CN115109156A - 一种靶向bcma的纳米抗体及其应用 - Google Patents
一种靶向bcma的纳米抗体及其应用 Download PDFInfo
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- CN115109156A CN115109156A CN202110301079.1A CN202110301079A CN115109156A CN 115109156 A CN115109156 A CN 115109156A CN 202110301079 A CN202110301079 A CN 202110301079A CN 115109156 A CN115109156 A CN 115109156A
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Abstract
本发明公开了一种纳米抗体,其包括含CDR1、CDR2和/或CDR3的重链可变区,并具有识别并结合BCMA的功能,具体CDR序列详见正文。本发明还公开了一种BCMA结合分子、含所述纳米抗体或BCMA结合分子的组合物、BCMA检测剂,以及所述纳米抗体、BCMA结合分子或组合物在制备治疗与BCMA相关疾病的药物中的应用。本发明的纳米抗体、BCMA结合分子以及组合物可识别并结合BCMA,具有潜在的治疗与BCMA相关的疾病的效用。
Description
技术领域
本发明属于生物制药领域,涉及一种靶向BCMA的纳米抗体及其应用。
背景技术
单域抗体(sdAb)由于具有单个单体抗体可变域而不同于传统的4链抗体。例如,骆驼科动物和鲨鱼产生天然缺乏轻链的抗体,其被称为仅重链抗体(HcAb,或简称为重链抗体)。骆驼科动物仅重链抗体的每个臂中的抗原结合片段具有单个重链可变域(VHH),所述重链可变域可在无需轻链的帮助下,对抗原具有高亲和力。骆驼科动物VHH即纳米抗体被称为最小的功能性抗原结合片段,分子量为大约15kD。
纳米抗体具有稳定性高、穿透力强、结合表位广的天然优势(Muyldermans S.AnnuRev Biochem.2013;82:775-97)。纳米抗体自发现以来,逐渐受到人们关注,对其的基础研究已比较成熟,在应用方面,已有自身免疫病、血液疾病、病毒感染及骨科疾病等进入临床,在抗感染、抗炎症性疾病以及神经退行性疾病等方面也都表现出了极大的优势(MorrisonC.Nat Rev Drug Discov.2019Jul;18(7):485-487)。
多发性骨髓瘤(MM)是第二常见的造血系统恶性肿瘤,占血液恶性肿瘤的10%。MM主要病状是骨髓(BM)中的浆细胞无限度的扩增和富集,进而导致骨坏死。MM受累患者可能经历因骨髓浸润、骨质破坏、肾衰竭、免疫缺陷以及癌症诊断的心理负担而经历多种与疾病相关的症状。目前主要的治疗方案为化疗和干细胞移植,化疗药物主要是类固醇、沙利度胺、来那度胺、硼替佐米或多种细胞毒素试剂的组合,对于较年轻的患者可采用高剂量化疗理念配合自体干细胞移植。然而,由于耐药克隆体的不断出现和进化,MM疾病复发仍然是一个主要障碍,显著的不良反应是不可避免的。因此,迫切需要更有效和更少毒性的治疗方法以克服耐药、改善复发难治性MM患者的生活质量、延迟生存期(Cho,S.-F.,Frontiers inImmunology,9)。
BCMA(B-cell maturation antigen)是B细胞成熟抗原,由184个氨基酸残基组成的III型跨膜蛋白,属TNF受体超家族,其配体属于TNF超家族,如增殖诱导配体(APRIL)、B淋巴细胞刺激因子(BAFF),BCMA与其配体结合后,可激活NF-κB和MAPK8/JNK信号从而介导B细胞的增殖和存活,对于长寿命浆细胞存活起重要作用。BCMA特异性高表达于晚期B细胞、短寿命增殖浆母细胞和长寿命浆细胞表面,并在一定程度上存在于记忆B细胞上,而在初始B细胞、CD34阳性造血干细胞和其他正常组织细胞中未见报道。研究表明BCMA的表达与血液恶性肿瘤有关,最明显的是多发性骨髓瘤(MM);BCMA的过表达与MM的发生、发展和差的愈后有关,因此BCMA是MM靶向性治疗的理想靶点(Tai,Immunotherapy,7(11),1187–1199)。高亲和力的抗体可阻断BCMA和其天然配体BAFF和APRIL之间的结合。抗BCMA sdAb可与使用CAR-T细胞的细胞免疫疗法组合使用,例如以增强针对肿瘤细胞的细胞毒性作用。目前缺乏效果好、毒性低的抗BCMA的纳米抗体。
发明内容
为克服现有技术中缺乏效果好、毒性低的靶向BCMA的纳米抗体的缺陷,本发明提供一种靶向BCMA的纳米抗体及其应用。
为解决上述技术问题,本发明技术方案的第一方面为:一种纳米抗体,其包括含CDR1、CDR2和CDR3的重链可变区,并具有识别并结合BCMA的功能,且:
其中,所述CDR1选自以下组:
(1)如SEQ ID NO:4的氨基酸序列所示,或在如SEQ ID NO:4所示的氨基酸序列上发生1~3种氨基酸残基的替换、缺失或增加;
(2)如SEQ ID NO:6的氨基酸序列所示,或在如SEQ ID NO:6所示的氨基酸序列上发生1~3种氨基酸残基的替换、缺失或增加;
所述CDR2为如SEQ ID NO:23所示的氨基酸序列,或在如SEQ ID NO:23所示的氨基酸序列发生1~3种氨基酸残基的替换、缺失或增加;
所述CDR3选自如SEQ ID NO:27~52所示的氨基酸序列。
优选地,当所述CDR1为在如SEQ ID NO:4所示的氨基酸序列上发生1~3种氨基酸残基的替换时,所述替换选自G1E、T3I、S5R和S6P/I;当所述CDR1为在如SEQ ID NO:6所示的氨基酸序列上发生1~3种氨基酸残基的替换时,所述替换选自F4S/D、S5R和I6F;和/或,当所述CDR2为在如SEQ ID NO:23所示的氨基酸序列发生1~3种氨基酸残基的替换时,所述替换选自I1V、Y2T、S3P/G/T、D4G/E/A、G5S/N、S6R/N/G/T和T7A/P/S。
在一较佳的具体实施例中,所述CDR1选自如SEQ ID NO:2~7所示的氨基酸序列;所述CDR2选自如SEQ ID NO:8~26所示的氨基酸序列;和/或,所述CDR3选自如SEQ ID NO:27~52所示的氨基酸序列。
在一更佳的具体实施例中,所述重链可变区包括以下组1到组26中任一组所示的CDR1、CDR2和CDR3:
在一更佳的具体实施例中,所述重链可变区的氨基酸序列如SEQ ID NO:53~78所示,或与如SEQ ID NO:53~78所示的氨基酸序列具有至少80%、90%、95%、96%、97%、98%或99%同一性。
在一些实施方式中,本发明还提供与本发明的任何纳米抗体结合BCMA相同表位的纳米抗体、重链抗体、抗体或其抗原结合片段,即能够与本发明的任何纳米抗体交叉竞争与BCMA的结合的纳米抗体、重链抗体、抗体或其抗原结合片段。
为解决上述技术问题,本发明技术方案的第二方面为:一种BCMA结合分子,其中,所述BCMA结合分子包含如第一方面所述的纳米抗体,例如为包含一条、两条或多条如第一方面所述的纳米抗体的单价或多价纳米抗体、多特异性纳米抗体、重链抗体或其抗原结合片段。
在一较佳的具体实施例中,所述BCMA结合分子为重链抗体。
在一更佳的具体实施例中,所述重链抗体的CH2和CH3的氨基酸序列如SEQ ID NO:1所示,或与如SEQ ID NO:1所示的氨基酸序列具有至少80%、90%、95%、96%、97%、98%或99%同一性。
本发明中,术语“纳米抗体”代表重链抗体的可变区(重链可变区)。纳米抗体、VHH、单域抗体(sdAb)在本发明中代表相同的分子。术语“重链抗体”除包括纳米抗体以外,还包括常规重链的CH2和CH3区域。术语“BCMA结合分子”可以是纳米抗体、重链抗体,也可以是包含一条、两条或多条相同特异性纳米抗体的多价纳米抗体/重链抗体、包含两条或多条不同特异性纳米抗体的多特异性抗体、常规抗体或其抗原结合片段等。
为解决上述技术问题,本发明技术方案的第三方面为:一种分离的核酸,其中,所述分离的核酸编码如本发明第一方面所述的纳米抗体、或如本发明第二方面所述的BCMA结合分子。
为解决上述技术问题,本发明技术方案的第四方面为:一种重组表达载体,其中,所述重组表达载体包含如本发明第三方面所述的分离的核酸。优选地,所述重组表达载体的骨架为pCDNA3.4。
为解决上述技术问题,本发明技术方案的第五方面为:一种转化体,其特征在于,所述转化体包含如本发明第三方面任一所述的分离的核酸,或如本发明第四方面任一所述的重组表达载体。优选地,所述转化体的宿主为原核细胞或真核细胞。更优选地,所述真核细胞为CHO细胞。
为解决上述技术问题,本发明技术方案的第六方面为:一种组合物,其特征在于,其包括一条、两条或多条如本发明第一方面所述的纳米抗体、本发明第二方面所述的BCMA结合分子、本发明第三方面所述的分离的核酸、本发明第四方面所述的重组表达载体或本发明第五方面所述的转化体。优选地,所述组合物还包括药学上可接受的辅料,由此该组合物为药物组合物。
为解决上述技术问题,本发明技术方案的第七方面为:一种BCMA检测剂,其中,所述BCMA检测剂包括如本发明第一方面任一所述的纳米抗体和/或如本发明第二方面任一所述的BCMA结合分子;优选地,所述BCMA检测剂用于流式检测。
为解决上述技术问题,本发明技术方案的第八方面为:如本发明第一方面所述的纳米抗体、本发明第二方面所述的BCMA结合分子、本发明第三方面所述的分离的核酸、本发明第四方面所述的重组表达载体或本发明第五方面所述的转化体在制备治疗与BCMA相关疾病的药物中的应用。所述疾病优选为血液恶性肿瘤,更优选为多发性骨髓瘤。
为解决上述技术问题,本发明技术方案的第九方面为:一种治疗有需要的受试者的方法,其包括将如本发明第一方面所述的纳米抗体、本发明第二方面所述的BCMA结合分子、本发明第三方面所述的分离的核酸、本发明第四方面所述的重组表达载体、本发明第五方面所述的转化体或本发明第六方面所述的组合物施用于有需要的受试者;其中所述有需要的受试者患有与BCMA相关的疾病。所述疾病优选为血液恶性肿瘤,更优选为多发性骨髓瘤。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
1、本发明的纳米抗体、BCMA结合分子以及组合物可识别并结合BCMA,具有潜在的治疗与BCMA相关的疾病的效用;
2、本发明的BCMA检测剂具有快速、高效检测BCMA的作用。
附图说明
图1为羊驼血清效价检测结果;图1的A、B分别为A1、A2羊驼不同次免疫后的血清效价;
图2为羊驼免疫前后血清纯化的IgG亚型与抗原的结合情况;图2的A与B分别展示了A1羊驼和A2羊驼免疫前后血清中IgG亚型变化;
图3为ELISA检测克隆上清与BCMA蛋白的结合情况;
图4为纳米抗体(VHH)改造后结构;
图5为CHO-K1/BCMA细胞水平配体竞争结合实验;其中图5的A为NB-67、NB-84、NB-90、NB-100、NB-122、NB-192、NB-257、NB-265和NB-367的MFI和IC50,图5的B为NB-27、NB-29、NB-34、NB-36、NB-51、NB-53、NB-65、NB-71、NB-83、NB-102、NB-216、NB-217、NB-170、NB-222和NB-352的MFI和IC50;
图6为CHO-K1/BCMA细胞水平亲和力检测;其中BMK2-H4为阳性对照抗体;其中图6的A为NB-1、NB-27、NB-29、NB-34、NB-36、NB-51、NB-53、NB-65、NB-67、NB-71、NB-82、NB-83和NB-84的MFI和EC50,图6的B为NB-90、NB-100、NB-102、NB-122、NB-192、NB-216、NB-217、NB-257、NB-265和NB-367的MFI和EC50;
图7为本发明抗体结合靶细胞的亲和力水平检测;其中图7的A、B、C分别为各抗体分别与RPMI8226细胞、Jeko-1细胞、Daudi细胞的结合亲和力水平;BMK1和BMK2-H4为阳性对照抗体,对照抗体的来源及序列见表6,EC50的单位为nM;
图8为MPA筛选流程图,以及4个抗体MPA检测结果;其中图8的A为MPA筛选流程,图8的B、C、D、E分别为NB-1、NB-29、NB-257、NB-367抗体的MPA检测结果。
具体实施方式
抗体
本文中,“BCMA结合分子”是具有识别并结合BCMA的功能的蛋白质,包括但不仅限于,抗体、抗体的抗原结合片段、重链抗体、纳米抗体、微型抗体、亲和体、受体的靶结合区、细胞粘附分子、配体、酶、细胞因子、和趋化因子。
本文中,术语“抗体”包括单克隆抗体(包括全长抗体,其具有免疫球蛋白Fc区),具有多表位特异性的抗体组合物,多特异性抗体(例如,双特异性抗体),双抗体和单链分子,以及抗体片段,尤其是抗原结合片段,例如,Fab,F(ab’)2和Fv。在本文一些实施例中,术语“免疫球蛋白”(Ig)和“抗体”可互换地使用。
基本的4链抗体单元是由两条相同的轻链(L)和两条相同的重链(H)构成的异四聚体糖蛋白。IgM抗体由5个基本的异四聚体单元及称作J链的另外多肽组成,包含10个抗原结合位点;而IgA抗体包含2-5个基本的4链单元,其可与J链组合聚合形成多价装配物。在IgG的情况中,4链单元通常约150,000道尔顿。每条轻链通过一个共价二硫键与重链相连,而两条重链通过一个或多个二硫键彼此相连,二硫键的数目取决于重链的同种型。每条重链和轻链还具有间隔规律的链内二硫桥。每条重链在N-末端具有可变结构域(VH),接着是三个(对于每种α和γ链,CH1、CH2和CH3)和四个(对于μ和ε同种型,CH1、CH2、CH3和CH4)恒定结构域(CH)以及位于CH1结构域与CH2结构域之间的绞链区(Hinge)。每条轻链在N-末端具有可变结构域(VL),接着是其另一端的恒定结构域(CL)。VL与VH排列在一起,而CL与重链的第一恒定结构域(CH1)排列在一起。特定的氨基酸残基被认为在轻链和重链可变结构域之间形成界面。成对的VH和VL一起形成一个抗原结合位点。关于不同类别抗体的结构和性质,参见如Basic and Clinical Immunology,第八版,Daniel P.Sties,Abba I.Terr和TristramG.Parsolw编辑,Appleton&Lange,Norwalk,CT,1994,第71页和第6章。来自任何脊椎动物物种的轻链,根据其恒定结构域氨基酸序列,可归入两种称作κ和λ的截然不同型中的一种。根据其重链恒定结构域(CH)氨基酸序列,免疫球蛋白可归入不同的类或同种型。有五类免疫球蛋白:IgA、IgD、IgE、IgG和IgM,分别具有称作α、δ、ε、γ和μ的重链。根据CH序列和功能的相对较小差异,γ和α类可进一步分为亚类,例如人表达下列亚类:IgG1、IgG2A、IgG2B、IgG3、IgG4、IgA1和IgA2。
