述结合第二抗体或其抗原结合部分的抗原选自肿瘤相关抗原(TAA)或免疫检查点。
18、根据方案15或16所述的多功能融合蛋白,其还包含细胞因子。
19、根据方案18所述的多功能融合蛋白,所述细胞因子选自IL8、IL10、IL15、IL18、TGF、VEGF、IFNγ、IFNα或GM-CSF。
20、方案1-10任一所述的抗NKp30单域抗体、方案15-19任一所述的多功能融合蛋白在制备用于治疗和/或预防和/或诊断疾病的药物中的用途。
21、根据方案20所述的用途,其中所述用途通过肿瘤免疫疗法、细胞疗法和基因疗法中的一种或多种来实现。
22、方案1-10任一所述的抗NKp30单域抗体、方案15-19任一所述的多功能融合蛋白在制备治疗癌症的药物中的用途。
23、根据方案22所述的用途,其中所述癌为肺癌、肝癌、黑色素瘤、恶性胶质瘤、头颈癌、结肠直肠癌、胃癌、前列腺癌、卵巢癌、膀胱癌、胰腺癌、胃癌、结肠癌、宫颈癌或相关肿瘤。
24、一种药物组合物,其包含方案1-10任一所述抗NKp30单域抗体和可接受的载体、稀释剂或赋形剂。
25、一种药物组合物,其包含方案15-19任一所述的多功能融合蛋白和可接受的载体、稀释剂或赋形剂。
有益效果
本发明提供的抗NKp30单域抗体能够特异性地与NKp30结合,激活NK免疫应答,促进NK细胞释放IFN-γ、TNF-α等细胞因子;上述功能接近或超过目前NKp30单抗的水准。
为了帮助理解本文中阐述的发明,现提供以下缩写解释及术语定义。
在本文中使用以下缩写:
IgG:免疫球蛋白G
ELISA:酶联免疫吸附测定
FACS:荧光激活细胞分选术
术语(多肽或蛋白的)“结构域”是指折叠蛋白结构,其能够独立于蛋白的其余部分维持其三级结构。一般而言,结构域负责蛋白的单个的功能性质,且在许多情况下可添加、移除或转移至其他蛋白而不损失蛋白的其余部分和/或结构域的功能。
可互换使用的术语“抗体”或“免疫球蛋白”在本文中无论是指重链抗体还是指常规4链抗体,均用作一般术语以包括全长抗体、其单个的链以及其所有部分、结构域或片段(包括但不限于抗原结合结构域或片段,分别例如VHH结构域或VH/VL结构域)。此外,本文所用的术语“序列”(例如在“免疫球蛋白序列”、“抗体序列”、“单一可变结构域序列”、“VHH序列”或“蛋白序列”等的术语中)一般应理解为既包括相关氨基酸序列,又包括编码所述序列的核酸序列或核苷酸序列,除非本文需要更限定的解释。
术语“免疫球蛋白单一可变结构域”是指能够在不与其他免疫球蛋白可变结构域配对的情况下特异性结合抗原表位的免疫球蛋白可变结构域。本发明含义中的免疫球蛋白单一可变结构域的一个实例为“结构域抗体”,例如免疫球蛋白单一可变结构域为如下文定义的骆驼科的“VHH结构域”(或简称为“VHH”)。
“VHH结构域”,亦称为重链单域抗体、单域抗体、VHH、VHH结构域、VHH抗体片段和VHH抗体,是称为“重链抗体”(即“缺乏轻链的抗体”)的抗原结合免疫球蛋白的可变结构域(Hamers-Casterman C,Atarhouch T,Muyldermans S,Robinson G,Hamers C,Songa EB,BendahmanN,Hamers R.:“Naturally occurring antibodies devoid of light chains”;Nature363,446-448(1993))。使用术语“VHH结构域”以将所述可变结构域与存在于常规4链抗体中的重链可变结构域(其在本文中称为“VH结构域”)以及存在于常规4链抗体中的轻链可变结构域(其在本文中称为“VL结构域”)进行区分。VHH结构域特异性结合表位而无需其他抗原结合结构域(此与常规4链抗体中的VH或VL结构域相反,在该情况下表位由VL结构域与VH结构域一起识别)。VHH结构域为由单一免疫球蛋白结构域形成的小型稳定及高效的抗原识别单元。
在本发明的上下文中,术语“单域抗体”、“重链单域抗体”、“VHH结构域”、“VHH”、“VHH结构域”、“VHH抗体片段”、“VHH抗体”、“纳米抗体”以及“Nanobody”可互换使用。
术语“免疫球蛋白可变结构域”是指基本上由本领域及下文中分别称为“框架区1”或“FR1”、“框架区2”或“FR2”、“框架区3”或“FR3”、及“框架区4”或“FR4”的四个“框架区”组成的抗体结构域,其中所述框架区由本领域及下文中分别称为“互补决定区1”或“CDR1”、“互补决定区2”或“CDR2”、及“互补决定区3”或“CDR3”的三个“互补决定区”或“CDR”间隔开。因此,免疫球蛋白可变结构域的一般结构或序列可如下表示为:FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4。免疫球蛋白可变结构域因具有抗原结合位点而赋予抗体对抗原的特异性。
术语“特异性”是指特定抗原结合分子或抗原结合蛋白(例如本发明的免疫球蛋白单一可变结构域)可结合的不同类型抗原或表位的数目。可基于抗原结合蛋白的亲和力和/或亲合力确定其特异性。由抗原与抗原结合蛋白的解离平衡常数(KD)所表示的亲和力,是表位与抗原结合蛋白上抗原结合位点之间结合强度的量度:KD值越小,表位与抗原结合蛋白之间的结合强度越强(或者,亲和力也可表示为缔合常数(KA),其为1/KD)。如本领域技术人员将了解,取决于具体感兴趣的抗原,可以以已知方式测定亲和力。亲合力为抗原结合蛋白(例如免疫球蛋白、抗体、免疫球蛋白单一可变结构域或含有其的多肽)与相关抗原之间结合强度的量度。亲合力与以下两者有关:与其抗原结合蛋白上的抗原结合位点之间的亲和力,以及存在于抗原结合蛋白上的相关结合位点的数目。
术语“多肽”是指任何长度的氨基酸链,而与修饰(例如磷酸化或糖基化)无关。术语多肽包括蛋白质及其片段。多肽可以是“外源的”,意指它们是“异源的”,即是所利用的宿主细胞外来的,例如由细菌细胞产生的人多肽。本文将多肽公开为氨基酸残基序列。那些序列按氨基末端到羧基末端的方向从左到右书写。根据标准命名法,氨基酸残基序列以三字母或单字母代码命名,如下所示:丙氨酸(Ala,A)、精氨酸(Arg,R)、天冬酰胺(Asn,N)、天冬氨酸(Asp,D)、半胱氨酸(Cys,C)、谷氨酰胺(Gln,Q)、谷氨酸(Glu,E)、甘氨酸(Gly,G)、组氨酸(His,H)、异亮氨酸(Ile,I)、亮氨酸(Leu,L)、赖氨酸(Lys,K)、甲硫氨酸(Met,M)、苯丙氨酸(Phe,F)、脯氨酸(Pro,P)、丝氨酸(Ser,S)、苏氨酸(Thr,T)、色氨酸(Trp,W)、酪氨酸(Tyr,Y)和缬氨酸(Val,V)。
关于参照多肽序列的“百分比(%)氨基酸序列同一性”定义为比对序列并在必要时引入缺口以获取最大百分比序列同一性后,候选序列中与参照多肽序列中的氨基酸残基相同的氨基酸残基的百分率。为测定百分比氨基酸序列同一性目的的对比可以以本领域技术范围内的多种方式进行,例如使用公众可得到的计算机软件,诸如BLAST,BLAST-2,Clustal W,Megalign(DNASTAR)软件或FASTA程序包。
术语“分离的多核苷酸”指非自然界中天然存在状态的多核苷酸,包括通过生物学技术从自然界(包括生物体内)分离出的多核苷酸,也包括人工合成的多核苷酸。分离的多核苷酸可以是基因组DNA、cDNA、mRNA或合成的其他RNA,或者它们的组合。本文提供了多个用于编码抗NKp30抗体的重链可变区和轻链可变区的核苷酸序列,基于密码子简并性,设计出与以上提供的核苷酸序列不完全相同的核苷酸序列,但都编码相同的氨基酸序列。这些经改的的核苷酸序列也包括在本发明的范围内。
术语“宿主细胞”指已经或者能够用核酸序列转化并从而表达所选的目的基因的细胞。该术语包括亲本细胞的后代,无论该后代与原来的亲本细胞在形态或基因组成上是否相同,只要后代存在所选目的基因即可。常用的宿主细胞包括细菌、酵母、哺乳动物细胞等。
术语“转染”指外来或外源DNA被细胞摄入,该技术可用于将一种或多种外源DNA部分导入适宜的宿主细胞。可通过理化方法(例如通过氯化钙处理)诱导细胞,使其处于最适摄取和容纳外来DNA的生理状态,即“感受态”。
术语“载体”指能够增殖与其连接的另一种核酸的核酸分子。该术语包括作为自身复制型核酸结构的载体及并入接受其导入的宿主细胞的基因组中的载体。某些载体能够指导与其可操作连接的核酸的表达。此类载体在本文中称为“表达载体”。
术语“药学上可接受的载体”包括任何标准药物载体,诸如磷酸盐缓冲盐水溶液、水和乳液,诸如油/水乳液或水/油乳液,和各种类型的润湿剂。
附图说明
图1为抗NKp30单域抗体与稳定表达细胞系结合FACS结果;
图2为抗NKp30单域抗体与稳定表达细胞系结合FACS结果;
图3为抗NKp30单域抗体刺激NK细胞激活释放细胞因子实验结果;
图4为抗NKp30单域抗体刺激NK细胞激活释放细胞因子实验结果;
图5为抗NKp30单域抗体刺激NK细胞激活释放细胞因子实验结果。
具体实施方式
以下结合附图与具体实施例对本发明做进一步的描述,本发明的保护内容不局限于以下实施例。还应该理解,本发明实施例中使用的术语是为了描述特定的具体实施方案,而不是为了限制本发明的保护范围。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求及其任何等同物为本发明的保护范围。在本发明的说明书和权利要求书中,除非文中另外明确指出,单数形式“一个”、“一”和“这个”包括复数形式。实施本发明的过程、条件、试剂、实验方法等,除专门提及的内容之外,均为本领域技术人员的普遍知识和公知常识,本发明没有特别限制内容。
本发明实施例中的对照抗体选自Biolegend公司的抗CD337(NKp30)抗体。
以下通过更具体的实施例来说明本发明。
实施例1动物免疫
准备重组人NKp30,Fc tag蛋白(ACRO,Cat:NC3-H5259)作为免疫原,每次免疫总的抗原量保持在1-2mg之间,体积在2mL以下,将抗原和佐剂1:1乳化使其形成均匀混合物4℃保存。记录骆驼耳号后开始免疫实验,每次在骆驼颈部淋巴结附近分左右两侧注射,每侧分2点注射,每点注射0.4mL混合好的抗原,免疫后观察半小时确认骆驼状态良好,无不适症状,分别在第0天,第21天,第42天,第63天进行免疫,在第28天,从骆驼颈部静脉采血10mL,第49天,第70天采血各50mL,每次采血均取出一部分进行血清效价检测。每2周免疫一次,一共进行7次免疫。在第6、7次免疫后间隔5-7天进行采血,每次取25-30mL血液,分3个采血管收集。在第4、5、6次免疫前进行采血用于免疫评价,采血从骆驼颈部静脉采取,每次取5mL血液,血液当天使用预冷25℃离心机,400xg离心30分钟,分离保存上层血清。而后分离淋巴细胞,即在15mL的离心管中先加入3mL细胞分离液,然后缓慢加入3mL血液。加入血液时小心缓慢以防止血液和分离液混匀,之后离心机预冷至室温,400g离心30分钟后,观察离心管中血液分离情况,用200μL移液器小心吸取出中间棉状上层免疫细胞至新的15mL离心管中,上层血清保存在新的离心管中,-80℃保存。每管加入室温放置的10mL PBS缓冲液,25℃、400g离心20分钟,去除上清液,每管加入室温放置的5mL PBS缓冲液,25℃,400g离心20分钟。使用血球计数板计算细胞数目。去除上清液,根据细胞数目使用RNAiso Plus溶解分离得到的淋巴细胞得到107/mL溶解液,-80℃保存。
实施例2噬菌体文库构建
第二次和第三次的采血用淋巴细胞分离液分离PBMC。提取PBMC中的总RNA,用反转录试剂盒进行反转录PrimeScriptTM II 1st Strand cDNA Synthesis Kit(Takara,货号:6210A),共转录5μg RNA。cDNA原液等比例混合之后稀释5倍,加5.0μL进行第一轮扩增,扩增产物割胶回收,回收产物作为模板进行第二轮扩增,扩增产物割胶回收,为目的片段。将载体与目的片段分别用SfiI进行酶切,50℃过夜酶切,然后回收目的片段。连接摩尔比例为Vector:VHH=1:3。共进行10次电转化,电击之后立即向电击杯中加入1mL 2YT培养基(37℃预热)复苏,吸出电击产物并用2YT培养基洗净电击杯,共计获得100ml复苏产物,在37℃、180rpm条件下复苏45min,取100μL梯度稀释至10-3和10-4测定库转化子数目,涂布于90mm的平板上,其余离心,加入8mL 2YT重悬,涂布于8块200mm的平板上。第二天在测定库转化子数目,计算库容量。
将细菌文库接入2×300mL 2YT+A+G(Amp:100ug/ml、Glu:1%)培养基中,至其初始OD600=0.1-0.2,37℃、230rpm培养至OD600=0.8以上。根据OD600值加入辅助噬菌体M13KO7(辅助噬菌体:细菌=20:1)。加入M13KO7后,混匀,37℃静置30min。37℃,180rpm缓摇30min。5000rpm离心10min,弃尽上清,用等体积2YT+A+K(Amp:100μg/ml、Kan:50μg/ml)培养基重悬沉淀,30℃,220rpm过夜。过夜培养物在4℃、10000rpm条件下离心20min,收取上清,弃沉淀。更换离心筒,在4℃、10000rpm条件下离心20min,收取上清。按上清体积的1/5加入PEG8000/NaCl,混匀,冰浴沉淀2小时以上。4℃,10000rpm,离心20min,弃上清,空离一次除尽上清。1mL 1×PBS悬起沉淀,加入1/5体积的PEG8000/NaCl二次沉淀1h。4℃,12000rpm,离心10min弃上清,空离一次除尽上清。根据沉淀的量,加入1×PBS重悬沉淀。加100%甘油至终浓度为50%,混匀后分装到1.5mL EP管中,-80℃保存。取10uL库噬菌体用2YT梯度稀释,从10-8和10-9管中取10ul加到90μL的TG1菌液中,轻柔混匀。37℃静置15min,分别涂布Amp抗性平板,过夜培养。第二天,计算滴度板上的克隆金属噬菌体文库滴度。
