CN114149504B - Baff-r结合分子及其应用 - Google Patents
Baff-r结合分子及其应用 Download PDFInfo
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Abstract
本公开涉及一种BAFF‑R结合分子及其应用,具体的,本公开通过小鼠免疫、细胞融合和抗体筛选技术获得单克隆细胞株B7G10、B12E9,经过抗体纯化鉴定、抗体枝接技术、人源化技术、糖工程改造技术获得具有高亲和力的鼠源抗体、嵌合抗体、人源化抗体和无岩藻糖修饰的抗体分子。
Description
技术领域
本公开属于生物医药技术领域,具体地,本公开涉及一种BAFF-R结合分子及其应用。
背景技术
BAFF属于肿瘤坏死因子(Tumor Necrosis Factor,TNF)配体家族,在B细胞动态平衡、免疫耐受和癌变中发挥重要作用。BAFF可以结合三种不同的TNF受体,即TACI,BCMA和BAFF-R,而BAFF-R是BAFF的主要受体,小鼠体内进行的基因敲除实验也证实,只有敲除BAFF-R能够完全模拟BAFF缺陷表型(Yan,M.,J.R.Brady,B.Chan,W.P.Lee,B.Hsu,S.Harless,M.Cancro,I.S.Grewal,and V.M.Dixit.2001.Identification of a novelreceptor for B lymphocyte stimulator that is mutated in a mouse strain withsevere B cell deficiency.Curr.Biol.11:1547,Schiemann,B.,J.L.Gommerman,K.Vora,T.G.Cachero,S.Shulga-Morskaya,M.Dobles,E.Frew,and M.L.Scott.2001.An essentialrole for BAFF in the normal development of B cells through a BCMA-independentpathway.Science 293:211,Schneider,P.,H.Takatsuka,A.Wilson,F.Mackay,A.Tardivel,S.Lens,T.G.Cachero,D.Finke,F.Beermann,andJ.Tschopp.2001.Maturation of marginal zone and follicular B cells requires Bcell activating factor of the tumor necrosis factor family and is independentof B cell maturation antigen.J.Exp.Med.194:1691)。BAFF/BAFF-R信号途径对正常以及癌变B细胞的存活和生长至关重要。BAFF表达于细胞表面,同时又能从细胞表面释放,变成可溶性形式。
B细胞由骨髓中的造血干细胞发育而来。这一过程的主要步骤现已研究的较为清晰。发生于种系细胞总的重组激活基因RAG1/2依赖的重链(H-chain)D、J基因重排,促使形成了原B细胞(pro-B),在前B细胞早期,又进一步发生V基因重排。功能性重链与过渡性的V-preB/l样多肽配对形成pre-BCR。Pre-BCR关闭等位重链基因的重排,同时启动轻链基因的重排,k和l轻链取代V-preB/l5与重链形成复合物IgM。IgM的形成标志着细胞发育进入幼B细胞(immature B,iB)期,iB细胞迁移进入脾,称移行性B细胞(transitional B)。自此开始,tB细胞通过BAFF-R接收存活信号,并完成第一阶段的B细胞发育:发育为marginal zoneB(MZ B)细胞或滤泡性(follicular)B细胞,并分别在此基础上进一步形成浆细胞或记忆性B细胞(Pieper K,J Allergy Clin Immunol 2013)。BAFF-R早在B细胞在骨髓中发育时就开始表达,而在移行性B细胞阶段进一步提高表达量。Baff-r或Baff小鼠基因敲除研究中,B细胞总量显著降低,B细胞发育在移行性T2期受到明显阻断(Thompson JS,Science 2001;293:2108-11;Sasaki Y,J Immunology2004;173::2245-52)。此外,Hu S等人证实BAFF还可以促进分离培养的T细胞存活,其中CD3+CD4+,CD4+CD25+,CD4+CD154+和CD4+CD69+亚群增加,而CD4+CD62L+CD亚群减少。进一步的研究证实BAFF/BAFF-R通过激活PI3K-Akt信号途径诱导T细胞激活(Hu,S等,BAFF Promotes T Cell Activation Through the BAFF-BAFF-R-PI3K-Akt Signaling Pathway)。