本文所述“重链抗体”是源自骆驼科生物或软骨鱼科生物的抗体。相比上述4链抗体,重链抗体缺失轻链和重链恒定区1(CH1),仅包含2条由可变区(VHH)和其他恒定区组成重链,可变区通过类似铰链区结构与恒定区相连。骆驼科重链抗体的每条重链包含1个可变区(VHH)和2个恒定区(CH2和CH3),软骨鱼科重链抗体的每条重链含有1个可变区和5个恒定区(CH1-CH5)。重链抗体的抗原结合片段包括VHH和单链重链抗体。通过与人IgG Fc的恒定区融合,重链抗体可以具有人IgG Fc的CH2和CH3。
如本文所用,术语“单域抗体”、“抗BCMA单域抗体”、“重链抗体的重链可变区结构域”、“VHH”、“纳米抗体”可互换使用,均指特异性识别和结合于BCMA的纳米抗体。纳米抗体是重链抗体的可变区。通常,纳米抗体含有三个CDR和四个FR。纳米抗体是最小的功能性抗原结合片段。通常先获得天然缺失轻链和重链恒定区1(CH1)的抗体后,再克隆抗体重链的可变区,构建仅由一个重链可变区组成的纳米抗体。
包含两条或多条纳米抗体的结合分子是多价纳米抗体;包含两条或多条不同特异性纳米抗体的结合分子是多特异性纳米抗体。多价纳米抗体或多特异性纳米抗体通过连接子连接多个纳米抗体。所述连接子通常由选自G和S的1-15个氨基酸组成,例如(G4S)3。
本文中,重链抗体和抗体旨在区分抗体的不同组合方式。由于二者的结构具有相似性,下述针对抗体的结构描述除涉及轻链外也均适用于重链抗体。
抗体的“可变区”或“可变结构域”是指抗体的重链或轻链的氨基末端结构域。重链和轻链的可变结构域可分别称为“VH”和“VL”。这些结构域通常是抗体的最可变的部分(相对于相同类型的其它抗体)并含有抗原结合位点。
术语“可变的”指可变结构域中的某些区段在抗体序列中差异广泛的情况。可变结构域介导抗原结合并限定特定抗体对其特定抗原的特异性。然而,变异性并非均匀分布于可变结构域跨越的全部氨基酸。相反,其集中在三个称为高变区(HVR)的区段(在轻链和重链可变结构域中均有),即分别为重链可变区的HCDR1、HCDR2、HCDR3(重链抗体中可简称为CDR1、CDR2、CDR3)以及轻链可变区的LCDR1、LCDR2和LCDR3。可变结构域中更为高度保守的部分称为构架区(FR)。天然重链和轻链的可变结构域各自包含四个FR区(FR1、FR2、FR3和FR4),它们大多采取β-折叠构象,通过形成环状连接且在有些情况中形成β-折叠结构一部分的三个HVR连接。每条链中的HVR通过FR区非常接近的保持在一起,并与另一条链的HVR一起促成抗体的抗原结合位点的形成。通常,轻链可变区的结构为FR1-LCDR1-FR2-LCDR2-FR3-LCDR3-FR4,重链可变区的结构为FR1-HCDR1-FR2-HCDR2-FR3-HCDR3-FR4。恒定结构域不直接参与抗体与抗原的结合,但展现出多种效应子功能,如在抗体依赖性细胞介导的细胞毒性中抗体的参与。
“Fc区”(可结晶片段区域)或“Fc结构域”或“Fc”是指抗体重链的C-末端区域,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受体的结合,或者与经典补体系统的第一组分(C1q)的结合。在IgG抗体同种型中,Fc区由来自抗体两条重链的CH2结构域和CH3结构域的两个相同的蛋白片段构成。虽然免疫球蛋白重链的Fc区的边界可以变化,但是人IgG重链Fc区通常定义为从重链位置C226或P230的氨基酸残基到羧基端的序列段,其中该编号是根据EU索引,如在Kabat中一样。如本文所使用的,Fc区可以是天然序列Fc或变体Fc。
“抗体片段”包含完整抗体的一部分,优选完整抗体的抗原结合区和/或可变区。抗体片段优选为抗体的抗原结合片段。抗体片段的例子包括Fab、Fab’、F(ab’)2和Fv片段;双抗体;线性抗体;单链抗体分子;scFv-Fc片段;由抗体片段形成的多特异性抗体;以及通过化学修饰或通过掺入脂质体中应能够增加半衰期的任何片段。用木瓜蛋白酶消化抗体产生称作“Fab”片段的两个相同的抗原结合片段,和一个残余“Fc”片段,其名称反映了它易于结晶的能力。Fab片段由完整轻链及重链可变结构域(VH)和一条重链第一恒定结构域(CH1)组成。每个Fab片段在抗原结合方面是单价的,即其具有单个抗原结合位点。胃蛋白酶处理抗体产生一个较大F(ab’)2片段,它粗略相当于两个通过二硫键相连的Fab片段,具有不同抗原结合活性且仍能够交联抗原。Fab’片段因在CH1结构域的羧基末端增加了一些另外的残基(包括来自抗体铰链区的一个或多个半胱氨酸)而与Fab片段有所不同。F(ab’)2抗体片段最初是作为成对Fab’片段生成的,在Fab’片段之间具有铰链半胱氨酸。抗体片段的其它化学偶联也是已知的。Fc片段包含通过二硫键保持在一起的两条重链的羧基末端部分。抗体的效应子功能是由Fc区中的序列决定的,该区还是由在某些类型细胞上发现的Fc受体(FcR)所识别的区。
“Fv”是含有完整抗原识别和结合位点的最小抗体片段。该片段由紧密、非共价结合的一个重链可变结构域和一个轻链可变结构域的二聚体组成。从这两个结构域的折叠中突出了六个高变环(重链和轻链各3个环),贡献出抗原结合的氨基酸残基并赋予抗体以抗原结合特异性。然而,即使是单个可变结构域(或只包含对抗原特异的三个HVR的半个Fv)也具有识别和结合抗原的能力,尽管亲合力低于完整结合位点。“单链Fv”也可缩写为“sFv”或“scFv”,是包含抗体VH和VL结构域的连接成一条多肽链的抗体片段。优选的是,sFv多肽在VH和VL结构域之间还包含多肽接头,使得sFv形成期望的抗原结合结构。
本文中,术语“单克隆抗体”指从一群基本上同质的抗体中获得的抗体,即除了可能以少量存在的可能的天然出现的突变和/或翻译后修饰(例如异构化、酰胺化)之外,构成群体的各个抗体是相同的。单克隆抗体是高度特异性的,针对单个抗原位点。与多克隆抗体制剂(其典型地包括针对不同决定簇(表位)的不同抗体)相比,每个单克隆抗体针对抗原上的单个决定簇。除它们的特异性外,单克隆抗体的优势在于它们通过杂交瘤培养合成,未受到其它免疫球蛋白的污染。修饰语“单克隆”表明抗体从基本上同质的抗体群获得的特征,不应解释为要求通过任何特定方法来生产抗体。例如,将根据本发明使用的单克隆抗体可通过多种技术来生成,包括例如杂交瘤法、噬菌体展示法、重组DNA法、及用于从具有部分或整个人免疫球蛋白基因座或编码人免疫球蛋白序列的基因的动物生成人或人样抗体的技术、单细胞测序法。
单克隆抗体在本文中也包括“嵌合”抗体,其中重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类别或亚类的抗体中的相应序列相同或同源,而链的剩余部分与衍生自另一物种或属于另一抗体类别或亚类的抗体中的相应序列相同或同源,以及此类抗体的片段,只要它们展现出期望的生物学活性。
非人(例如鼠)抗体的“人源化”形式指最低限度包含衍生自非人免疫球蛋白的序列的嵌合抗体。因此,“人源化抗体”通常指可变结构域构架区与在人抗体中发现的序列交换的非人抗体。通常在人源化抗体中,整个抗体(除CDR以外)由人来源的多核苷酸编码或与这种抗体相同(除CDR以外)。CDR(其中一些或全部由源自非人生物体的核酸编码)被移植到人抗体可变区的β-折叠骨架中以产生抗体,其特异性由被移植的CDR来决定。这类抗体的产生方法本领域周知,例如使用具有基因工程免疫系统的小鼠而产生。本发明中,抗体、纳米抗体、重链抗体等均包括各所述抗体的经人源化的变体。
“人抗体”指这样的抗体,其具有与由人生成的抗体的氨基酸序列对应的氨基酸序列和/或使用本文所公开的用于生成人抗体的任何技术产生。人抗体的这种定义明确排除包含非人抗原结合残基的人源化抗体。人抗体可使用本领域已知的多种技术来生成,包括噬菌体展示文库。
本发明还包括所述各种抗体(例如纳米抗体、重链抗体或其抗原结合片段、多价纳米抗体、多特异性纳米抗体、抗体或其抗原结合片段)的衍生物和类似物。“衍生物”和“类似物”是指基本上保持本发明各种抗体相同的生物学功能或活性的多肽。本发明的衍生物或类似物可以是(i)在一个或多个氨基酸残基中具有取代基团的多肽,或(ii)成熟多肽与另一个化合物(比如延长多肽半衰期的化合物,例如聚乙二醇)融合所形成的多肽,或(iii)附加的氨基酸序列融合到此多肽序列而形成的多肽(如前导序列或分泌序列或用来纯化此多肽的序列或蛋白原序列,或与6His标签形成的融合蛋白)。根据本文的教导,这些衍生物和类似物属于本领域熟练技术人员公知的范围。
在不实质性影响抗体活性的前提下,本领域技术人员可以对本发明的序列改变一个或更多个(例如1、2、3、4、5、6、7、8、9或10个或更多个)氨基酸,以获得所述抗体或其功能性片段序列的变体。这些变体包括(但并不限于):一个或多个(通常为1-50个,较佳地1-30个,更佳地1-20个,最佳地1-10个)氨基酸的缺失、插入和/或取代,以及在C末端和/或N末端添加一个或数个(通常为20个以内,较佳地为10个以内,更佳地为5个以内)氨基酸。在本领域中,用性能相近或相似的氨基酸进行保守性取代时,通常不会改变蛋白质的功能。如在可变区的FR和/或CDR区中将具有类似性质的氨基酸进行取代。可进行保守性取代的氨基酸残基为本领域所周知。这样的取代的氨基酸残基可以是也可以不是由遗传密码编码的。又比如,在C末端和/或N末端添加一个或数个氨基酸通常也不会改变蛋白质的功能。它们都被视为包括在本发明保护的范围内。
本文所述各种抗体的变异形式包括:同源序列、保守性变异体、等位变异体、天然突变体、诱导突变体、在高或低的严紧度条件下能与本发明各种抗体的编码DNA杂交的DNA所编码的蛋白、以及利用抗本发明各种抗体的抗血清获得的多肽或蛋白。
在一些实施方案中,本发明所述变体的序列可以与其来源序列有至少有95%、96%、97%、98%或99%的一致性。本发明所述的序列一致性可以使用序列分析软件测量。例如使用缺省参数的计算机程序BLAST,尤其是BLASTP或TBLASTN。本发明还包括那些具有带CDR的抗体重链可变区的分子,只要其CDR与此处鉴定的CDR具有90%以上(较佳地95%以上,最佳地98%以上)的同源性。
可采用本领域常规的方法制备本发明的抗体,如本领域熟知的杂交瘤技术。可采用本领域常规的方法制备本发明的纳米抗体和重链抗体,如本领域熟知的噬菌体展示技术。或者,本发明的各种抗体可在其他细胞系中表达。可用编码本发明各种抗体的序列转化合适的哺乳动物宿主细胞。转化可采用任何已知的方法进行,例如包括将多核苷酸包装在病毒(或病毒载体中)并用病毒(或载体)转导宿主细胞。所用的转化程序取决于将转化的宿主。用于将异源多核苷酸引入哺乳动物细胞中的方法为本领域所熟知,包括葡聚糖介导的转染、磷酸钙沉淀、聚凝胺介导的转染、原生质体融合、电穿孔、将多核苷酸囊封在脂质体中和将DNA直接微注射至核中等。可用作用于表达的宿主的哺乳动物细胞系为本领域所熟知,包括但不限于可从美国典型培养物保藏中心(ATCC)获得的多种永生化细胞系,包括但不限于中国仓鼠卵巢(CHO)细胞、HeLa细胞、幼仓鼠肾(BHK)细胞、猴肾细胞(COS)、人肝细胞癌细胞(例如,HepG2)等。尤其优选的细胞系通过确定哪些细胞系具有高表达水平并产生具有基本BCMA结合特性的抗体来进行选择。
核酸
本发明还提供了编码上述各种抗体或其片段的多核苷酸。本文提供编码重链可变区、轻链可变区、重链、轻链以及各CDR的多核苷酸。本发明的多核苷酸可以是DNA形式或RNA形式。DNA形式包括cDNA、基因组DNA或人工合成的DNA。DNA可以是单链的或是双链的。DNA可以是编码链或非编码链。
如本领域技术人员将了解,由于遗传密码的简并性,可制得极大量的核酸,它们全部编码本发明的抗体或其抗原结合片段。因此,在已鉴定特定氨基酸序列的情况下,本领域技术人员可通过以不改变编码蛋白质的氨基酸序列的方式简单地修饰一个或多个密码子的序列来制得任何数量的不同的核酸。所以,本发明还涉及与上述多核苷酸序列杂交且两个序列之间具有至少50%,较佳地至少70%,更佳地至少80%相同性的多核苷酸。本发明特别涉及在严谨条件下与本发明所述多核苷酸可杂交的多核苷酸。在本发明中,“严谨条件”是指:(1)在较低离子强度和较高温度下的杂交和洗脱,如0.2×SSC,0.1%SDS,60℃;或(2)杂交时加有变性剂,如50%(v/v)甲酰胺,0.1%小牛血清/0.1%Ficoll,42℃等;或(3)仅在两条序列之间的相同性至少在90%以上,更好是95%以上时才发生杂交。并且,可杂交的多核苷酸编码的多肽与成熟多肽有相同的生物学功能和活性。
本发明各种抗体的核苷酸全长序列或其片段通常可以用PCR扩增法、重组法或人工合成的方法获得。一种可行的方法是用人工合成的方法来合成有关序列,尤其是片段长度较短时。通常,通过先合成多个小片段,然后再进行连接可获得序列很长的片段。此外,还可将重链的编码序列和表达标签(如6His)融合在一起,形成融合蛋白。
一旦获得了有关的序列,就可以用重组法来大批量地获得有关序列。这通常是将其克隆入载体,再转入细胞,然后通过常规方法从增殖后的宿主细胞中分离得到有关序列。本发明所涉及的生物分子(核酸、蛋白等)包括以分离的形式存在的生物分子。目前,已经可以完全通过化学合成来得到编码本发明蛋白(或其片段,或其衍生物)的DNA序列。然后可将该DNA序列引入本领域中已知的各种现有的DNA分子(或如载体)和细胞中。此外,还可通过化学合成将突变引入本发明蛋白序列中。
所以,本发明还涉及包含上述的适当DNA序列以及适当启动子或者控制序列的核酸构建物,例如表达载体和重组载体。这些载体可以用于转化适当的宿主细胞,以使其能够表达蛋白质。载体通常含有用于质粒维系和用于克隆与表达外源性核苷酸序列的序列。所述序列(在某些实施方案中总称为“侧翼序列”)通常包括一个或多个以下核苷酸序列:启动子、一个或多个增强子序列、复制起点、转录终止序列、含有供体和受体剪接位点的完全内含子序列、编码用于多肽分泌的前导序列的序列、核糖体结合位点、聚腺苷酸化序列、用于插入编码将要表达的抗体的核酸的多连接子区和可选标记元件。