实施例3噬菌体文库筛选阳性抗体
将靶分子NKP30his用pH值为9.6的碳酸盐缓冲液稀释至终浓度为5μg/mL,按100μL/孔加入酶标孔中,每个靶分子包被8孔(第二轮筛选包被4孔,第三轮和第四轮筛选各包被2孔),4℃包被过夜。弃包被液,PBS洗涤3次,每孔加入300μL 3%BSA-PBS封闭液,37℃封闭1h。PBS洗涤3次,加入100μL噬菌体文库,37℃孵育1h。吸出未结合的噬菌体,用PBST洗涤6次,PBS洗涤2次。加入100μL Gly-HCl洗脱液,37℃孵育8min,洗脱特异性结合的噬菌体;将该洗脱液转移至1.5mL无菌离心管中,迅速用10μL Tris-HCl中和缓冲液中和。取10μL进行梯度稀释,测定滴度,计算淘选回收率,其余洗脱物混合后进行扩增和纯化,用于下一轮亲和淘选。
将淘选洗脱物与处于对数生长前期的E.coli TG1培养物5mL混匀,37℃,静置30min,220r/min振荡培养30min;1000g离心15min,去上清,用500μL 2×YT重悬涂布于200mm 2×YT-GA平板。用10ml 2×YT液体培养基刮菌,取500μl悬液加入50ml 2×YT液体培养基中,37℃振摇30min;按cell:phage=1:20的比例加入M13K07辅助噬菌体,37℃静置30min,220r/min振摇培养30min;将培养物分装于离心管中,25℃,5000r/min,离心10min,细胞沉淀以50mL 2×YT-AK液体培养基重悬,30℃,230r/min振荡培养过夜。将过夜培养物4℃,10000r/min离心20min,将上清转移至新离心管,加入1/5体积的PEG/NaCl,混匀后置于4℃2h以上。4℃,10000r/min,离心20min,去除上清,将沉淀重悬于1mL PBS中,加入1/5体积的PEG/NaCl,混匀后置于4℃1h以上。4℃,12000r/min,离心2min,去除上清,将沉淀悬浮于200μL PBS中,即为扩增产物,测定滴度,用于下一轮淘选或者分析。
从淘选洗脱物滴度的平板上,用灭菌牙签从从第二轮滴度测定平板上随机挑选96个克隆(编号为1-96),第一轮滴度平板上随机挑选96个克隆(编号为97-192)接种于1mL 2×YT-A中,37℃,230r/min振荡培养8h。取200μL上述培养物,按cell:phage=1:20的比例加入M13K07噬菌体,37℃,静置15min,220r/min振荡培养45min。补加800μL体积的2×YT-AK,30℃,剧烈振荡培养过夜。第二天12000rpm离心2min,取上清,用于单克隆ELISA鉴定。
将靶分子NKP30抗原用PH值为9.6的碳酸盐缓冲液稀释至终浓度为2μg/mL,按100μL/孔加入酶标孔中,4℃包被过夜。弃包被液,PBST洗涤3次,每孔加入300μL 5%脱脂牛奶,37℃封闭1h。PBST洗涤3次,每孔加入50μL噬菌体培养菌液上清和50μL 5%脱脂牛奶,37℃,孵育1h。PBST洗涤5次,加入辣根过氧化物酶标记的抗M13抗体(用PBS按1:10000稀释),100μL/孔,37℃作用1h。PBST洗板6次。加入TMB显色液显色,100μL/孔,37℃,7min,加入终止液终止反应,50μL/孔,于450nm下测光密度。
实施例4抗体基因序列测序
将噬菌体文库筛选得到的序列进行抗体基因测序。选出23条抗体,其氨基酸/核苷酸序列分别为:
(1)抗体1可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:47、SEQ ID NO:70和SEQ ID NO:93;
抗体1可变结构域的氨基酸序列为SEQ ID NO:1;
抗体1可变结构域的核苷酸序列为SEQ ID NO:24;
(2)抗体2可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:48、SEQ ID NO:71和SEQ ID NO:94;
抗体2可变结构域的氨基酸序列为SEQ ID NO:2;
抗体2可变结构域的核苷酸序列为SEQ ID NO:25;
(3)抗体3可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:49、SEQ ID NO:72和SEQ ID NO:95;
抗体3可变结构域的氨基酸序列为SEQ ID NO:3;
抗体3可变结构域的核苷酸序列为SEQ ID NO:26;
(4)抗体4可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:50、SEQ ID NO:73和SEQ ID NO:96;
抗体4可变结构域的氨基酸序列为SEQ ID NO:4;
抗体4可变结构域的核苷酸序列为SEQ ID NO:27;
(5)抗体5可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:51、SEQ ID NO:74和SEQ ID NO:97;
抗体5可变结构域的氨基酸序列为SEQ ID NO:5;
抗体5可变结构域的核苷酸序列为SEQ ID NO:28;
(6)抗体6可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:52、SEQ ID NO:75和SEQ ID NO:98;
抗体6可变结构域的氨基酸序列为SEQ ID NO:6;
抗体6可变结构域的核苷酸序列为SEQ ID NO:29;
(7)抗体7可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:53、SEQ ID NO:76和SEQ ID NO:99;
抗体7可变结构域的氨基酸序列为SEQ ID NO:7;
抗体7可变结构域的核苷酸序列为SEQ ID NO:30;
(8)抗体8可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:54、SEQ ID NO:77和SEQ ID NO:100;
抗体8可变结构域的氨基酸序列为SEQ ID NO:8;
抗体8可变结构域的核苷酸序列为SEQ ID NO:31;
(9)抗体9可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:55、SEQ ID NO:78和SEQ ID NO:101;
抗体9可变结构域的氨基酸序列为SEQ ID NO:9;
抗体9可变结构域的核苷酸序列为SEQ ID NO:32;
(10)抗体10可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:56、SEQ ID NO:79和SEQ ID NO:102;
抗体10可变结构域的氨基酸序列为SEQ ID NO:10;
抗体10可变结构域的核苷酸序列为SEQ ID NO:33;
(11)抗体11可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:57、SEQ ID NO:80和SEQ ID NO:103;
抗体11可变结构域的氨基酸序列为SEQ ID NO:11;
抗体11可变结构域的核苷酸序列为SEQ ID NO:34;
(12)抗体12可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:58、SEQ ID NO:81和SEQ ID NO:104;
抗体12可变结构域的氨基酸序列为SEQ ID NO:12;
抗体12可变结构域的核苷酸序列为SEQ ID NO:35;
(13)抗体13可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:59、SEQ ID NO:82和SEQ ID NO:105;
抗体13可变结构域的氨基酸序列为SEQ ID NO:13;
抗体13可变结构域的核苷酸序列为SEQ ID NO:36;
(14)抗体14可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:60、SEQ ID NO:83和SEQ ID NO:106;
抗体14可变结构域的氨基酸序列为SEQ ID NO:14;
抗体14可变结构域的核苷酸序列为SEQ ID NO:37;
(15)抗体15可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:61、SEQ ID NO:84和SEQ ID NO:107;
抗体15可变结构域的氨基酸序列为SEQ ID NO:15;
抗体15可变结构域的核苷酸序列为SEQ ID NO:38;
(16)抗体16可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:62、SEQ ID NO:85和SEQ ID NO:108;
抗体16可变结构域的氨基酸序列为SEQ ID NO:16;
抗体16可变结构域的核苷酸序列为SEQ ID NO:39;
(17)抗体17可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:63、SEQ ID NO:86和SEQ ID NO:109;
抗体17可变结构域的氨基酸序列为SEQ ID NO:17;
抗体17可变结构域的核苷酸序列为SEQ ID NO:40;
(18)抗体18可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:64、SEQ ID NO:87和SEQ ID NO:110;
抗体18可变结构域的氨基酸序列为SEQ ID NO:18;
抗体18可变结构域的核苷酸序列为SEQ ID NO:41;
(19)抗体19可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:65、SEQ ID NO:88和SEQ ID NO:111;
抗体19可变结构域的氨基酸序列为SEQ ID NO:19;
抗体19可变结构域的核苷酸序列为SEQ ID NO:42;
(20)抗体20可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:66、SEQ ID NO:89和SEQ ID NO:112;
抗体20可变结构域的氨基酸序列为SEQ ID NO:20;
抗体20可变结构域的核苷酸序列为SEQ ID NO:43;
(21)抗体21可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:67、SEQ ID NO:90和SEQ ID NO:113;
抗体21可变结构域的氨基酸序列为SEQ ID NO:21;
抗体21可变结构域的核苷酸序列为SEQ ID NO:44;
(22)抗体22可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:68、SEQ ID NO:91和SEQ ID NO:114;
抗体22可变结构域的氨基酸序列为SEQ ID NO:22;
抗体22可变结构域的核苷酸序列为SEQ ID NO:45;
(23)抗体23可变结构域的CDR1、CDR2和CDR3的氨基酸序列分别为:SEQ ID NO:69、SEQ ID NO:92和SEQ ID NO:115;
抗体23可变结构域的氨基酸序列为SEQ ID NO:23;
抗体23可变结构域的核苷酸序列为SEQ ID NO:46。
其中,抗体1至抗体23的免疫球蛋白Fc区的氨基酸序列都相同,如SEQ ID NO:116所示。
实施例5嵌合抗体的构建与表达
将噬菌体文库筛选得到的序列进行抗体基因测序,将测序得到的抗体片段进行基因合成,构建到人IgG框架中,而后利用分子克隆技术,将抗体片段插入PCDNA3.1载体中,构建成哺乳动物细胞表达质粒,利用脂质体转染方式,导入宿主细胞株CHO细胞,利用细胞fed-batch获得发酵上清液,取发酵液上清进行亲和层析、离子交换层析等一系列步骤的纯化,最终纯化得到构建的抗体。对纯化后的抗体检测表达量、纯度、内毒素等。
实施例6抗NKp30抗体与NKp30亲和力验证
设备:OCTET Red96e(Fortebio)。
传感器:AHC。
(1)实验设置:
传感器准备:在使用前以0.02%PBST(0.02%吐温20,pH7.4,1*PBS)作为缓冲液浸润AHC传感器600s,除去传感器表面覆盖的蔗糖。