B细胞介导的非霍奇金淋巴瘤(B cell non-Hodgkin lymphoma,B-NHL),各型慢性淋巴细胞白血病(CLL)等通常会异常高表达BAFF,此种异常高表(自分泌或旁分泌)通过激活NF-κB信号转导途径,促进肿瘤细胞存活,免受自发或药物诱导的凋亡。设计药物,拮抗BAFF/BAFF-R途径可能具有特殊的临床治疗价值(Yang,S.et al 2014Role of BAFF/BAFF-R Axis in B-cell non-Hodgkin Lymphoma)。Emily M.McWilliams等报道一种全人抗体VAY-736靶向BAFF-R,阻断BAFF/BAFF-R结合,可以有效抑制该信号途径介导的慢性淋巴肿瘤细胞的存活,更进一步的,该药物与BTK抑制剂药物具有联用的潜力(Anti–BAFF-Rantibody VAY-736demonstrates promising preclinical activity in CLL andenhances effectiveness of ibrutinib.McWILLIAMS et al 12FEBRUARY 2019,VOLUME3,NUMBER 3,Blood Advances)。Qin H等人开发了一种针对BAFF-R的CAR T细胞,可以有效针对对靶向CD19的CAR T产生耐药而复发的B细胞介导的癌变。研究显示原发性急性淋巴细胞白血病ALL经CD19靶向治疗后,会演化为CD19抗原丢失的肿瘤,从而不再被CD19-CAR T细胞识别,但这些肿瘤细胞却带有BAFF-R,故而,BAFF-R-CAR可以有效克服抗原丢失造成的耐药(Qin H.et al.,2019.CAR T Cells Targeting BAFF-R Can Overcome CD19 AntigenLoss in B Cell Malignancies)。我们推断,开发高亲和力并能阻断BAFF/BAFF-R结合的抗体,在B细胞介导的恶性肿瘤治疗领域具有巨大的应用潜力。
发明内容
本发明提供了BAFF-R结合分子。所述结合分子通常是免疫特异性结合BAFF-R的抗体或其抗原结合片段,其包含重链可变区和轻链可变区。
在本发明一个优选的实施方案中,本发明提供一种BAFF-R结合分子其中所述的重链可变区包含分别如SEQ ID NO:38、39、40所示的HCDR1、HCDR2和HCDR3。
在本发明一个优选的实施方案中,本发明提供一种BAFF-R结合分子,其所述的轻链可变区包分别如SEQ ID NO:41、42、43所示的LCDR1、LCDR2和LCDR3。
在本发明一个优选的实施方案中,本发明提供一种BAFF-R结合分子,其中所述的重链可变区包含分别如SEQ ID NO:44、45、46所示的HCDR1、HCDR2和HCDR3。
在本发明一个优选的实施方案中,本发明提供一种BAFF-R结合分子,其所述的轻链可变区包分别如SEQ ID NO:47、48、49所示的LCDR1、LCDR2和LCDR3。
在本发明一个优选的实施方案中,本发明提供一种BAFF-R结合分子,其中所述的重链可变区包含分别如SEQ ID NO:38、39、40所示的HCDR1、HCDR2和HCDR3;和/或,其所述的轻链可变区包分别如SEQ ID NO:41、42、43所示的LCDR1、LCDR2和LCDR3。
在本发明一个优选的实施方案中,本发明提供一种BAFF-R结合分子,其中所述的重链可变区包含分别如SEQ ID NO:44、45、46所示的HCDR1、HCDR2和HCDR3;和/或,其所述的轻链可变区包含分别如SEQ ID NO:47、48、49所示的LCDR1、LCDR2和LCDR3。
在本发明一个优选的实施方案中,根据本发明提供的BAFF-R结合分子,其中所述的结合分子为鼠源抗体或其片段。
在本发明一个优选的实施方案中,根据本发明提供的BAFF-R结合分子,其中所述的结合分子为嵌合抗体或其片段。
在本发明一个优选的实施方案中,根据本发明提供的BAFF-R嵌合抗体或其片段,其中所述的嵌合抗体重链可变区序列为:SEQ ID NO:9或11。