宿主细胞可以是原核细胞,如细菌细胞;或是低等真核细胞,如酵母细胞;或是高等真核细胞,如哺乳动物细胞。代表性例子有:大肠杆菌,链霉菌属;鼠伤寒沙门氏菌的细菌细胞;真菌细胞如酵母;果蝇S2或Sf9的昆虫细胞;CHO、COS7、293细胞的动物细胞等。
在某些实施方案中,宿主细胞可以是本领域周知的各种功能细胞,例如各种杀伤性细胞,包括但不限于细胞因子诱导的杀伤细胞(CIK)、树突状细胞刺激的细胞因子诱导的杀伤细胞(DC-CIK)、细胞毒性T淋巴细胞(CTL)、γδT细胞、自然杀伤细胞(NK)、肿瘤浸润淋巴细胞(TIL)、淋巴因子激活杀伤细胞(LAK)、CD3AK细胞(抗CD3单抗的杀伤细胞)和CAR-T/TCR-T细胞。在某些实施方案中,所述杀伤性细胞为T细胞或NK细胞。示例性的NK细胞包括但不限于原代NK细胞、NK细胞株(如NK92)和NKT细胞。在某些实施方案中,所述NK细胞为原代NK细胞。示例性的T细胞包括但不限于外周血T淋巴细胞、细胞毒杀伤T细胞(CTL)、辅助T细胞、抑制/调节性T细胞、γδT细胞以及细胞因子诱导的杀伤细胞(CIK)、肿瘤浸润淋巴细胞(TIL)等混合细胞群体的T细胞。在某些实施方案中,所述T细胞为外周血T淋巴细胞与源自TIL的T细胞。
用重组DNA转化宿主细胞可用本领域技术人员熟知的常规技术进行。当宿主为原核生物如大肠杆菌时,能吸收DNA的感受态细胞可在指数生长期后收获,用CaCl2法处理,所用的步骤在本领域众所周知。另一种方法是使用MgCl2。如果需要,转化也可用电穿孔的方法进行。当宿主是真核生物,可选用如下的DNA转染方法:磷酸钙共沉淀法,常规机械方法如显微注射、电穿孔,脂质体包装等。
获得的转化子可以用常规方法培养,表达本发明的基因所编码的多肽。根据所用的宿主细胞,培养中所用的培养基可选自各种常规培养基。在适于宿主细胞生长的条件下进行培养。当宿主细胞生长到适当的细胞密度后,用合适的方法(如温度转换或化学诱导)诱导选择的启动子,将细胞再培养一段时间。
在上面的方法中的多肽可在细胞内、或在细胞膜上表达、或分泌到细胞外。如果需要,可利用其物理的、化学的和其它特性通过各种分离方法分离和纯化重组的蛋白。这些方法是本领域技术人员所熟知的。这些方法的例子包括但并不限于:常规的复性处理、用蛋白沉淀剂处理(盐析方法)、离心、渗透破菌、超处理、超离心、分子筛层析(凝胶过滤)、吸附层析、离子交换层析、高效液相层析(HPLC)和其它各种液相层析技术及这些方法的结合。
治疗用途和药物组合物
本文所述各种抗体的所有方面都可用于制备用以预防或治疗本文所述各种病况和疾病的药物,所述病况和疾病尤其病况与表达BCMA的细胞相关的疾病或病况。在一些实施方案中,所述病况和疾病是癌症,优选为血液恶性肿瘤,更优选为多发性骨髓瘤。
本文的药物组合物含有本文所述结合分子,以及药学上可接受的辅料,包括但不限于稀释剂、载剂、增溶剂、乳化剂、防腐剂和/或佐剂。辅料优选地在所采用的剂量和浓度下对接受者无毒。这类辅料包括(但并不限于):盐水、缓冲液、葡萄糖、水、甘油、乙醇、及其组合。在某些实施方案中,药物组合物可含有用于改善、维持或保留例如组合物的pH、渗透性、粘度、澄清度、颜色、等渗性、气味、无菌性、稳定性、溶解或释放速率、吸收或渗透的物质。这些物质为现有技术已知。可视预期的施用途径、递送方式和所需的剂量来确定最佳的药物组合物。
用于体内施用的药物组合物通常以无菌制剂的形式提供。通过经无菌过滤膜过滤来实现灭菌。在组合物冻干时,可在冻干和复水之前或之后使用此方法进行灭菌。可选择本发明的药物组合物用于肠胃外递送。用于肠胃外施用的组合物可以冻干形式或在溶液中储存。例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。肠胃外组合物通常放在具有无菌进入孔的容器中,例如具有皮下注射针可刺穿的塞子的静脉内溶液带或小瓶。或者,可选择组合物用于吸入或通过消化道(诸如经口)递送。所述药学上可接受的组合物的制备在本领域的技术内。其它药物组合物将为本领域技术人员显而易见,包括在持续或控制释放递送配制物中包含抗体的配制物。用于配制多种其它持续或可控传递方式的技术(诸如脂质体载剂、生物易蚀微粒或多孔珠粒和积存注射)也为本领域技术人员所知。
药物组合物一经配制,就以溶液、悬浮液、凝胶、乳液、固体、晶体或以脱水或冻干粉末的形式储存在无菌小瓶中。所述配制物可储存成即用形式或在施用前复水的形式(例如,冻干)。本发明还提供用于产生单剂量施用单位的试剂盒。本发明的试剂盒可各自含有具有干燥蛋白的第一容器和具有含水配制物的第二容器。在本发明的某些实施方案中,提供含有单腔和多腔预填充注射器(例如,液体注射器和冻干注射器)的试剂盒。
本发明也提供通过施用本发明任一实施方案所述的结合分子或其药物组合物来治疗患者(尤其是患者的BCMA相关疾病)的方法。本文中,术语“患者”、“受试者”、“个体”、“对象”在本文中可互换使用,包括任何生物体,优选动物,更优选哺乳动物(例如大鼠、小鼠、狗、猫、兔等),且最优选的是人。“治疗”指向受试者采用本文所述治疗方案以达到至少一种阳性治疗效果(比如,癌症细胞数目减少、肿瘤体积减小、癌细胞浸润至周边器官的速率降低或肿瘤转移或肿瘤生长的速率降低)。有效治疗患者的治疗方案可根据多种因素(比如患者的疾病状态、年龄、体重及疗法激发受试者的抗癌反应的能力)而变。
将采用的含有本发明结合分子的药物组合物的治疗有效量将取决于例如治疗程度和目标。本领域技术人员将了解,用于治疗的适当剂量水平将部分取决于所递送的分子、适应症、施用途径和患者的大小(体重、体表或器官大小)和/或状况(年龄和一般健康状况)而变化。在某些实施方案中,临床医生可滴定剂量并改变施用途径来获得最佳的治疗效果。例如每天约10微克/千克体重-约50毫克/千克体重。
给药频率将取决于所用配制物中结合分子的药物动力学参数。临床医生典型地施用组合物直到达到实现所需效果的剂量。组合物因此可作为单次剂量施用,或随时间以作为两次或多次剂量(可含有或不含有相同量的所需分子)施用,或通过植入装置或导管以连续输液的方式施用。
药物组合物的施用途径是根据已知方法,例如经口、通过静脉内、腹膜内、脑内(脑实质内)、脑室内、肌肉内、眼内、动脉内、门静脉或病灶内途径注射;通过持续释放系统或通过植入装置。
诊断、检测和试剂盒
本发明的结合分子因其与BCMA的高亲合力可用于测定,例如结合测定来检测和/或定量在组织或细胞中表达的BCMA。结合分子例如单域抗体可用在进一步研究BCMA在疾病中的作用的研究中。检测BCMA的方法大致如下:获得细胞和/或组织样本;检测样本中BCMA的水平。
本发明的BCMA结合分子可用于诊断目的,用来检测、诊断或监控与BCMA相关的疾病和/或病况。本发明提供使用本领域技术人员已知的经典免疫组织学方法检测样本中BCMA的存在。可以体内或体外进行BCMA的检测。适用于检测BCMA的存在的方法实例包括ELISA、FACS、RIA等。
对于诊断应用来说,通常用可检测的标记基团来标记结合分子例如单域抗体。合适的标记基团包括(但不限于)以下:放射性同位素或放射性核素(例如,3H、14C、15N、35S、90Y、99Tc、111In、125I、131I)、荧光基团(例如,FITC、罗丹明、镧系元素磷光体)、酶促基团(例如,辣根过氧化物酶、β根半乳糖苷酶、荧光素酶、碱性磷酸酶)、化学发光基团、生物素基基团或由二级报导体识别的预定多肽表位(例如,亮氨酸拉链对序列、用于二级抗体的结合位点、金属结合结构域、表位标签)、MRI(磁共振成像)或CT(电子计算机X射线断层扫描技术)造影剂。用于标记蛋白质的各种方法在本领域中已知且可用来进行本发明。
本发明的另一方面提供检测与本发明的抗体竞争结合BCMA的测试分子的存在的方法。一种所述测定的实例将涉及在存在或不存在测试分子的情形下检测含有一定量BCMA的溶液中的游离抗体的量。游离抗体(即,未结合BCMA的抗体)的量增加将表示测试分子能与该抗体竞争结合BCMA。在一个实施方案中,用标记基团标记抗体。或者,标记测试分子并在存在或不存在抗体的情形下监控游离测试分子的量。
本发明还提供了用于检测BCMA水平的检测试剂盒,该试剂盒包括识别BCMA蛋白的抗体,用于溶解样本的裂解介质,检测所需的通用试剂和缓冲液,如各种缓冲液、检测标记、检测底物等。该检测试剂盒可以是体外诊断装置。
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1.羊驼免疫接种和免疫响应测定法
1.1羊驼免疫接种
采用购自Acro公司的具有C-末端Fc标签的重组人BCMA蛋白(Acrobiosystems,货号:BC7-H5254)进行羊驼免疫,共免疫两只羊驼(A1和A2)。首次免疫采用400μg免疫原和CFA(完全弗氏佐剂)混匀,选取沿肩胛骨和背部皮下十点注射免疫,每点200μL。第2~第6次加强免疫,采用IFA(弗氏不完全佐剂)作为免疫佐剂。在首次免疫后间隔3周进行第2次免疫,此后每两周免疫一次;第2次~第5次免疫的免疫原为200μg,第6次免疫的免疫原为100μg。在免疫接种前和每次免疫接种1周之后,收集外周血样品10mL,分离血清样本,取一部分进行免疫效价检测,其余样本冻存于﹣80℃。
1.2IgG分级分离
根据标准操作程序进行IgG子类分级分离。使用蛋白G和蛋白A树脂从羊驼血清对IgG子类进行分级分离。将5ml血清样品上样至5ml蛋白G HP柱上,并用磷酸盐缓冲剂(20mM,pH7.4)洗涤柱。用0.15M NaCl、0.58%乙酸(pH3.5)洗脱IgG3(MW 90,000Da)级分,并用1MTris-HCl(pH8.2)中和洗脱液至pH7.4。随后,用0.1M甘氨酸-HCl(pH2.7)洗脱IgG1(MW 150,000Da)级分,并用1M Tris-HCl(pH8.2)中和洗脱液至pH7.4。然后将蛋白G HP柱的流出物上样至5ml蛋白A HP柱上,并用20ml磷酸盐缓冲(20mM,pH7.0)洗涤柱。用0.15M NaCl、0.58%乙酸(pH4.5)洗脱IgG2(MW80,000Da)级分,并用1M Tris-HCl(pH8.2)中和洗脱液至pH7.4。通过OD280测定纯化的IgG1、IgG2和IgG3抗体的浓度,并通过还原和非还原SDS-PAGE分析评估各自的纯度。
1.3免疫效价检测
1.3.1通过ELISA评估羊驼的免疫响应,其中测定了血清样品和经纯化的IgG与固定化的免疫原的结合。评估免疫接种之前、每次免疫后一周进行采血时收集的血清。用2μg/mL人重组BCMA his tag稀释抗原(Acrobiosystem,BCA-H522y)包被ELISA板,4℃过夜包被;然后用洗涤缓冲剂洗涤板3次,接着在室温下封闭2小时。随后用洗涤缓冲剂洗涤板3次,将梯度稀释的血清加入ELISA板孔中,37℃孵育1小时。用洗涤缓冲剂洗涤板3次,再使用anti-llama IgG HRP抗体(金斯瑞)进行孵育30分钟,在洗涤之后,每孔加入TMB底物,室温显色3分钟,然后用3M HCl终止。
1.3.2实验结果显示(图1~图2),经过6次免疫后两只羊驼效价都维持在较高水平(效价>5×105),达到预期,可满足后续噬菌体库构建需求。图1的A、B分别为A1、A2羊驼不同次免疫后的血清效价。图2的A与B分别展示了A1羊驼和A2羊驼免疫前后血清中IgG亚型变化。
实施例2.VHH噬菌体展示文库构建
2.1RNA提取和VHH扩增
(1)6次免疫结束后,提取骆驼外周血淋巴细胞100mL并提取总RNA。RNA的提取参照TAKARA公司RNAiso试剂说明书进行。
(2)以RNA为模板,oligo dT为引物,参照TAKARA公司反转录酶说明书合成cDNA第一链。
(3)采用PrimeSTAR高保真DNA聚合酶,经巢式PCR获得VHH的编码基因。用巢式PCR扩增VHH的可变区片段:
第一轮PCR:
上游引物1:GTCCTGGCTGCTCTTCTACAAGGC(SEQ ID NO:84)
下游引物1:GGTACGTGCTGTTGAACTGTTCC(SEQ ID NO:85)
扩增重链抗体引导肽和抗体CH2之间的片段,55℃退火,30个循环;回收约600bp的DNA片段,作为第二轮PCR的模板。
第二轮PCR:
上游引物2:GATGTGCAGCTGCAGGAGTCTGGRGGAGG(SEQ ID NO:86)
下游引物2:GGACTAGTGCGGCCGCTGGAGACGGTGACCTGG GT(SEQ ID NO:87)
扩增纳米抗体FR1区和长、短铰链区之间的片段(长片段和短片段),55℃退火,30个循环,回收目的片段,结果显示该片段的大小约为500bp,即纳米抗体基因电泳带约为500bp。
(4)将噬菌粒pME207和PCR扩增产物分别用Sfi I和Not I双酶切(NEB),回收、定量后,以1∶3摩尔比,用T4 DNA连接酶(TaKaRa)连接两个片段,在16℃,过夜连接。
(5)连接产物经乙醇沉淀后,溶于100μL无菌水,分十次进行电穿孔转化大肠杆菌TG1。取100μL电击、培养后的菌液倍比稀释,涂布氨苄青霉素LB培养板,计算库容,其余部分全部涂布于氨苄青霉素2×YT培养板,37℃,倒置培养13~16h。用10mL,2×YT培养基将培养板上的菌苔刮洗后,加入终浓度25%甘油,分装,-80℃保存备用。库容的大小为4.3×109。为检测文库的插入率,随机选取48个克隆做菌落PCR,结果显示插入率已达到90%以上。
(6)根据计算的库容量结果,接种10倍库容量的活细胞于200mL的2×YT(含2%葡萄糖,100μg/mL氨苄青霉素),37℃,200r/min培养至OD600达0.5,按感染复数20∶1加入辅助噬菌体,37℃静置30min后,37℃,200r/min,30min。将培养物离心,用200mL的2×YT(含100μg/mL氨苄青霉素和50μg/mL卡那霉素)重悬沉淀,37℃,250r/min过夜培养后,8000rpm离心取上清,加入5×PEG/NaCl溶液,冰上放置60min,8000rpm离心30min,重悬沉淀于5mL的PBS中,即得到抗BCMA的VHH免疫文库,取10μL测定滴度,其余分装于-80℃保存备用。
实施例3.噬菌体展示淘选
3.1生物淘选