根据样品的实际加样位置设置样品板及传感器位置。
设置需要进行的步骤,并设置时间和转速,实验温度设置为30℃,震荡速度为1000rpm。
(2)固化及捕获:
AHC传感器以0.02%PBST(0.02%吐温20,pH7.4,1*PBS)作为缓冲液平衡60s,固化样品板中的NKp30抗体300s,二次平衡缓冲液180s。100nm的人NKp30-his蛋白(KACTUS;Cat:NKP-HM430)与NKp30抗体结合300s,然后解离600s。解离后以10mM甘氨酸(pH2.0)作为再生缓冲液,再生30s。
(3)再生:
用10mM甘氨酸(pH2.0)再生传感器。
(4)数据分析:
从测试结果图中减去参考通道H1的结果图。实验数据符合1:1结合模型。用分子量35kDa计算人NKp30蛋白的摩尔浓度。结果见表1。
由表1可知,除了抗体5的KD为1.04×10-7,抗体21的KD为2.01×10-8外,其他抗体的KD值都为纳米级甚至更小,说明NKp30单域抗体与NKp30亲和力高。
表1
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实施例7抗体与细胞结合能力检测
取待测抗体按照40μg/mL为初始终浓度,3倍稀释,稀释8个梯度。取出培养箱内NK细胞,将细胞悬液转至15mL离心管中,离心,PBS重悬计数。留出空白对照组(Blank)、阴性对照组(NC)、实验组和无关抗体组。按照约3×105个细胞/孔,将细胞悬液铺于96孔板中。离心(1000rpm,5min)后用PBS清洗,再离心,重复两次去除培养基残留。弃去上清,实验组、无关抗体组分别加入100μL的一抗溶液、无关抗体溶液,重悬细胞后,室温孵育1h。Blank、NC组使用等量的PBS进行孵育。1h后离心,加入PBS清洗两次。弃上清后,除Blank组加入100μLPBS外,其余样品组分别加入100μL荧光二抗稀释液(羊抗人Fc-FITC Abcam cat:ab97224),室温避光孵育0.5h后,离心加入PBS清洗两次。弃去上清后,加入120μL的PBS重悬并按顺序进行流式细胞检测,测其平均荧光强度,结果见图1和图2。
分析结果表明,抗NKp30抗体的结合活性都比较好。
实施例8抗体刺激NK细胞激活释放细胞因子实验
取出96孔板,将待测抗体,阳性对照抗体和同型对照抗体按照150nM起始,3倍稀释,进行7个梯度稀释,设置2个平行孔,PBS溶解,置于96孔板中。放于4度冰箱孵育过夜约16h后取出进行后续操作。取出96孔板,弃抗体孵育液,用PBS清洗2次。取出NK细胞并进行细胞计数,设置细胞数为4×104个/孔用含终浓度为400U的IL-2(STEMCELL,78036)的培养基进行重悬,200μL/孔加入抗体孵育完成的96孔板中,设置空白对照孔和阴性对照孔。处理好的96孔板放置在37℃CO2恒温培养箱孵育约24h后,提取上清,将离心后的上清用试剂盒(Biolegend Cat:430104)测其最大IFN-γ分泌量。结果见图3、图4和图5。
分析结果表明,抗NKp30抗体刺激的NK细胞释放细胞因子的效果显著优于对照抗体和同型抗体。
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求为保护范围。
序列表
<110> 盛禾(中国)生物制药有限公司
<120> 一种抗NKp30抗体及其应用
<160> 116
<170> SIPOSequenceListing 1.0
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Gln Leu Gln Leu Val Glu Ser Gly Gly Gly Thr Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ala Cys Val Val Ser Gly Pro Thr Tyr Ser Phe Tyr
20 25 30
Asp Met Gly Trp Phe Arg Arg Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Val Thr Ala Ser Gly Asp Thr Thr Ile Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ala Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Gly Ala Tyr Tyr Cys
85 90 95
Ala Ala Gly Glu Tyr Ser Ser Thr Ala Ala Thr Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 2
<211> 115
<212> PRT
<213> 人工序列(Artificial Sequence)
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Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Ser Val Asn
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Glu Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Leu Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Asp Gly Thr Thr Ala Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Asp Cys Asn
85 90 95
Thr Trp Pro Glu Ala Arg Gly Asp Trp Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser
115
<210> 3
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
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Gln Leu Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Asp
1 5 10 15
Ser Thr Lys Leu Ser Cys Thr Ala Ser Gly Arg Ser Phe Ser Ile Asn
20 25 30
Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Leu Arg Glu Leu Val
35 40 45
Ala Gly Ile Thr Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
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Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Leu Gly Trp Pro Asp Phe Gly Ser Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser
115
<210> 4
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
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Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Lys Ile Asn
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Leu Arg Glu Leu Val
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Ala Gly Ile Thr Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
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Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
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Gln Met Asn Ser Leu Lys Pro Asp Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Gln Leu Gly Phe Pro Gln Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
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Ser Ser
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Glu Val Gln Val Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Pro Phe Ser Thr Phe
20 25 30
Pro Thr Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
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Phe Val Ala Ala Ile Ser Glu Ser Gly Leu Asn Thr Tyr Tyr Arg Asp
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Ser Val Lys Gly Arg Phe Gly Ile Ser Arg Asp Asn Ala Lys Asn Thr
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Val Tyr Leu Gln Met Asn Thr Leu Thr Ala Glu Asp Thr Ala Val Tyr
85 90 95
Phe Cys Ala Ala Ala Pro Gly Tyr Met Thr Thr Asp Ser Gln Tyr Tyr
100 105 110
Leu Gly Asn Lys Tyr Gln Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
115 120 125
Ser Ser
130
<210> 6
<211> 124
<212> PRT
<213> 人工序列(Artificial Sequence)
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Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Ala Ile Phe Pro Glu Tyr
20 25 30
Ser Ile Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Leu Val Ser Arg Ile Gly Asp Arg Val Asp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr His Cys
85 90 95
Ala Ala Gly Gln Leu Ser Ser Ser Thr Tyr Tyr Gly Asp Glu Tyr Val
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 7
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Glu Val Gln Val Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asn Tyr
20 25 30
Asn Val Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Leu
35 40 45
Ala Thr Ile Ser Glu Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Gly Ile Asn Met Val Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Glu Ser Arg Ile Phe Ser Phe Ser Tyr Ala Asp Gly Arg Gly Tyr