在本发明一个优选的实施方案中,根据本发明提供的BAFF-R嵌合抗体或其片段,其中所述的嵌合抗体轻链可变区序列为:SEQ ID NO:10或12。
在本发明一个优选的实施方案中,根据本发明提供的BAFF-R嵌合抗体或其片段,其进一步包含人IgG1,IgG2,IgG3或IgG4或其变体的重链恒定区,优选包含人IgG1或IgG4重链恒定区,更优选包含人IgG1或其变体的重链恒定区。
在本发明一个优选的实施方案中,根据本发明提供的BAFF-R嵌合抗体或其片段,其进一步包含人κ、λ链或其变体的轻链恒定区,优选包含人κ链或其变体的轻链恒定区。
在本发明一个优选的实施方案中,根据本发明提供的BAFF-R结合分子,其中所述的结合分子为人源化抗体或其片段。
在本发明一个优选的实施方案中,根据本发明提供的BAFF-R人源化抗体或其片段,其中所述人源化抗体重链可变区上的重链FR区序列,来源于人种系重链IGHV3-21。
在本发明一个优选的实施方案中,根据本发明提供的BAFF-R人源化抗体或其片段,其中所述人源化抗体重链可变区序列选自SEQ ID NO:23、24、25、26、31、32、33所示的序列或其变体;
在本发明一个优选的实施方案中,根据本发明提供的BAFF-R人源化抗体或其片段,其进一步包含人IgG1,IgG2,IgG3或IgG4或其变体的重链恒定区,优选包含人IgG1或IgG4重链恒定区,更优选包含人IgG1恒定区。
在本发明一个优选的实施方案中,根据本发明提供的BAFF-R人源化抗体或其片段,其中所述人源化抗体轻链可变区上的FR区序列,来源于人种系轻链IGKV2-30或/和IGKV2-29。
在本发明一个优选的实施方案中,根据本发明提供的BAFF-R人源化抗体或其片段,其中所述人源化抗体轻链可变区序列选自SEQ ID NO:27、28、29、30、34、35、36、37所示的序列或其变体。
在本发明一个优选的实施方案中,根据本发明提供的BAFF-R人源化抗体或其片段,其进一步包含人κ、λ链或其变体的轻链恒定区,优选包含人κ链或其变体的轻链恒定区。
在本发明一个优选的实施方案中,本发明提供的BAFF-R结合分子为抗体或其抗原结合片段,其中所述的抗原结合片段为Fab、Fab’、Fv、sFv、F(ab’)2。
在本发明一个优选的实施方案中,所述本发明提供的BAFF-R结合分子为抗体或其抗原结合片段为糖工程改造。
本发明进一步提供编码如上所述的BAFF-R结合分子的核酸序列或组合。
本发明进一步提供含有如上所述的核苷酸序列或组合的表达载体。
本发明进一步提供如上所述的表达载体转化的宿主细胞。所述宿主细胞包括原核细胞、酵母细胞、昆虫细胞或哺乳动物细胞,优选哺乳动物细胞,更优选为HEK293F细胞、ExpiCHO S细胞或CHO-K1细胞,其中所述CHO-K1细胞优选为FUT8双等位基因敲除的。
本发明同时提供一种药物或药物组合物,其含有如前所述的抗BAFF-R结合分子以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本发明提供一种包含如前所述的抗BAFF-R结合分子,或包含如前所述的药物组合物,或如前所述的核苷酸序列或组合在制备治疗癌症和/或自身免疫性疾病的药物中的用途;
优选地,所述癌症疾病包括非霍奇金淋巴瘤(B-NHL),各型慢性淋巴细胞白血病(CLL)原发性急性淋巴细胞白血病(ALL),多发性骨髓瘤;所述自身免疫性疾病包含:系统性红斑狼疮,特发性肺纤维化,类风湿性关节炎(RA),原发性干燥综合征(PSS),自身免疫性肝炎,多发性硬化症,重症肌无力,IgA肾病,视神经脊髓炎,肉芽肿病合并多血管炎,显微多血管炎,免疫性血小板减少性紫癜,特发性血小板减少性紫癜。
有益效果:
本发明提供的BAFF-R结合分子,其具有不同于MOR6654-hG1(VAY-736)的结合表位,且具有显著高于MOR6654-hG1(VAY-736)的亲和力和体外药效活性。
附图说明:
图1:实施例3ELISA-结合检测鼠源B7G10、B12E9抗体与MOR6654-mG2a抗体结合活性比较
图2:实施例3ELISA-结合检测鼠源B7G10、B12E9抗体与MOR6654-mG2a/hG1抗体阻断活性比较
图3:实施例3FACS-结合检测鼠源B7G10、B12E9抗体与MOR6654-mG2a抗体结合活性比较
图4:实施例3FACS-结合检测鼠源B7G10、B12E9抗体与MOR6654-mG2a抗体阻断活性比较
图5:实施例3ELISA-结合检测鼠源B7G10、B12E9抗体与Mus-BAFFR交叉反应活性比较