共进行2轮固相panning筛选噬菌体库,以BCMA his tag蛋白为正筛蛋白、人IgG蛋白为负筛蛋白;第一轮BCMA蛋白浓度为4μg/mL,第二轮panning将BCMA蛋白浓度降低到2μg/mL。具体步骤如下:
按4μL/mL的浓度,100μL每孔将人BCMA his tag蛋白包被在酶标板上,4℃放置过夜,同时包被人IgG蛋白负筛孔。第二天5个孔中分别加入200μL,3%BSA,室温封闭2小时。2小时后用PBST(PBS中含有0.05%吐温20)洗3遍。洗板后先在每个负筛孔加入100μL用5%脱脂牛奶预封闭的噬菌体(2~3×1011tfu免疫骆驼纳米抗体噬菌展示基因库),在室温下作用1.5小时,再将负筛后上清转移至目的抗原包被孔中,室温下作用1.5小时。用PBST(PBS中含有0.05%吐温20)洗12遍,以洗掉不结合的噬菌体。用Glycine(SIGMA)将与BCMA his tag特异性结合的噬菌体解离下,洗脱的噬菌体经Tris(Invitrogen,1M,PH 8.0)中和后感染处于对数期的TG1,经扩增,进行下一轮“吸附-洗脱”。最后洗脱下的噬菌体浸染TG1,利用IPTG(Thermo)诱导TG1表达纳米抗体。
3.2克隆筛选
通过ELISA和FACS技术以鉴定靶标抗原特异性克隆(见图3)。以BCMA his包被ELISA板,取上清做ELISA检测。图3所示为BCMA全长蛋白ELISA筛选结果,挑选部分阳性克隆送测序。通过序列分析后,挑选CDR3区域不同的克隆重新诱导,通过FACS检测与过表达人BCMA蛋白的CHO-K1/BCMA细胞株、RPMI8226细胞株的结合,最终筛选出如表1所示的27个与人BCMA靶标抗原特异性克隆。
ELISA方法:使单个输出噬菌体克隆的TG1菌在96孔深孔板中诱导生长过夜,为了鉴定结合至抗原蛋白的克隆,分别用重组人BCMA his tag蛋白和PD-1his对照蛋白在涂覆缓冲剂中4℃下涂覆96孔ELISA微量滴定板过夜,然后用封闭缓冲剂封闭板。在封闭之后,将来自过夜细胞培养物的大约100μL/孔的噬菌体上清液加入板,在室温下孵育1小时。洗涤板四次,并将HRP缀合的抗c-myc抗体加入板中,在室温孵育30分钟。再洗涤板五次,并将底物溶液加入孔以进行显色。测量每个孔在450nm下的吸光度。
FACS方法:取克隆上清液加入到含5×105个CHO-K1/BCMA细胞或RPMI8226细胞的96孔板中,4℃孵育40min;220g离心5min,弃上清,每孔加入200μL预冷的DPBS重悬,再离心弃上清;每孔加入150μL 2.5μg/mL biotin-anti-his抗体(金斯瑞,A00186-100)重悬细胞,4℃孵育40min;用预冷的DPBS洗涤一次后,每孔加入150μL用DPBS按照1:500稀释的PEStreptavidin(Biolegend),重悬细胞,4℃孵育30min。30min后,在4℃以220g,离心5分钟,弃上清液,各孔加入200μL预冷的DPBS洗涤液,用排枪轻轻吹打重悬细胞,220g离心5min,弃上清液,重复洗涤步骤一次。共洗涤2次后,用DPBS重悬,上流式分析仪(Beckman,Cytoflex)检测。
实施例4.优选克隆筛选
4.1优选克隆表达纯化
将筛选到的纳米抗体VHH序列插入到pCDNA3.4-IgG4质粒载体中,构建成VHH-hIgG4形式(图4),通过ExpiCHOTM(Thermo Fisher)表达系统表达。表达一周后收取上清经Protein A(GE)纯化后,然后使用Nanodrop检测蛋白质量,HPLC检测蛋白纯度。如表1所示,所得抗体纯度(缓冲液为pH7.4的PBS)及产量满足后续试验需要。
表1. 27个纯化纳米抗体QC检测结果
实施例5.优选克隆亲和力检测
5.1配体阻断试验
5.1.1经ELISA测定抗BCMA抗体竞争阻断两个配体(APRIL、BAFF)与人BCMA的结合
平板(Corning)用2μg/mL的人BCMA his tag蛋白(Acrobiosystems,BCA-H522y),4℃包被过夜。封闭和洗涤后,每孔加入50μL稀释好的抗体(78μg/mL、19.5μg/mL、4.875μg/mL、1.218μg/mL)和50μL生物素标记的1μg/mL APRIL(Acrobiosystems,APL-H82F5)或1.25μg/mL BAFF(Acrobiosystems,BAF-H82F3)配体,并在37℃下孵育1小时。洗涤3次后,每孔加入100μL 1:2000稀释的HRP标记的链亲和素(Biolegend,405210),37℃孵育30分钟。洗涤后,每孔加入100μL TMB底物(Abcam,ab171524)显色5分钟,并用3M HCl终止反应。使用酶标仪(Tecan,SPARK)读取450nM吸收光值。结果显示所有27个抗BCMA抗体均可竞争两个配体APRIL、BAFF与BCMA的结合,其中部分抗BCMA抗体的实验结果如表2所示。
表2.配体竞争ELISA结果(OD450)
表2中BMK1和Isotype-2的氨基酸序列参见表6。
5.1.2经FACS测定抗BCMA抗体对APRIL配体的竞争阻断活性
在96孔无吸附深孔板中,将纯化抗体、对照抗体用DPBS分别稀释至1000nM,再按照3倍比连续稀释8个浓度点。将biotin-APRIL用DPBS稀释至4μg/mL。向加有5×105个过表达人BCMA的CHO-K1/BCMA细胞的无吸附96孔板孔中分别加入50μL上一步稀释的抗体或DPBS(Blank、Blank-PE管),再加入50μL上一步稀释好的APRIL混合,4℃孵育40min。用预冷的DPBS洗涤一次后,每孔加入150μL用DPBS按照1:500稀释的PE Streptavidin(Biolegend,405210),重悬细胞,4℃孵育30min。30min后,在4℃以220g,离心5分钟,弃上清液,各孔加入200μL预冷的DPBS洗涤液,用排枪轻轻吹打重悬细胞,220g离心5min,弃上清液,重复洗涤步骤一次。共洗涤2次后,用DPBS重悬,上流式分析仪(Beckman,Cytoflex)检测。结果如图5所示,我们的VHH-hIgG4Fc抗体以剂量依赖性方式竞争了配体biotin-APRIL与CHO-K1/BCMA细胞的结合,抗体浓度越高,配体结合信号越弱。通过Graphprism软件进行曲线拟合,计算抗体的IC50,结果见图5中的表格。
5.2同源基因(跨物种)和同源物(跨家族)筛选
5.2.1与食蟹猴BCMA和鼠科BCMA的交叉反应性:
经ELISA测定交叉反应性。平板(Corning)用2μg/mL的食蟹猴BCMA(Acrobiosystems,BCA-C52H7-100ug)和小鼠BCMA(Acrobiosystems,BCA-M52H3)在4℃包被过夜。封闭和洗涤后,将10μg/mL、2μg/mL、0.4μg/mL的抗体分别加入到包被有BCMA抗原的孔板中,并在37℃下孵育1小时。洗涤3次后,每孔加入100μL 1:10000稀释的HRP标记的羊抗人IgG Fc抗体(Bethyl,A80-104P),37℃孵育30分钟。洗涤后,每孔加入100μL TMB底物(Abcam)显色5分钟,并用2M HCl终止反应。使用酶标仪(Tecan,SPARK)读取450nM吸收光值。
跨物种实验的结果显示所有27个抗BCMA抗体与食蟹猴BCMA不结合,但大部分与鼠科BCMA结合(表3)。
5.2.2与人BCMA同源蛋白TACI、BAFFR的交叉反应性:
经ELISA方法测定交叉反应性。平板(Corning)分别将27个待测抗体及BMK对照抗体、anti-TACI antibody(Abcam,ab89744)、anti-BAFFR antibodies(Abcam,ab16232)分别用包被液进行稀释至5μg/mL,100μL/孔加入96孔板条中,4℃孵育过夜。封闭和洗涤后,向包被了不同抗体的板中分别加入100μL 4μg/mL的biotin-TACI(Acrobiosystems,TAI-H82F6-25ug)、biotin-BAFFR(Acrobiosystems,BAR-H5257-100ug)或对照蛋白,并在37℃下孵育1小时。洗涤3次后,每孔加入100μL 1:2000稀释HRP Streptavidin(Biolegend,405210)后,加入到上样孔中,每孔100μL,37℃孵育30分钟。洗涤后,每孔加入100μLTMB底物(Abcma,ab171524)显色5分钟,并用3M HCl终止反应。使用酶标仪(Tecan,SPARK)读取450nM吸收光值。结果显示所有27个抗BCMA抗体与同源蛋白人TACI、BAFFR均无明显交叉反应(表3)。
5.3蛋白水平亲和力检测
通过表面等离子共振技术(SPR)检测VHH-hIgG4抗体与人BCMA his tag蛋白的结合亲和力。过程如下:本实验使用仪器Biacore T200(GE),检测温度25℃,缓冲液1×HBS-EP+(10mM HEPES,150mM NaCl,3mM EDTA and 0.05%v/v Surfactant P20,GE)。在Protein A芯片(GE)通道2、3、4(FC-2,3,4)分别捕获1ug/ml VHH-hIgG4Fc,通道1(FC-1)做空白对照,捕获时间15-20s,流速10ul/min。向FC-1,2,3,4分别注射BCMA-His 0.375,0.75,1.5,3,6,12nM,结合时间180s,流速30ul/min,解离时间300-3000s(具体时间取决于样品)。注射10mMGlycine-HCl pH1.5(GE)30s对芯片表面再生。数据处理采用BIA evaluation Software2.0(GE),传感图双参比扣除,Langmuir 1:1模型拟合计算动力学常数。
结果如表4所示,我们获得多株不同亲和力的抗人BCMA的VHH-hIgG4抗体,KD范围在10-9~10-12之间,Kd在10-2~10-6范围。
表4.不同抗体SPR检测结果
5.4细胞水平亲和力检测:
通过基于细胞的测定法来测定抗BCMA的VHH-hIgG4抗体与靶细胞(过表达人BCMA的稳定CHO细胞系“CHO-K1/BCMA”)的结合亲和力。简而言之,预先将VHH-hIgG4重组抗体以100nM为起始浓度,4倍比例连续8个浓度点。将表达人BCMA全长蛋白的CHO-K1/BCMA细胞铺于96孔板中,每孔5×105细胞,再将梯度稀释的重链抗体(VHH-hIgG4重组抗体)与CHO-K1/BCMA细胞在4℃共孵育40分钟,洗涤后,再加入检测二抗anti-human IgG PE(JacksonImmuno Research,Code:109-117-008)共孵育30分钟,洗涤后使用CytoFLEX流式细胞仪进行检测。通过Graphprism软件进行曲线拟合,计算抗体的EC50。结果如图6所示,EC50范围在0.6~2.8nM之间。
5.5肿瘤细胞结合检测:用梯度稀释的重链抗体分别与不表达BCMA抗原的U-87MG细胞株、过表达BCMA抗原的RPMI8226细胞、Jeko-1细胞、Daudi细胞细胞共孵育,检测抗体为anti-human IgG PE(Jackson Immuno Research,Code:109-117-008,Lot:145501)。通过拟合曲线计算抗体的EC50。结果如图7的A、B、C所示,各抗体与RPMI8226细胞的结合亲和力范围为0.8nM~7nM,各抗体与Jeko-1细胞的结合亲和力范围为8nM~100nM。各抗体与Daudi细胞的结合亲和力范围为1.5~300nM。各抗体与不表达BCMA的U-87MG未显示结合。
实施例6:优选克隆特异性检测:
(1)Membrane Proteome Array筛选:Membrane Proteome Array是由美国Integral molecular公司开发的膜蛋白阵列筛选平台,他们将人的5300种不同膜蛋白通过转染HEK293细胞展示在细胞表面,通过FACS检测抗体在这些蛋白上的结合信号,以此评价待检测抗体的特异性(如图8的A所示)。综合亲和力及与各BCMA过表达细胞系的结合检测结果,我们选取了最具有代表性的4个抗体进行了MPA筛选,结果显示,NB-1抗体除与靶蛋白BCMA蛋白结合外,还与DGCR2蛋白有非特异性结合(如图8的B所示);其余3个抗体包括NB-29、NB-257、NB-367特异性都较好(分别如图8的C、D、E所示),只与靶蛋白BCMA有特异性结合。
(2)组织交叉反应:本试验主要由上海细胞治疗集团下属临床试验检测中心完成。研究目的是应用链霉菌抗生物素蛋白与生物素结合的免疫组织化学染色方法评价几个优选抗体是否与正常人体34种冰冻组织(每种组织均来源于3个不同个体)存在交叉反应(表5)。本试验分为3个供试品组(NB-29抗体-Biotin、NB-257抗体-Biotin、NB-367抗体-Biotin)、重组Anti-BCMA抗体EPRBOB-R1-R1-F1-24(abcam,cat#ab245940)、3个生物标记的BMK抗体(通过CHO细胞表达纯化获得,序列及来源见表6);以及1个NSG602_OLIGO_31阴性同型对照抗体组(序列信息见表6)。
a)供试品组(NB-29抗体)在扁桃体、甲状腺滤泡上皮、肝、十二指肠、胃粘膜、肾小管和集合管等组织染色见阳性。
b)供试品组(NB-257抗体)的正常人体组织未见特异性的阳性染色。
c)供试品组(NB-367抗体)在甲状腺滤泡上皮、肝、十二指肠、肾小管和集合管等组织染色见阳性。
d)阳性对照组除扁桃体组织染色见明显阳性外,与其他正常组织未见特异性的阳性染色。
e)BMK1、BMK3-IgG1与34种人体组织未见阳性结合,BMK2-H4与扁桃体淋巴区生发中心、胃粘膜、十二指肠见阳性。
f)阴性对照组的正常人体组织未见特异性的阳性染色。
表5.组织交叉反应结果汇总表
备注:本试验所使用各种组织均来源于3个不同人体。除血细胞外,这些人体组织均已确认为肌动蛋白阳性染色,证明组织具有活性。
表6.对照抗体及hIgG4 Fc信息
实施例7.抗体可变区序列汇总
7.1抗体CDR区序列汇总如下表7所示
表7.抗BCMA抗体CDR区序列汇总表(IMGT编码规则)
7.2抗体可变区序列汇总如下表8所示:
表8. 27个抗BCMA的VHH抗体氨基酸序列
SEQUENCE LISTING