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Phe Ser
115 120 125
<210> 8
<211> 126
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Asp
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Tyr Asp Asn Tyr
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ala Phe Ser Gln Asn Gly Gly Arg Thr Asp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ala Ile Ser Asp Asp Arg Ser Thr Val His Leu Asp
65 70 75 80
Met Asn Ser Leu Leu Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala
85 90 95
Arg Pro Pro Ala Tyr Phe Ser Asn Ala Val Tyr Ser Lys Val Asp Glu
100 105 110
Tyr Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 9
<211> 124
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Asp Tyr
20 25 30
Val Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Gly Thr Ile Thr Arg Ile Gly Gly Met Pro Tyr Tyr Ala Asp Phe Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Tyr Ala Lys Asn Ala Gly Tyr
65 70 75 80
Leu Gln Leu Asn Asn Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Leu Asp Leu Arg Leu Arg Leu Gly Val Thr Pro Arg Glu Tyr Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 10
<211> 115
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Val Ser Gly Ile Thr Phe Ser Arg Ser
20 25 30
Val Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Leu Arg Glu Leu Val
35 40 45
Ala Gly Ile Thr Ser Asp Asp Asn Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ile Leu Pro Asp Ser Arg Leu Gly Trp Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser
115
<210> 11
<211> 115
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Gly Asp Phe Arg Phe Lys
20 25 30
Ser Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Leu Arg Glu Leu Val
35 40 45
Ala Gly Ile Thr Thr Gly Gly Val Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Asn Lys Ala Val Trp Leu
65 70 75 80
Gln Met Asn Arg Leu Lys Pro Asp Asp Thr Ala Val Tyr Asp Cys Asn
85 90 95
Thr Leu Gly Ala Ala Ala Tyr Asp Trp Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser
115
<210> 12
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Phe Gly Ser Ser Phe Ser Ile Asp
20 25 30
Met Met Gly Trp Tyr Arg Gln Val Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Thr Lys Gly Gly Phe Ala Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Met Asp Ala Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Thr Leu Pro Thr His Ser Asp Trp Gly Gln Gly Thr Gln Val Thr Val
100 105 110
Ser Ser
<210> 13
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Ile Phe Gly Ser Thr
20 25 30
His Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Leu Arg Glu Met Val
35 40 45
Ala Gly Ile Thr Ser Thr Gly Asn His Arg Asn Val Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Asn Ser Phe Pro Asp Gln Val Phe Asn Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser
115
<210> 14
<211> 115
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Gln Leu Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Ala Ser Ile Phe Ser Val Asn
20 25 30
Glu Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Leu Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Asp Gly Thr Thr Ala Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Asp Cys Asn
85 90 95
Thr Trp Pro Gln Ala Arg Gly Asp Trp Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser
115
<210> 15
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Pro Thr Phe Asn Phe Tyr
20 25 30
Gly Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val
35 40 45
Ala Ser Ile Ile Pro Gly Ser Gly Asp Thr Ser Tyr Ala Ser Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Glu Asp Asn Ala Arg Asn Asn Ala Tyr
65 70 75 80
Leu Gln Met Asn Thr Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Thr Gly Gly Ile Tyr Ser Ser Asp Tyr Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 16
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Ser Leu Ile Thr Tyr
20 25 30
Asn Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Leu Arg Glu Leu Val
35 40 45
Ala Gly Ile Thr Thr Gly Gly Ile Thr Asp Tyr Thr Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Thr Leu Gly Met Ala Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
100 105 110
Ser Ser
<210> 17
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Gln Leu Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Asp Ser Ile Asn
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Leu Arg Glu Leu Val
35 40 45
Ala Gly Ile Thr Arg Gly Gly Asp Val Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Val Asp Ala Arg Asn Thr Val Thr Val
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Asn Asn Leu Gly Phe Pro Ser Asp Trp Ala Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser
115
<210> 18
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ala Gly Ile Arg Phe Ser Ile Ala
20 25 30
Asn Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Leu His Glu Met Val
35 40 45
Ala Gly Ile Thr Ser Asp Gly Phe Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Ser Phe Pro Thr Arg His Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
100 105 110
Ser Ser
<210> 19
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Glu Val Gln Val Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Phe Gly Ser Ser Phe Ser Ile Asp
20 25 30
Met Met Gly Trp Tyr Arg Gln Val Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Gly Ile Thr Lys Gly Gly Phe Ala Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Met Asp Ala Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Thr Leu Pro Thr His Ser Asp Trp Gly Gln Gly Thr Gln Val Thr Val
100 105 110
Ser Ser
<210> 20
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ala Phe Ser Ile Glu
20 25 30
Pro Trp Gly Trp Tyr Arg Gln Ala Pro Gly Gln Leu Arg Glu Leu Val
35 40 45