图6A:实施例3抗体间竞争结合ELISA试验(一抗孵育时加入生物素标记(biotin-labeled)的B12E9)
图6B:实施例3抗体间竞争结合ELISA试验(一抗孵育时加入生物素标记(biotin-labeled)的B7G10)
图7:实施例5ELISA检测-B7G10-CHI、B12E9-CHI与MOR6654-hG1的抗体结合活性比较
图8:实施例5ELISA检测B7G10-CHI、B12E9-CHI与MOR6654-hG1的抗体阻断活性比较
图9:实施例5FACS检测B7G10-CHI、B12E9-CHI与MOR6654-hG1的抗体结合活性比较
图10A:实施例7B-7G10人源化抗体结合活性测评
图10B:实施例7B-12E9人源化抗体结合活性测评
图11A:实施例7B-7G10人源化抗体阻断活性测评
图11B:实施例7B-12E9人源化抗体阻断活性测评
图12:实施例8基于PBMC的ADCC活性方法筛选B7G10CHI
图13:实施例8报告基因法测定ADCC活性筛选B7G10CHI
图14:实施例8报告基因法测定ADCC活性筛选Hu7G10分子
图15:实施例8报告基因法测定Hu7G10-22AF的ADCC活性
图16:实施例8报告基因法测定Hu7G10-22AF与Hu7G10-22不同比例混合后的ADCC活性
具体实施方式
1、术语说明
本发明中,所述CDR为互补决定区(complementarity-determining region);所述ScFv为单链抗体(single-chain fragment variable);所述HEK293F细胞为人胚肾293F细胞(human embryonic kidney 293Fcell);CHO细胞为中国仓鼠卵巢细胞(chinese hamsterovary cell);ExpiCHO S细胞(Thermo Fisher)为悬浮生长的CHO细胞;CHO-K1为贴壁生长的CHO细胞。
本发明中的“抗原结合片段”一词,指由含有一个或多个CDR的抗体片段或者任何其他结合抗原但不具有完整天然抗体结构的抗体的片段所形成的一种抗体片段。在某些实施方式中,本申请所述的抗体是抗原结合片段。
抗体的“Fab”片段是指抗体的单价抗原结合片段,其由一条轻链(包括可变区和恒定区)和一条重链的可变区和第一恒定区经二硫键结合组成。Fab可以通过在抗体铰链区的重链之间近二硫键N-末端的残基处经由木瓜蛋白酶消化来获得。
“F(ab)2”是指Fab的二聚体,其包含两条轻链和两条重链的一部分。
抗体的“Fv”段指的是含有完整抗原结合位点的最小抗体片段。Fv片段由一条轻链的可变区结合至一条重链的可变区组成。
“scFv”是指由轻链可变区与重链可变区直接相连或通过一个多肽连接子序列连接而成的工程化抗体。
2、实施例
实施例1 BAFF-R、BAFF和对照抗体的制备(可简化)
1.1真核表达载体构建、表达与纯化
依据公开的BAFF-R(Uniprot:Q96RJ3)序列,截取其胞外区(extracellulardomain,ECD),SEQ ID NO:1,反向翻译成编码DNA序列,SEQ ID NO:2-4,采用重合PCR的方法,进行基因合成,并构建到pHr表达载体上,通过设计,使表达的BAFF-R-ECD蛋白带有不同的标签(tag),分别为BAFF-R-ECD-Hisx6、BAFF-R-ECD-mFc和BAFF-R-ECD-hFc,BAFF-R-ECD的C-端连接Hisx6、mFc或者hFc标签,便于纯化和检测。其中Hisx6代表连续的6个组氨酸肽段,mFc为mouse IgG2a的Fc区段,hFc为人IgG1的Fc区段。同样的方式,截取BAFF胞外区/可溶性片段,进行克隆、构建,序列如SEQ ID NO:5、6。
1.1.1BAFF/-R-ECD-mFc/-hFc蛋白表达与纯化
按照制造商所述,使用ExpiFectamine CHO转染试剂盒(Gibco)将编码BAFF-R胞外区蛋白的pHr-BAFF-R-ECD-mFc或者pHr-BAFF-R-ECD-hFc质粒DNA瞬时转染到ExpiCHO S细胞(Thermo Fisher)中,ExpiCHO-S表达培养基培养10天,收集细胞上清,用于蛋白纯化。CHO细胞上清,离心6,000×g,10min,用0.45μm滤膜抽滤后备用。Hitrap MabSelectSuReProtein A预装柱(GE,#11-0034-93-GEC),用10倍体积buffer1#(PBS,pH7.4)平衡。采用AKTA仪器上样,流速为1ml/min。buffer1#清洗,约30ml,直到A280值稳定。保持速率不变,用buffer3#(100mM甘氨酸,150mM NaCl,pH3.0)洗脱结合在柱中的蛋白,收集A280值在30以上的峰值。收集试管中加入15μL/ml中和缓冲液(1M Tris-HCl,pH9.0),使所得抗体液的PH值保持中性(pH=7.0-8.0)。采用10KD超滤管对洗脱液进行缓冲液置换与浓缩,缓冲液更换为PBS,Nanodrop检测蛋白浓度与SDS-PAGE检测蛋白纯度。