<110> 浙江纳米抗体技术中心有限公司
<120> 一种靶向BCMA的纳米抗体及其应用
<130> P20016708C
<160> 87
<170> PatentIn version 3.5
<210> 1
<211> 232
<212> PRT
<213> Artificial Sequence
<220>
<223> Human IgG4 FC
<400> 1
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
<210> 2
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-170 CDR1
<400> 2
Glu Phe Ile Phe Ser Ile Ser Ala
1 5
<210> 3
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-53/79/90/102/217/257/352/367 CDR1
<400> 3
Gly Phe Thr Phe Ser Pro Ser Ala
1 5
<210> 4
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-29/36/51/65/71/84/100/122/192/265 CDR1
<400> 4
Gly Phe Thr Phe Ser Ser Ser Ala
1 5
<210> 5
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-222 CDR1
<400> 5
Gly Ser Ile Asp Arg Phe Tyr Ala
1 5
<210> 6
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-34/67/82/216 CDR1
<400> 6
Gly Ser Ile Phe Ser Ile Tyr Ala
1 5
<210> 7
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-27/83 CDR1
<400> 7
Gly Ser Ile Ser Ser Ile Tyr Ala
1 5
<210> 8
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-83 CDR2
<400> 8
Ile Thr Ser Asp Asn Ser Ala
1 5
<210> 9
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-27 CDR2
<400> 9
Ile Thr Ser Gly Gly Asn Thr
1 5
<210> 10
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-222 CDR2
<400> 10
Ile Thr Ser Gly Gly Ser Thr
1 5
<210> 11
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-67 CDR2
<400> 11
Ile Thr Ser Gly Ser Ser Thr
1 5
<210> 12
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-170 CDR2
<400> 12
Ile Thr Thr Asp Gly Asn Ser
1 5
<210> 13
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-90 CDR2
<400> 13
Ile Tyr Gly Asp Gly Asn Ala
1 5
<210> 14
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-79 CDR2
<400> 14
Ile Tyr Gly Asp Gly Arg Ala
1 5
<210> 15
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-352 CDR2
<400> 15
Ile Tyr Gly Asp Gly Arg Pro
1 5
<210> 16
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-367 CDR2
<400> 16
Ile Tyr Gly Glu Gly Ser Thr
1 5
<210> 17
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-1/102 CDR2
<400> 17
Ile Tyr Pro Asp Gly Arg Thr
1 5
<210> 18
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-51 CDR2
<400> 18
Ile Tyr Pro Asp Gly Ser Ala
1 5
<210> 19
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-36/53 CDR2
<400> 19
Ile Tyr Pro Asp Gly Ser Thr
1 5
<210> 20
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-84/100 CDR2
<400> 20
Ile Tyr Pro Asp Gly Thr Ala
1 5
<210> 21
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-71 CDR2
<400> 21
Ile Tyr Pro Asp Gly Thr Pro
1 5
<210> 22
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-257 CDR2
<400> 22
Ile Tyr Ser Asp Gly Arg Ala
1 5
<210> 23
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-29/65/122/192/217/265 CDR2
<400> 23
Ile Tyr Ser Asp Gly Ser Thr
1 5
<210> 24
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-216 CDR2
<400> 24
Val Thr Ser Ala Gly Asn Thr
1 5
<210> 25
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-34 CDR2
<400> 25
Val Thr Ser Glu Gly Gly Thr
1 5
<210> 26
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-82 CDR2
<400> 26
Val Thr Thr Glu Gly Ser Thr
1 5
<210> 27
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-192 CDR3
<400> 27
Ala Ile Gly Ala Pro Asp Pro Phe Asp Tyr Ser Gly Trp Arg Arg His
1 5 10 15
Leu
<210> 28
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-122 CDR3
<400> 28
Ala Ile Gly Ala Pro Asp Pro Phe Asp Tyr Ser Gly Trp Arg Arg Asn
1 5 10 15
Leu
<210> 29
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-65 CDR3
<400> 29
Ala Ile Gly Asp Val Arg Gly Arg Trp Asp Ser Arg Pro Arg His Glu
1 5 10 15
Trp Thr Tyr
<210> 30
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-53 CDR3
<400> 30
Ala Ile Gly Leu Ala Pro Gly Tyr Arg Asp Pro Asn Leu
1 5 10
<210> 31
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-84 CDR3
<400> 31
Ala Ile Gly Arg Trp Tyr Asp Gln Arg Lys Lys Glu Pro Gly Leu
1 5 10 15
<210> 32
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-90 CDR3
<400> 32
Ala Ile Gly Arg Trp Tyr Glu Gly Arg Lys Lys Glu Glu Gly Leu
1 5 10 15
<210> 33
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-29 CDR3
<400> 33
Ala Val Gly Ala Pro Leu Val Tyr Ala Ala Tyr Arg Pro
1 5 10
<210> 34
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-265 CDR3
<400> 34
Ala Val Gly Ala Pro Leu Val Tyr Ala Ser Tyr Arg Pro
1 5 10
<210> 35
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-217 CDR3
<400> 35
Ala Val Gly Ile Val Val Pro Tyr Ser Glu Asp Ala Trp Tyr Ser Thr
1 5 10 15
Leu
<210> 36
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-352 CDR3
<400> 36
Ala Val Gly Leu Trp Tyr Glu Lys Arg Glu Lys Glu Lys Asp Leu
1 5 10 15
<210> 37
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-100 CDR3
<400> 37
Ala Val Gly Arg Trp Tyr Glu Gln Arg Lys Lys Glu Pro Gly Leu
1 5 10 15
<210> 38
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-170 CDR3
<400> 38
Asp Val Ala Pro Trp Gly Tyr His Ala Pro Glu Val Gly Ser
1 5 10
<210> 39
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-79 CDR3
<400> 39
Gly Ile Gly Arg Trp Tyr Asp Gln Arg Glu Lys Glu Lys Asp Leu
1 5 10 15
<210> 40
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-257 CDR3
<400> 40
Gly Ile Gly Arg Trp Tyr Glu Lys Arg Glu Lys Glu Lys Gly Phe
1 5 10 15
<210> 41
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-102 CDR3
<400> 41
Gly Ile Gly Arg Trp Tyr Glu Asn Arg Glu Lys Glu Lys Asp Leu
1 5 10 15
<210> 42
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-367 CDR3
<400> 42
Gly Val Gly Arg Trp Tyr Glu Gly Arg Gln Tyr Glu His Asp Tyr
1 5 10 15
<210> 43
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-222 CDR3
<400> 43
Asn Ala Ala Pro Trp Gly Asp Tyr Thr Ala His Asp Phe Ala Ser
1 5 10 15
<210> 44
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-34 CDR3
<400> 44
Asn Ala Ala Pro Trp Gly Ser Tyr His Pro Gln Ser Asp Ile Phe Ser
1 5 10 15
<210> 45
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-82 CDR3
<400> 45
Asn Ala Ala Pro Trp Gly Ser Tyr His Pro Gln Thr Asp Ile Val Ser
1 5 10 15
<210> 46
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-27 CDR3
<400> 46