Ala Gly Ile Thr Ser Asp Asp Lys Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Phe Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Leu Gly Trp Pro Arg Asp Asp Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser
115
<210> 21
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Tyr Ala Phe Tyr
20 25 30
Asn Met Gly Trp Phe Arg Gln Arg Pro Gly Lys Glu Arg Glu Phe Ala
35 40 45
Ala Ala Ile Leu Trp Gly Arg Ser Gly Val Tyr Thr Thr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Gln Asn Thr
65 70 75 80
Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala Gly Leu Gly Thr Met Arg Ala Asn Glu Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 22
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Ser Ala Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Leu Arg Glu Leu Val
35 40 45
Ala Gly Met His Ser Gly Gly Ser Ala Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Met Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Phe Gly Leu Gly Phe Asp Gly His Asp Tyr Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ala
115
<210> 23
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Ser Pro Asn
20 25 30
Gly Ile Gly Trp Tyr Arg Gln Ala Pro Gly Lys Leu Arg Glu Leu Val
35 40 45
Ala Gly Ile Thr Gly Asn Gly Leu Thr Asp Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Leu Leu Leu Asn His Ala Glu Trp Gly Gln Gly Thr Gln Val Thr Val
100 105 110
Ser Ser
<210> 24
<211> 387
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 24
cagttgcagc tcgtggagtc tgggggagga acggtacaaa ctgggggctc tctgagactc 60
gcctgtgtag tctctggacc aacctacagt ttctatgaca tgggctggtt ccgccgggct 120
ccagggaagg agcgtgaatt tgtggcagct gttacggcga gcggtgatac tacaatctat 180
gcagactccg tgaagggccg attcaccatc gccagagaca acgccaagaa cacggtgtat 240
ctgcaaatga acagcctgaa atctgaggac acgggcgcgt attactgtgc agcgggagag 300
tatagtagta ccgctgccac ctattactac tggggccagg ggacccaggt caccgtctcc 360
tcagcgcacc acagcgaaga ccccagc 387
<210> 25
<211> 369
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 25
caggtgcagc tcgtggagtc agggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcttcagt gtcaatgaga tgggctggta ccgccaggct 120
ccagggaagc tgcgcgagtt ggtcgccgct attactagcg atggtaccac ggcatatgca 180
gactccgtga agggccgatt caccatctcc agagataacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatg actgtaatac ttggccagag 300
gcacgtggcg actggggcca ggggacccag gtcaccgttt cctcagcgca ccacagcgaa 360
gaccccagc 369
<210> 26
<211> 375
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 26
cagttgcagc tcgtggagtc cgggggagga ttggtacaga ctggggactc tacgaaactc 60
tcctgtacag cctctggacg cagcttcagt atcaatgaca tgggctggta ccgccaggct 120
ccagggaagc tgcgcgagtt ggtcgccggt attactagtg gtggtagcac aaactatgca 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgtaatgt tttgggctgg 300
cctgattttg gttcctgggg ccaggggacc caggtcaccg tctcctcgga acccaagaca 360
ccaaaaccac aacca 375
<210> 27
<211> 369
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 27
caggtgcagc tcgtggagtc ggggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcttcaag atcaatgcca tgggctggta ccgccaggct 120
ccagggaagc tgcgcgagtt ggtcgcaggt attactagtg gtggtagtac aaactatgca 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac gctgtatctg 240
caaatgaaca gcctgaaacc tgacgacacg gccgtctatt actgcaatca actgggattt 300
ccacagtact ggggccaggg gacccaggtc accgtctcct cagaacccaa gacaccaaaa 360
ccacaacca 369
<210> 28
<211> 417
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 28
gaggtgcagg tggtggagtc cggtggagga ttggtgcagg ctggcggctc tctgaccctc 60
tcctgtgcag cctctggacg ccccttcagt acatttccaa catccatggg ctggttccgc 120
caggctccag ggaaggagcg tgagtttgta gcagcaatta gcgagagtgg gcttaataca 180
tactatcgag actccgtgaa gggccgattc ggcatctcca gagacaacgc caagaacacg 240
gtgtatctgc agatgaacac tttgacagct gaagacacgg ccgtttattt ctgtgcagcg 300
gcgcccggtt acatgaccac tgatagccag tactacttgg gcaacaagta tcagtactgg 360
ggccagggga cccaggtcac cgtctcctca gaacccaaga caccaaaacc acaacca 417
<210> 29
<211> 399
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 29
caggtgcagc tcgtggagtc cgggggaggc ttagtgcagc ctggggggtc tctgagactc 60
tcctgtgctg cctctagggc catctttcct gaatatagta tagcctggtt ccgccaggcc 120
ccagggaagg agcgtgaggg ggtcgcattg gttagtagga ttggtgatag ggtagactat 180
gcagactccg tgaagggccg gttcaccatc tccagagata acgccaagaa tacggtgtat 240
ctgcaaatga acagcctgaa acctgaggac acagccgttt atcattgtgc agcaggtcaa 300
ctgtcttcgt ctacttatta tggggatgag tatgtctact ggggccaggg gacccaggtc 360
accgtctcct cagaacccaa gacaccaaaa ccacaacca 399
<210> 30
<211> 402
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 30
gaggtgcagg tggtggagtc tggtggagga ttggtgcagg ctgggggctc tctgagactc 60
tcctgtgcag cctctggacg caccttcagt aactacaacg tgggctggtt ccgccaggct 120
ccagggaagg agcgtgagtt cctagcaact attagcgaga gtggtggcag tacatactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca acggcatcaa catggtgtat 240
ctgcagatga gcagcctgaa accagaggac acggccgttt attactgtgc tgaatcacga 300
atcttcagtt ttagttacgc cgacggaaga gggtatgcct actggggcca ggggacccag 360
gtcaccgtct tttccgaacc caagacacca aaaccacaac ca 402
<210> 31
<211> 405
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 31
caggtgcagc tcgtggagtc cgggggagga ttggtgcaga ctggggactc tctgagactc 60
tcctgtgcag cctctggacg cacctacgat aactatgcca tgggctggtt ccgccaggct 120
ccagggaagg agcgtgagtt tgtagcagcc tttagccaga atggtggtag aacagactat 180
gcggactccg tgaagggccg cttcgccatc tccgacgaca ggagtacggt gcatctcgat 240
atgaacagcc tgttacctga ggacacggcc gtttattact gtgcagcgag acccccggca 300
tactttagta atgctgtcta ctcaaaagtc gatgagtatc gttactgggg ccaggggacc 360
caggtcaccg tgtcctcaga acccaagaca ccaaaaccac aacca 405
<210> 32
<211> 399
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 32