Nanodrop检测洗脱的BAFF-R-ECD-mFc/Fc蛋白溶液在波长280nm的光吸收,所得数值除以理论吸光系数,估算其浓度。SDS-PAGE非还原电泳,并以考马斯亮蓝染色,检测蛋白纯度,大于95%。
1.1.2BAFF-R-ECD-HIS蛋白表达与纯化
按照制造商所述,使用K293转染试剂盒(珠海恺瑞生物科技有限公司)将编码BAFF-R-ECD蛋白的pHr-BAFF-R-ECD–Hisx6质粒DNA瞬时转染到K293 F细胞(珠海恺瑞生物科技有限公司)中,K293表达培养基培养7天,收集细胞上清,用于蛋白纯化。
收集培养7天的293细胞上清,离心6,000×g,10min,用0.45μm滤膜抽滤后备用。用10倍柱床体积的去离子水清洗HIS-excel预装柱(GE,17-3712-05),用10倍柱床体积PBS缓冲液平衡柱子。采用AKTA仪器,以1mL/min流速上样。50mLPBS-10咪唑清洗杂蛋白,PBS-500咪唑缓冲液洗脱目的蛋白。采用10KD超滤管对洗脱液进行缓冲液置换与浓缩,缓冲液更换为PBS。粗纯得到的蛋白再次经DEAE层析,得到纯品,用SDS-PAGE进行电泳和考马斯亮蓝染色,判定其纯度为80%。
1.2对照抗体MOR6654-mG2a与MOR6654-hG1真核表达载体构建、表达与纯化
在一些实施例中,使用了针对BAFF-R的比较抗体(MOR6654-mG2a、MOR6654-hG1),引用专利抗BAFFR抗体制剂MOR6654(专利申请公布号:CN 104363920 A),其VH和VL序列被克隆到pHr-hG1/pHr-hkappa和pHr-mG2a/pHr-mkappa表达载体中。以Protein A亲和层析的方法进行一步纯化,获得纯度大于95%的样品。
实施例2动物免疫和抗体筛选
2.1小鼠免疫
选用6-8周龄SJL雌鼠(Jackson Lab),一般20克左右,健康无病。第一次免疫时采用弗氏完全佐剂,BAFF-R-ECD-hFc免疫抗原与免疫佐剂比例为1:1,在免疫前只需将抗原和佐剂轻柔混合即可,采用腹部皮下多点注射方式,50μg/只。间隔两周后加强免疫,采用弗氏不完全佐剂,30μg/只。总共进行3次加强免疫。最后一次加强免疫10天后眼眶内眦静脉窦采血进行ELISA检测抗体效价。随即进行冲刺免疫,此时不加佐剂只用抗原进行腹腔免疫,50μg/只,冲刺免疫3天后进行细胞融合。
2.2 ELISA法检测抗体效价
以BAFF-R-ECD-Hisx6包被ELISA板孔,浓度为2μg/mL,50μl/孔。封闭后,每孔加50μl梯度稀释的待检小鼠血清,同时设立阴性对照孔(未免疫小鼠血清),37℃孵育1h;漂洗后加anti-mouse-IgG-HRP酶标二抗,每孔50μl,37℃孵育1h;洗涤后加底物液TMB 50μl,37℃显色2~15min,50μl 2mol/L H2SO4终止反应,酶标仪读取OD450值。根据实验结果,抗体效价达到10的4次方以上,可进行细胞融合。
表1小鼠效价检测结果
稀释倍数 | 200 | 400 | 800 | 1600 | 3200 | 6400 | 12800 | 25600 | 51200 | 102400 | 空白 | 阴性 |
B-h-1 | 1.644 | 1.572 | 1.576 | 1.624 | 1.52 | 1.428 | 1.424 | 1.231 | 0.952 | 0.707 | 0.06 | 0.059 |
B-h-3 | 1.691 | 1.573 | 1.593 | 1.639 | 1.593 | 1.396 | 1.326 | 1.263 | 0.912 | 0.715 | 0.077 | 0.069 |
B-h-4 | 1.61 | 1.555 | 1.545 | 1.508 | 1.498 | 1.329 | 1.229 | 1.077 | 0.73 | 0.518 | 0.062 | 0.067 |
B-h-5 | 1.646 | 1.653 | 1.55 | 1.538 | 1.54 | 1.429 | 1.285 | 1.136 | 0.82 | 0.566 | 0.056 | 0.064 |