Asn Ala Ala Pro Trp Gly Ser Tyr Ser Pro Gly Pro Gly Asp Ile Ala
1 5 10 15
Ser
<210> 47
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-67 CDR3
<400> 47
Asn Pro Ala Pro Trp Gly Asp Tyr Thr Ala Thr Asp Phe His Ser
1 5 10 15
<210> 48
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-216 CDR3
<400> 48
Asn Ser Ala Pro Trp Gly Ser Tyr Ser Pro Gly Pro Ala Asp Val Ser
1 5 10 15
Ser
<210> 49
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-83 CDR3
<400> 49
Asn Val Ala Pro Trp Gly Ser Tyr Ser Pro Gly Pro Ala Asp Ile Ala
1 5 10 15
Ser
<210> 50
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-51 CDR3
<400> 50
Gln Val Gly Arg Tyr Val Ser Gly Val Asp Tyr Gln Pro
1 5 10
<210> 51
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-36 CDR3
<400> 51
Val Ile Gly Arg Arg Gly Tyr Ala Met Gly Asp Arg Arg Leu
1 5 10
<210> 52
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-71 CDR3
<400> 52
Val Val Gly Arg Arg Gly Tyr Ala Met Gly Asp Arg Ala Leu
1 5 10
<210> 53
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-27抗体氨基酸序列
<400> 53
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 Ser Ser Ile Tyr
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Leu Arg Gly Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Gly Asn Thr Phe 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
Ala Ala Pro Trp Gly Ser Tyr Ser Pro Gly Pro Gly Asp Ile Ala Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 54
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-29抗体氨基酸序列
<400> 54
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 Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Asp Gly Ser Thr Tyr 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 Leu Cys Ala
85 90 95
Val Gly Ala Pro Leu Val Tyr Ala Ala Tyr Arg Pro Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 55
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-34抗体氨基酸序列
<400> 55
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 Ile Tyr
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Val Thr Ser Glu Gly Gly Thr Phe Tyr Arg 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 Gln Cys Asn
85 90 95
Ala Ala Pro Trp Gly Ser Tyr His Pro Gln Ser Asp Ile Phe Ser Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 56
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-36抗体氨基酸序列
<400> 56
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 Phe Thr Phe Ser Ser Ser
20 25 30
Ala Met Ser Trp Ala Arg Arg Pro Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Tyr Pro Asp Gly Ser Thr Thr Tyr Ala Asp Ser Met Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Glu Ile Tyr Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Val
85 90 95
Ile Gly Arg Arg Gly Tyr Ala Met Gly Asp Arg Arg Leu Arg Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 57
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-51抗体氨基酸序列
<400> 57
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ala Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Tyr Pro Asp Gly Ser Ala Tyr Tyr Ala Asp Ser Met 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 Asp Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr His Cys Gln
85 90 95
Val Gly Arg Tyr Val Ser Gly Val Asp Tyr Gln Pro Arg Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 58
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-53抗体氨基酸序列
<400> 58
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 Phe Thr Phe Ser Pro Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Asp Gly Ser Thr Leu Tyr Ala Asp Ser Met Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Ser Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ile Gly Leu Ala Pro Gly Tyr Arg Asp Pro Asn Leu Arg Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 59
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-65抗体氨基酸序列
<400> 59
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 Phe Thr Phe Ser Ser Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Glu Leu Glu Trp Val
35 40 45
Ser Ala Ile Tyr Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ile Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Asn Tyr Ile Cys Ala
85 90 95
Ile Gly Asp Val Arg Gly Arg Trp Asp Ser Arg Pro Arg His Glu Trp
100 105 110
Thr Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 60
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-67抗体氨基酸序列
<400> 60
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 Thr Ala Ser Gly Ser Ile Phe Ser Ile Tyr
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Pro Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Ser Ser Thr Phe Tyr Arg 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
Arg Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Pro Ala Pro Trp Gly Asp Tyr Thr Ala Thr Asp Phe His Ser Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 61
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-71抗体氨基酸序列
<400> 61
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 Phe Thr Phe Ser Ser Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Tyr Pro Asp Gly Thr Pro Thr Tyr Ala Asp Ser Met Glu
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val His Leu
65 70 75 80
Gln Ile Asp Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Val
85 90 95
Val Gly Arg Arg Gly Tyr Ala Met Gly Asp Arg Ala Leu Arg Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 62
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-79抗体氨基酸序列
<400> 62
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Pro Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Gly Phe Glu Trp Val
35 40 45
Ser Ser Ile Tyr Gly Asp Gly Arg Ala Tyr Tyr Ala Asp Ser Met Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys His Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Gly
85 90 95
Ile Gly Arg Trp Tyr Asp Gln Arg Glu Lys Glu Lys Asp Leu Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 63
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-82抗体氨基酸序列
<400> 63
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 Ile Tyr
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Pro Arg Glu Leu Val
35 40 45
Ala Ala Val Thr Thr Glu Gly Ser Thr Phe Tyr Arg Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ala Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Gln Cys Asn
85 90 95