caggtgcagc tcgtggagtc gggtggagga tcggtgcagg ctgggggctc actgagactc 60
tcctgtgcag cctctggacg caccttcagt gactacgtca tgggctggtt ccgccaggct 120
ccagggaagg agcgtgagtt tgtgggaact attacccgca ttggtggtat gccatactat 180
gcagacttcg tgaagggccg attcaccatc tccagagact acgccaagaa cgcgggatat 240
ctgcaactga acaacctgaa acctgaggac acggcccttt attactgtgc actagacctc 300
cgactacggc ttggggtgac cccgcgggag tatgactact ggggccaggg gacccaggtc 360
accgtctcct cagaacccaa gacaccaaaa ccacaacca 399
<210> 33
<211> 372
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 33
caggtgcagc tcgtggagtc cgggggaggc ttggtgcagc ctggggggtc tctgacgctc 60
tcctgtgcag tctctggaat caccttcagt aggtcagtta tgggctggtt ccgccaggct 120
ccagggaagc tgcgtgagtt ggtcgcaggt attacgagtg atgataacac tgactatgca 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaatac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgtaatat attgccggac 300
agccggctgg ggtggggcca ggggactcag gtcaccgtct cctcagaacc caagacacca 360
aaaccacaac ca 372
<210> 34
<211> 372
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 34
gaggtgcagc tggtggagtc cgggggaggc ttggtgcagc ctggggaatc tctgagactc 60
tcctgtgtag cctctggagg cgactttcgt ttcaagtcca tgggctggta ccgccaggct 120
ccagggaagc tgcgcgagtt ggtcgcagga attaccacgg gtggtgttac ggactatgca 180
gactccgtca agggccgatt caccatctcc agagacaacg ccaacaaagc ggtgtggctg 240
caaatgaaca gattgaaacc tgacgacacg gccgtctatg actgtaatac tcttggcgcc 300
gctgcttatg actggggcca ggggacccag gtcaccgtct cctccgaacc caagacacca 360
aaaccacaac ca 372
<210> 35
<211> 369
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 35
gaggtgcagc tggtggagtc cgggggagac ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag ctttcggaag cagcttcagt atcgatatga tgggctggta ccgccaggtt 120
ccagggaagc agcgcgagtt ggtcgcaggc attactaaag gtgggttcgc cgactatgca 180
gactccgtga agggccgatt caccatctcc atggacgccg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgtaatac gctccctacg 300
cactctgact ggggccaggg gacccaggtc accgtctcct cagaacccaa gacaccaaaa 360
ccacaacca 369
<210> 36
<211> 375
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 36
gaggtgcagc tggtggagtc cgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggagg catcttcggt agtactcaca tgggctggta ccgccaggct 120
ccagggaagt tgcgcgaaat ggtcgcggga attactagca ctggtaacca cagaaacgtc 180
gcagactccg tgaagggccg attcaccatc tccaaggaca acgccaagaa cacgctgtat 240
ctgcaaatga acagcctgaa acctgaggac acggccgtct attactgtaa ttcctttccc 300
gaccaagtat ttaactgggg ccaagggacc caggtcaccg tctcctcgga acccaagaca 360
ccaaaaccac aacca 375
<210> 37
<211> 372
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 37
cagttgcagc tcgtggagtc cgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag tctctgcaag catcttcagt gtcaatgaga tgggctggta ccgccaggct 120
ccagggaagc tgcgcgagtt ggtcgccgct attactagcg atggtaccac ggcatatgca 180
gactccgtga agggccgatt caccatctcc agagataacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatg actgtaatac ttggccacag 300
gcacgtggcg actggggcca ggggacccag gtcaccgttt cctcagaacc caagacacca 360
aaaccacaac ca 372
<210> 38
<211> 390
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 38
gaggtgcagc tggtggagtc agggggagga tcggtgcaga ctgggggctc tctgagactc 60
tcctgtgcag cctctggacc caccttcaat ttctatggca tggcctggtt ccgccaggct 120
ccaggcaagg agcgagaatt tgtagcaagt attattccgg gtagtggtga cacaagctat 180
gcatcctccg tgaggggccg attcaccatc tccgaagaca acgcccggaa caatgcatat 240
ctgcaaatga acaccctgaa acctgaggac acggcggttt attactgtgc agcgggaact 300
ggtggtatct attcaagtga ctatccttac tggggccagg ggacccaggt caccgtctcc 360
tcagaaccca agacaccaaa accacaacca 390
<210> 39
<211> 369
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 39
gaggtgcagc tggtggagtc ggggggaggc ttggtgcagg ctggggggtc tctgagactc 60
tcctgtgcag cctctggaat cagcctcatt acctataaca tgggctggta ccgccaggct 120
ccagggaagc tgcgtgagtt ggtcgcaggt attactactg gtggtatcac cgattataca 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac gctgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgtgacac cctagggatg 300
gcgaactact ggggccaggg gacccaggtc accgtctcct cagaacccaa gacaccaaaa 360
ccacaacca 369
<210> 40
<211> 375
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 40
cagttgcagc tcgtggagtc ggggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcgacagt atcaatgcca tgggctggta ccgccaggct 120
ccagggaagc tgcgcgagtt ggtcgcggga attactagag gtggtgacgt aaattatgca 180
gactccgtga agggccgatt caccatctcc agagtcgacg ccaggaacac ggtgacggtg 240
tatctgcaaa tgaacagcct gaaacctgag gacacggccg tctattactg taataatttg 300
gggtttcctt ccgactgggc ccaggggacc caagtcaccg tctcctcaga acccaagaca 360
tcaaaaccac aacca 375
<210> 41
<211> 369
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 41
gaggtgcagc tggtggagtc aggtggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag ccgctggaat cagattcagt atcgctaaca tgggctggta ccgccaggct 120
ccagggaagc tgcacgaaat ggtcgcgggt attactagtg atggtttcac aaactatgca 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtctatcta 240
caaatgaaca acctgaaacc cgaggacacg gccgtctatt actgcgattc gttccctacc 300
cgacactact ggggtcaggg gacccaggtc accgtctcct cagaacccaa gacaccaaaa 360
ccacaacca 369
<210> 42
<211> 369
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 42
gaggtgcagg tggtggagtc ggggggagac ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag ctttcggaag cagcttcagt atcgatatga tgggctggta ccgccaggtt 120
ccagggaagc agcgcgagtt ggtcgcaggc attactaaag gtgggttcgc cgactatgca 180
gactccgtga agggccgatt caccatctcc atggacgccg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgtaatac gctccctacg 300
cactctgact ggggccaggg gacccaggtc accgtctcct cagaacccaa gacaccaaaa 360
ccacaacca 369
<210> 43
<211> 375
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 43