2.3细胞融合与阳性杂交瘤细胞初次筛选、克隆化细胞融合
将对数生长期的SP2/0髓瘤细胞用弯头滴管将细胞从瓶壁瘤轻轻吹下,1640培养基洗涤二次,然后将细胞重悬浮于10ml 1640培养基,混匀,用血球计数板计数。将小鼠拉颈处死,解剖,取脾研磨,收集脾脏细胞,计数。脾细胞与骨髓瘤细胞SP2/0-Ag14按照比例为5:1-2:1进行混合,采用PEG1450(Sigma)进行细胞融合,加入400ml HAT培养基(1640培养基,20%血清,双抗5ml,HAT贮存液5ml,定容至500ml),分装至20块96孔板,37℃,5%CO2培养箱内培养7天,然后取细胞上清进行抗体筛选检测。
2.4酶联免疫吸附试验(ELISA)筛选阳性杂交瘤孔
包被BAFF-ECD-hFc抗原,浓度为2μg/mL,每孔加50μl按照1:1混合的待检杂交瘤细胞培养上清和BAFF-R-ECD-mFc(2μg/ml)的阻断检测混合反应液,同时设立阴性对照孔(PBS+1%BSA)、阳性对照孔(MOR6654-mG2a,浓度为20μg/mL)37℃孵育1h;洗涤后加anti-mouse-IgG-HRP酶标二抗,50μl/孔,37℃孵育1h;洗涤后加显色液TMB 50μl,37℃显色2~15min,50μl/孔2mol/LH2SO4终止反应,酶标仪读取OD450值。
包被BAFF-R-ECD-hFc抗原,浓度为2μg/mL,每孔加50μl待检杂交瘤细胞培养上清,同时设立阴性对照孔(PBST+1%BSA)、阳性对照孔(MOR6654-mG2a,浓度为20μg/mL)37℃孵育1h;洗涤后加anti-mouse-IgG-HRP酶标二抗,每孔50μl,37℃孵育1h;洗涤后加显色液TMB50μl,37℃显色2~15min,50μl/孔2mol/L H2SO4终止反应,酶标仪读取OD450值。
筛得杂交瘤上清高于阳性抗体株且阻断效率较高的抗体株2个:B7G10、B12E9。
采用有限稀释法方法对B7G10、B12E9两株杂交瘤细胞进行亚克隆,经过酶联免疫吸附试验(ELISA)筛选获得单克隆细胞株B7G10、B12E9。
2.5鼠源单抗生产、纯化与鉴定
取扩大培养并计数的B7G10-C2、B7G10-D2、B12E9-B2、B12E9-B5,细胞数量为5×106,转入T75瓶,每瓶放入20ml培养基(CD Hybridoma+1%P/S+8mM L-Glu),密度为2.5×105个/mL,37℃、5%CO2培养5天,即可收集细胞上清用于抗体纯化。采用MabSelect SuRe(GE,#11-0034-93-GEC)Protein A预装柱,对鼠单抗B7G10、B12E9进行亲和纯化,经SDS-PAGE和考马斯亮蓝染色检测,确定纯度大于95%,用Nanodrop仪器进行光吸收并进行浓度计算,标记后冻存于-80℃冰箱。
实施例3鼠源B7G10、B12E9单抗生化活性的测定
通过ELISA-结合、阻断与FACS-结合、阻断实验比较鼠源B7G10、B12E9抗体(B7G10-C2、B7G10-D2、B12E9-B2、B12E9-B5)与MOR6654-mG2a抗体活性。
3.1ELISA-结合活性分析
BAFFR-hFc包被液稀释到2μg/mL,按50μL/孔,加入酶标板孔中,进行孵育,然后每孔加200μL封闭液(5%脱脂牛奶),放置于4℃过夜。次日以PBST(PBS,0.05%吐温20)洗涤液200μl/孔洗5次。次之,进行抗原抗体反应,即加入50μL的B7G10-C2、B7G10-D2、B12E9-B2、B12E9-B5与MOR6654-mG2a等,每种测试品最大浓度为20μg/mL,以5倍比例做梯度稀释,同时设置空白对照;37℃孵育60min。反应结束后,漂洗板孔,加入Goat-anti-mouse-IgG-Fc-Secondary-Antibody(1:10000稀释,Jackson Immun)的第二抗体,孵育;二抗反应结束后,再次漂洗孔板,然后加显色液,孵育15min后读取光吸收OD450值。B7G10-C2的EC50=12.74,B7G10-D2的EC50=13.97,B12E9-B2的EC50=5.358,B12E9-B5的EC50=8.811,MOR6654-mG2a的EC50=3.837(单位均为ng/mL)。
结果如图1所示,在ELISA结合水平,B7G10、B12E9结合活性高于阳性参照MOR6654-mG2a。
3.2ELISA-阻断活性分析