Ala Ala Pro Trp Gly Ser Tyr His Pro Gln Thr Asp Ile Val Ser Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 64
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-83抗体氨基酸序列
<400> 64
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 Ser Ser Ile Tyr
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Thr Ser Asp Asn Ser Ala Phe Tyr Arg 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 Asp Ser Leu Lys Val Glu Asp Thr Ala Val Tyr Asp Cys Asn
85 90 95
Val Ala Pro Trp Gly Ser Tyr Ser Pro Gly Pro Ala Asp Ile Ala Ser
100 105 110
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 65
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-84抗体氨基酸序列
<400> 65
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 Phe Thr Phe Ser Ser Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Asp Gly Thr Ala Tyr Tyr Ala Asp Ser Met Lys
50 55 60
Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Arg Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Gln Cys Ala
85 90 95
Ile Gly Arg Trp Tyr Asp Gln Arg Lys Lys Glu Pro Gly Leu Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Ile Ser Ser
115 120
<210> 66
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-90抗体氨基酸序列
<400> 66
Gln 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 Ala Ala Ser Gly Phe Thr Phe Ser Pro Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Gly Asp Gly Asn Ala Tyr Tyr Ser Asp Ser Met 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 Leu Tyr Tyr Cys Ala
85 90 95
Ile Gly Arg Trp Tyr Glu Gly Arg Lys Lys Glu Glu Gly Leu Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ala Ser
115 120
<210> 67
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-100抗体氨基酸序列
<400> 67
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 Phe Thr Phe Ser Ser Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Asp Gly Thr Ala Tyr Tyr Ala Asp Ser Met Lys
50 55 60
Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Arg Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Gln Cys Ala
85 90 95
Val Gly Arg Trp Tyr Glu Gln Arg Lys Lys Glu Pro Gly Leu Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Ile Ser Ser
115 120
<210> 68
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-102抗体氨基酸序列
<400> 68
Gln 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 Ser Gly Phe Thr Phe Ser Pro Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Gly Phe Glu Trp Val
35 40 45
Ser Thr Ile Tyr Pro Asp Gly Arg Thr Tyr Tyr Ser Asp Ser Met 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 His Ser Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Gly
85 90 95
Ile Gly Arg Trp Tyr Glu Asn Arg Glu Lys Glu Lys Asp Leu Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 69
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-122抗体氨基酸序列
<400> 69
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 Phe Thr Phe Ser Ser Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Met Gly Leu Glu Arg Val
35 40 45
Ser Ser Ile Tyr Ser Asp Gly Ser Thr Tyr Tyr Pro Asp Ser Met 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 Ile Cys Ala
85 90 95
Ile Gly Ala Pro Asp Pro Phe Asp Tyr Ser Gly Trp Arg Arg Asn Leu
100 105 110
Leu Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 70
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-170抗体氨基酸序列
<400> 70
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 Glu Phe Ile Phe Ser Ile Ser
20 25 30
Ala Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Val Leu Glu Leu Val
35 40 45
Ser Asp Ile Thr Thr Asp Gly Asn Ser Phe Tyr Ala Asp Ser Met Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr Leu
65 70 75 80
Gln Met Asn Ile Leu Lys Ser Glu Asp Thr Ala Ala Tyr Asp Cys Asp
85 90 95
Val Ala Pro Trp Gly Tyr His Ala Pro Glu Val Gly Ser Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 71
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-192抗体氨基酸序列
<400> 71
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 Phe Thr Phe Ser Ser Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Arg Val
35 40 45
Ser Ser Ile Tyr Ser Asp Gly Ser Thr Tyr Tyr Ser Asp Ser Met 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 Ala
85 90 95
Ile Gly Ala Pro Asp Pro Phe Asp Tyr Ser Gly Trp Arg Arg His Leu
100 105 110
Leu Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 72
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-216抗体氨基酸序列
<400> 72
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Thr Cys Ala Ala Ser Gly Ser Ile Phe Ser Ile Tyr
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Val Thr Ser Ala Gly Asn Thr Phe Tyr Arg Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser 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
Ser Ala Pro Trp Gly Ser Tyr Ser Pro Gly Pro Ala Asp Val Ser Ser
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 73
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-217抗体氨基酸序列
<400> 73
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Thr Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Pro Ser
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Asp Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Asn Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Val Gly Ile Val Val Pro Tyr Ser Glu Asp Ala Trp Tyr Ser Thr Leu
100 105 110
Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 74
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-222抗体氨基酸序列
<400> 74
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 Asp Arg Phe Tyr
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Ser Arg Thr Leu Val
35 40 45
Thr Ala Ile Thr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Met Leu 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
Ala Ala Pro Trp Gly Asp Tyr Thr Ala His Asp Phe Ala Ser Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 75
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-257抗体氨基酸序列
<400> 75
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 Phe Thr Phe Ser Pro Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Gly Phe Glu Trp Val
35 40 45
Ser Ser Ile Tyr Ser Asp Gly Arg Ala Tyr Tyr Ala Asp Thr Met 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 Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Gly
85 90 95