gaggtgcagc tggtggagtc ggggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag tgccttcagt atcgaaccct ggggctggta ccgccaggct 120
ccagggcaac tgcgcgagtt ggtcgcaggt attacttcag atgataaaac agactatgca 180
gactccgtga aggaccgatt caccatctcc agagacaatg ccaagaacac ggtgtttctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgtaatgt actgggctgg 300
ccgagagatg actactgggg ccaggggacc caggtcaccg tctcctcaga acccaagaca 360
ccaaaaccac aacca 375
<210> 44
<211> 396
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 44
gaggtgcagc tggtggagtc agggggaggc ttggtgcagc cgggggggtc tctgaggctc 60
tcctgtgcag cctctggaag tacctacgct ttctataaca tgggctggtt ccgccagcgt 120
cctgggaagg agcgtgagtt tgcagcagct atattatggg gtcgcagtgg ggtctacaca 180
acgtatgcag actccgtgaa gggccgattc accatctcta gagacaacgc ccagaacacg 240
gtgtatctgc aaatgaacag cctgaaacct gaggacacgg ccgtttatta ctgtgcagca 300
ggcctcggga ctatgcgggc aaatgaatat gactactggg gccaggggac ccaggtcacc 360
gtctcctcag aacccaagac accaaaacca caacca 396
<210> 45
<211> 378
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 45
caggtgcagc tcgtggagtc ggggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcttcagt gccaatgtca tgggctggta ccgccaggct 120
ccagggaagc tgcgcgagtt ggtcgcaggt atgcatagtg gtggtagcgc aaactatgca 180
gactccgtga agggccgatt caccatctcc aaagacaacg ccaagaacac gatgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgtaattt cgggttgggg 300
tttgatgggc atgactactg gggccagggg acccaggtca ccgtctccgc agaacccaag 360
acaccaaaac cacaacca 378
<210> 46
<211> 369
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 46
gaggtgcagc tggtggagtc tgggggaggc ttggtgcaac ctggggggtc tctgagactc 60
tcctgtgcag cctctggaag catcttcagc cccaatggca taggctggta ccgccaggct 120
ccggggaagt tgcgcgaatt ggtcgcaggt attacaggca acgggctcac tgactatgca 180
gactccgtga agggccgatt caccatctcc agagacagcg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaaac cgaagacacg gccgtctatt actgtaacct actattgaac 300
cacgcggagt ggggccaggg gacccaggtc accgtctcct cagaacccaa gacaccaaaa 360
ccacaacca 369
<210> 47
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 47
Phe Tyr Asp Met Gly
1 5
<210> 48
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 48
Val Asn Glu Met Gly
1 5
<210> 49
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 49
Ile Asn Asp Met Gly
1 5
<210> 50
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 50
Ile Asn Ala Met Gly
1 5
<210> 51
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 51
Thr Phe Pro Thr Ser Met Gly
1 5
<210> 52
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 52
Glu Tyr Ser Ile Ala
1 5
<210> 53
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 53
Asn Tyr Asn Val Gly
1 5
<210> 54
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 54
Asn Tyr Ala Met Gly
1 5
<210> 55
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 55
Asp Tyr Val Met Gly
1 5
<210> 56
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 56
Arg Ser Val Met Gly
1 5
<210> 57
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 57
Phe Lys Ser Met Gly
1 5
<210> 58
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 58
Ile Asp Met Met Gly
1 5
<210> 59
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 59
Ser Thr His Met Gly
1 5
<210> 60
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 60
Val Asn Glu Met Gly
1 5
<210> 61
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 61
Phe Tyr Gly Met Ala
1 5
<210> 62
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 62
Thr Tyr Asn Met Gly
1 5
<210> 63
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 63
Ile Asn Ala Met Gly
1 5
<210> 64
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 64
Ile Ala Asn Met Gly
1 5
<210> 65
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 65
Ile Asp Met Met Gly
1 5
<210> 66
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 66
Ile Glu Pro Trp Gly
1 5
<210> 67
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 67
Phe Tyr Asn Met Gly
1 5
<210> 68
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 68
Ala Asn Val Met Gly
1 5
<210> 69
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 69
Pro Asn Gly Ile Gly
1 5
<210> 70
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 70
Ala Val Thr Ala Ser Gly Asp Thr Thr Ile Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 71
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 71
Ala Ile Thr Ser Asp Gly Thr Thr Ala Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 72
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 72
Gly Ile Thr Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 73
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 73
Gly Ile Thr Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 74
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 74
Ala Ile Ser Glu Ser Gly Leu Asn Thr Tyr Tyr Arg Asp Ser Val Lys
1 5 10 15
Gly
<210> 75
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 75
Leu Val Ser Arg Ile Gly Asp Arg Val Asp Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 76
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 76
Thr Ile Ser Glu Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 77
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 77
Ala Phe Ser Gln Asn Gly Gly Arg Thr Asp Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 78
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 78
Thr Ile Thr Arg Ile Gly Gly Met Pro Tyr Tyr Ala Asp Phe Val Lys
1 5 10 15
Gly
<210> 79
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 79
Gly Ile Thr Ser Asp Asp Asn Thr Asp Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 80
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 80
Gly Ile Thr Thr Gly Gly Val Thr Asp Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 81