BAFF-ECD-hFc包被液稀释到2μg/mL,进行包被。包被50μL/孔量加入酶标板孔中,37℃孵育2小时。弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加200μL封闭液4℃过夜。弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加入25μLBAFF-R-ECD-mFc(4μg/mL)以及25μLB7G10-C2、B7G10-D2、B12E9-B2、B12E9-B5或MOR6654-mG2a、MOR6654-hG1浓度为首孔20μg/mL,依次5倍稀释,7种不同浓度,同时设置空白对照;37℃预孵育30min,转板,37℃孵育120min;弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加入50μL的Goat-anti-Mouse-IgG-Fc-Secondary-Antibody(1:10000稀释)的第二抗体,37℃孵育60min;弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。加显色液50μL/孔,37℃孵育15min。加入50μL/孔2mol/L H2SO4终止反应,在酶标仪上读取OD450值。结果如图2所示,在ELISA-阻断水平,B7G10、B12E9阻断活性高于阳性参照MOR6654-mG2a、MOR6654-hG1。
3.3FACS-结合活性比较
Raji细胞计数,每孔加入3E5细胞,PBS洗两次;孔内加入B7G10-C2、B7G10-D2、B12E9-B2、B12E9-B5或MOR6654-mG2a浓度为首孔20μg/mL,依次5倍稀释,7个梯度的抗体,同时设置空白对照;4℃孵育30min;1000rpm离心2min,弃去孔内的液体,PBS洗液,200μl/孔洗2次。每孔加入50μL的PE-anti-Mouse-IgG-Fc-Secondary-Antibody(1:200稀释)的第二抗体,4℃孵育30min;1000rpm离心2min,弃去孔内的液体,PBS洗液,200μl孔洗2次,1000rpm离心2min;加入200μL/孔PBS液,重悬细胞,流式细胞仪读数。结果如图3所示,在FACS-结合水平,B7G10、B12E9结合活性高于阳性参照MOR6654-mG2a。
3.4FACS阻断活性比较
Raji细胞计数,每孔加入3E5细胞,PBS洗两次;孔内加入25μLBAFF-ECD-hFc(浓度为20μg/mL)+25μL的B7G10-C2、B12E9-B5或MOR6654-mG2a浓度为20μg/mL,5倍稀释,7个梯度的抗体,同时设置空白对照;4℃孵育30min;1000rpm离心2min,弃去孔内的液体,PBS洗液,200μl/次洗2次。每孔加入50μLPE标记anti-Human-IgG-Fc(1:200稀释)的第二抗体,4℃孵育30min;1000rpm离心2min,弃去孔内的液体,PBS洗液,200μl/次洗2次,1000rpm离心2min;加入200μL/孔PBS液,重悬细胞,流式细胞仪读数。结果如图4所示:在FACS-阻断水平,B7G10-C2、B12E9-B5阻断活性相当于阳性参照MOR6654-mG2a,且其阻断活性随剂量增加逐渐增高,使用剂量可控性提高。
3.5交叉反应
Mus-BAFFR包被液稀释到1μg/mL,包被50μL/孔量加入酶标板孔中,37℃孵育2小时。弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加200μL封闭液4℃过夜。弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加入50μL的B7G10-C2、B7G10-D2、B12E9-B2、B12E9-B5浓度为20μg/mL,5倍稀释,7个梯度的抗体,37℃孵育60min;弃去孔内的液体,用洗板机,洗涤液200μl孔洗5次。每孔加入50μL的Goat-anti-mouse-IgG-Fc-Secondary-Antibody(1:10000稀释)的第二抗体,37℃孵育60min;弃去孔内的液体,用洗板机,洗涤液200μl/次洗5次。加显色液50μL/孔,37℃孵育15min。加入50μL/孔2mol/L H2SO4终止反应,在酶标仪上读取OD450值。结果如图5所示:B-12E9-B2、B-12E9-B5与Mus存在交叉反应;
B-7G10-C2、B-7G10-D2与Mus无交叉反应。