Ile Gly Arg Trp Tyr Glu Lys Arg Glu Lys Glu Lys Gly Phe Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 76
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-265抗体氨基酸序列
<400> 76
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 Ala Ala Ser Gly Phe Thr Phe Ser Ser Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Tyr Ser Asp Gly Ser Thr Tyr 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 Lys Cys Ala
85 90 95
Val Gly Ala Pro Leu Val Tyr Ala Ser Tyr Arg Pro Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 77
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-352抗体氨基酸序列
<400> 77
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 Phe Thr Phe Ser Pro Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Tyr Gly Asp Gly Arg Pro Tyr Tyr Ala Asp Ser Met 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 Leu Tyr Tyr Cys Ala
85 90 95
Val Gly Leu Trp Tyr Glu Lys Arg Glu Lys Glu Lys Asp Leu Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 78
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-367抗体氨基酸序列
<400> 78
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 Phe Thr Phe Ser Pro Ser
20 25 30
Ala Met Ser Trp Ala Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Gly Glu Gly Ser Thr Val Tyr Ala Asp Ser Met Lys
50 55 60
Asp 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 Gly
85 90 95
Val Gly Arg Trp Tyr Glu Gly Arg Gln Tyr Glu His Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 79
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-1 CDR1
<400> 79
Gly Phe Thr Phe Arg Ser Ser Ala
1 5
<210> 80
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-1 CDR3
<400> 80
Gln Val Gly Arg Tyr Val Ser Gly Val Tyr Tyr Gln Pro
1 5 10
<210> 81
<211> 246
<212> PRT
<213> Artificial Sequence
<220>
<223> BMK1
<400> 81
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Lys Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Ser Val Ile
20 25 30
Gly Ala His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Thr Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Ala Ala Ile Tyr Tyr Cys Leu Gln Ser Arg
85 90 95
Ile Phe Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly
100 105 110
Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys
115 120 125
Gly Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly
130 135 140
Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp
145 150 155 160
Tyr Ser Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp
165 170 175
Met Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp
180 185 190
Phe Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala
195 200 205
Tyr Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Ala Arg Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
225 230 235 240
Leu Val Thr Val Ser Ser
245
<210> 82
<211> 243
<212> PRT
<213> Artificial Sequence
<220>
<223> BMK3
<400> 82
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asn Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Thr Tyr Arg Gly His Ser Asp Thr Tyr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Tyr Asp Gly Tyr Asp Val Leu Asp Asn Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser
145 150 155 160
Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Asn Leu His Ser
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Arg Lys Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 83
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> NB-1抗体氨基酸序列
<400> 83
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 Phe Thr Phe Arg Ser Ser
20 25 30
Ala Met Ser Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Asp Ile Tyr Pro Asp Gly Arg Thr Asp Tyr Ala Asp Ser Ile Lys
50 55 60
Gly Arg Phe Thr Met Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Leu Met Asp Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr His Cys Gln
85 90 95
Val Gly Arg Tyr Val Ser Gly Val Tyr Tyr Gln Pro Arg Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 84
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> 上游引物1
<400> 84
gtcctggctg ctcttctaca aggc 24
<210> 85
<211> 23
<212> DNA
<213> Artificial Sequence
<220>
<223> 下游引物1
<400> 85
ggtacgtgct gttgaactgt tcc 23
<210> 86
<211> 29
<212> DNA
<213> Artificial Sequence
<220>
<223> 上游引物2
<400> 86
gatgtgcagc tgcaggagtc tggrggagg 29
<210> 87
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 下游引物2
<400> 87
ggactagtgc ggccgctgga gacggtgacc tgggt 35
Claims (12)
1.一种纳米抗体,其特征在于,其包括含CDR1、CDR2和/或CDR3的重链可变区,并具有识别并结合BCMA的功能,且其中:
所述CDR1选自以下组:
(1)如SEQ ID NO:4的氨基酸序列所示,或在如SEQ ID NO:4所示的氨基酸序列上发生1~3种氨基酸残基的替换、缺失或增加;
(2)如SEQ ID NO:6的氨基酸序列所示,或在如SEQ ID NO:6所示的氨基酸序列上发生1~3种氨基酸残基的替换、缺失或增加;
所述CDR2为如SEQ ID NO:23所示的氨基酸序列,或在如SEQ ID NO:23所示的氨基酸序列发生1~3种氨基酸残基的替换、缺失或增加;
所述CDR3选自如SEQ ID NO:27~52所示的氨基酸序列。
2.如权利要求1所述的纳米抗体,其特征在于,当所述CDR1为在如SEQ ID NO:4所示的氨基酸序列上发生1~3种氨基酸残基的替换时,所述替换选自G1E、T3I、S5R和S6P/I;当所述CDR1为在如SEQ ID NO:6所示的氨基酸序列上发生1~3种氨基酸残基的替换时,所述替换选自F4S/D、S5R和I6F;和/或,当所述CDR2为在如SEQ ID NO:23所示的氨基酸序列发生1~3种氨基酸残基的替换时,所述替换选自I1V、Y2T、S3P/G/T、D4G/E/A、G5S/N、S6R/N/G/T和T7A/P/S;
优选地,所述CDR1选自如SEQ ID NO:2~7所示的氨基酸序列;所述CDR2选自如SEQ IDNO:8~26所示的氨基酸序列;和/或,所述CDR3选自如SEQ ID NO:27~52所示的氨基酸序列。
4.如权利要求1~3任一项所述的纳米抗体,其特征在于,所述重链可变区的氨基酸序列如SEQ ID NO:53~78所示,或与如SEQ ID NO:53~78的氨基酸序列具有至少80%、90%、95%、96%、97%、98%或99%同一性。
5.一种BCMA结合分子,其中,所述BCMA结合分子包含如权利要求1~4任一项所述的纳米抗体;优选地,所述BCMA结合分子为包含一条、两条或多条如权利要求1~4任一项所述的纳米抗体的单价或多价纳米抗体、双特异性抗体、多特异性抗体、重链抗体或其抗原结合片段。
6.如权利要求5所述的BCMA结合分子,其特征在于,所述BCMA结合分子为重链抗体;优选地,所述重链抗体的Fc的氨基酸序列如SEQ ID NO:1所示,或与如SEQ ID NO:1所示的氨基酸序列具有至少80%、90%、95%、96%、97%、98%或99%同一性。
7.一种分离的核酸,其特征在于,所述分离的核酸编码如权利要求1~4任一项所述的纳米抗体、或如权利要求5或6所述的BCMA结合分子。
8.一种重组表达载体,其特征在于,所述重组表达载体包含如权利要求7所述的分离的核酸;优选地,所述重组表达载体的骨架为pCDNA3.4。
9.一种转化体,其特征在于,所述转化体包含如权利要求7所述的分离的核酸,或如权利要求8所述的重组表达载体;优选地,所述转化体的宿主为原核细胞或真核细胞;更优选地,所述真核细胞为CHO细胞。
10.一种组合物,其特征在于,其包括一条、两条或多条如权利要求1~4任一项所述的纳米抗体、权利要求5或6所述的BCMA结合分子、权利要求7所述的分离的核酸、权利要求8所述的重组表达载体或权利要求9所述的转化体;优选地,所述组合物还包括药学上可接受的辅料。
11.一种BCMA检测剂,其特征在于,所述BCMA检测剂包括如权利要求1~4所述的纳米抗体,和/或,如权利要求5或6所述的BCMA结合分子;优选地,所述BCMA检测剂用于流式检测。
12.如权利要求1~4任一项所述的纳米抗体、权利要求5或6所述的BCMA结合分子、权利要求7所述的分离的核酸、权利要求8所述的重组表达载体或权利要求9所述的转化体在制备治疗与BCMA相关疾病的药物中的应用;所述疾病优选为血液恶性肿瘤,更优选为多发性骨髓瘤。
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CN117186229B (zh) * | 2022-12-06 | 2024-03-29 | 成都赛恩吉诺生物科技有限公司 | 具有长cdr3序列的抗人bcma纳米抗体及car-t和应用 |
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