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 81
Gly Ile Thr Lys Gly Gly Phe Ala Asp Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 82
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 82
Gly Ile Thr Ser Thr Gly Asn His Arg Asn Val Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 83
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 83
Ala Ile Thr Ser Asp Gly Thr Thr Ala Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 84
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 84
Ser Ile Ile Pro Gly Ser Gly Asp Thr Ser Tyr Ala Ser Ser Val Arg
1 5 10 15
Gly
<210> 85
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 85
Gly Ile Thr Thr Gly Gly Ile Thr Asp Tyr Thr Asp Ser Val Lys Gly
1 5 10 15
<210> 86
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 86
Gly Ile Thr Arg Gly Gly Asp Val Asn Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 87
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 87
Gly Ile Thr Ser Asp Gly Phe Thr Asn Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 88
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 88
Gly Ile Thr Lys Gly Gly Phe Ala Asp Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 89
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 89
Gly Ile Thr Ser Asp Asp Lys Thr Asp Tyr Ala Asp Ser Val Lys Asp
1 5 10 15
<210> 90
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 90
Ala Ile Leu Trp Gly Arg Ser Gly Val Tyr Thr Thr Tyr Ala Asp Ser
1 5 10 15
Val Lys Gly
<210> 91
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 91
Gly Met His Ser Gly Gly Ser Ala Asn Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 92
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 92
Gly Ile Thr Gly Asn Gly Leu Thr Asp Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 93
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 93
Gly Glu Tyr Ser Ser Thr Ala Ala Thr Tyr Tyr Tyr
1 5 10
<210> 94
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 94
Trp Pro Glu Ala Arg Gly Asp
1 5
<210> 95
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 95
Leu Gly Trp Pro Asp Phe Gly Ser
1 5
<210> 96
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 96
Leu Gly Phe Pro Gln Tyr
1 5
<210> 97
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 97
Ala Pro Gly Tyr Met Thr Thr Asp Ser Gln Tyr Tyr Leu Gly Asn Lys
1 5 10 15
Tyr Gln Tyr
<210> 98
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 98
Gly Gln Leu Ser Ser Ser Thr Tyr Tyr Gly Asp Glu Tyr Val Tyr
1 5 10 15
<210> 99
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 99
Ser Arg Ile Phe Ser Phe Ser Tyr Ala Asp Gly Arg Gly Tyr Ala Tyr
1 5 10 15
<210> 100
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 100
Arg Pro Pro Ala Tyr Phe Ser Asn Ala Val Tyr Ser Lys Val Asp Glu
1 5 10 15
Tyr Arg Tyr
<210> 101
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 101
Asp Leu Arg Leu Arg Leu Gly Val Thr Pro Arg Glu Tyr Asp Tyr
1 5 10 15
<210> 102
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 102
Leu Pro Asp Ser Arg Leu Gly
1 5
<210> 103
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 103
Leu Gly Ala Ala Ala Tyr Asp
1 5
<210> 104
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 104
Leu Pro Thr His Ser Asp
1 5
<210> 105
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 105
Phe Pro Asp Gln Val Phe Asn
1 5
<210> 106
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 106
Trp Pro Gln Ala Arg Gly Asp
1 5
<210> 107
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 107
Gly Thr Gly Gly Ile Tyr Ser Ser Asp Tyr Pro Tyr
1 5 10
<210> 108
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 108
Leu Gly Met Ala Asn Tyr
1 5
<210> 109
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 109
Leu Gly Phe Pro Ser Asp
1 5
<210> 110
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 110
Phe Pro Thr Arg His Tyr
1 5
<210> 111
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 111
Leu Pro Thr His Ser Asp
1 5
<210> 112
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 112
Leu Gly Trp Pro Arg Asp Asp Tyr
1 5
<210> 113
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 113
Gly Leu Gly Thr Met Arg Ala Asn Glu Tyr Asp Tyr
1 5 10
<210> 114
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 114
Gly Leu Gly Phe Asp Gly His Asp Tyr
1 5
<210> 115
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 115
Leu Leu Asn His Ala Glu
1 5
<210> 116
<211> 232
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 116
Glu Pro Lys Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
Claims (4)
1.一种抗NKp30单域抗体,其特征在于,其能够激活NK细胞或γδT细胞释放细胞因子,其包含免疫球蛋白单一可变结构域,其中所述单一可变结构域包含以下的CDR1、CDR2和CDR3:
(1)SEQ ID NO:64所示的CDR1,SEQ ID NO:87所示的CDR2,SEQ ID NO:110所示的CDR3。
2.根据权利要求1所述的抗NKp30单域抗体,其中所述免疫球蛋白单一可变结构域是VHH,所述VHH为SEQ ID NO:18的氨基酸序列。
3.根据权利要求1-2任一所述的抗NKp30单域抗体,其还包含免疫球蛋白Fc区,所述免疫球蛋白Fc区选自IgG1、IgG2、IgG3和/或IgG4。
4.根据权利要求3所述的抗NKp30单域抗体,所述免疫球蛋白Fc区的氨基酸序列如SEQID NO:116所示。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2020172605A1 (en) * | 2019-02-21 | 2020-08-27 | Elstar Therapeutics, Inc. | Antibody molecules that bind to nkp30 and uses thereof |
CN112029001A (zh) * | 2020-09-02 | 2020-12-04 | 南京北恒生物科技有限公司 | 靶向nk激活性受体的嵌合抗原受体 |
CN112384534A (zh) * | 2018-05-21 | 2021-02-19 | 指南针制药有限责任公司 | 用于增强nk细胞对靶细胞的杀死的组合物和方法 |
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CN112384534A (zh) * | 2018-05-21 | 2021-02-19 | 指南针制药有限责任公司 | 用于增强nk细胞对靶细胞的杀死的组合物和方法 |
WO2020172605A1 (en) * | 2019-02-21 | 2020-08-27 | Elstar Therapeutics, Inc. | Antibody molecules that bind to nkp30 and uses thereof |
CN112029001A (zh) * | 2020-09-02 | 2020-12-04 | 南京北恒生物科技有限公司 | 靶向nk激活性受体的嵌合抗原受体 |
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