3.6抗体间的竞争结合
为了探究B7G10、B12E9和参考抗体的结合表位是否一致,我们进行了抗体间的竞争结合ELISA实验(competition assay)。抗原包被、抗体结合以及二抗检测均与正常的一致,除了在一抗孵育时加入了100ng的生物素标记(biotin-labeled)的B7G10或B12E9。结果如图6A和图6B所示:MOR6654-mG2a不与B7G10或B12E9抗体竞争结合BAFF-R,而B7G10和B12E9可以互相竞争结合BAFF-R。这表明,B7G10和B12E9结合BAFF-R-ECD分子上的相同或相近表位,但与参考抗体的结合表位不同。
实施例4B7G10、B12E9抗体可变区的测序及B7G10-CHI、B12E9-CHI嵌合抗体构建
收集5×106B7G10、B12E9杂交瘤细胞,PBS清洗2次,按照RNAprep Pure培养细胞/细菌总RNA提取试剂盒(天根,DP430)进行RNA提取。采用Nanodrop进行定量。按照HighCapacity RNA-to-cDNAKit(Thermo fisher,4387406)说明书进行反转录。参考Dubel,S.的方法设计引物,并以PCR扩增B7G10、B12E9-F11细胞系H、K链可变区,PCR产物直接测序(Dubel,S.Isolation of IgG antibody Fv-DNA from various mouse and rathybridoma cell lines using the polymerase chain reaction with a simple set ofprimers.Journal of Immunological Methods 175(1):89-95,1994)。Sanger测序法得到的DNA序列于IMGT-V quest数据库进行比对分析(Brochet,X.et al.,Nucl.Acids Res.36,W503-508(2008).PMID:18503082.),证实B7G10进行亚克隆得到的两个单克隆株B7G10-C2和D2为单一序列,其DNA序列如SEQ ID 7和SEQ ID 8,经比对翻译,其氨基酸序列应为SEQID 9和SEQ ID 10;类似的,B12E9的两种单克隆株也是相同序列,其重链和轻链可变区DNA序列为SEQ ID 11和SEQ ID 12,比对翻译后的氨基酸序列为SEQ ID 13和SEQ ID 14。通过将B7G10和B12E9的轻重链V区氨基酸序列嫁接到到人κ和G1的恒定区,序列如SEQ ID 15、SEQ ID 16、SEQ ID 17和SEQ ID 18所示。氨基酸序列进行反向翻译为DNA后进行基因合成,序列如SEQ ID 19、SEQ ID 20、SEQ ID 21和SEQ ID 22所示。进一步以基因工程技术构建到pHr载体上,进行瞬时转染ExpiCHO S细胞(Thermo Fisher)表达系统进行蛋白表达,获得嵌合抗体B7G10-CHI和B12E9-CHI。表达的嵌合抗体采用Hitrap MabSelect SuRe层析柱进行亲和层析,获得纯化的抗体,纯度大于95%。
实施例5B7G10-CHI、B12E9-CHI嵌合抗体活性评价
通过ELISA-结合、ELISA-阻断与FACS-结合试验检测抗体B7G10-CHI、B12E9-CHI抗体与抗原BAFFR的亲和力,来比较B7G10-CHI、B12E9-CHI抗体与MOR6654-hG1抗体活性。
5.1ELISA-结合活性比较
BAFFR-mFc包被液稀释到2μg/mL,包被50μL/孔量加入酶标板孔中,37℃孵育2小时。弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加200μL封闭液4℃过夜。弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加入50μL的B7G10、B12E9-CHI或MOR6654-hG1浓度为20μg/mL,5倍稀释,7个梯度的抗体,同时设置空白对照;37℃孵育60min;弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加入50μL的Goat-anti-human-IgG-Fc-Secondary-Antibody(1:10000稀释)的第二抗体,37℃孵育60min;弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。加显色液50μL/孔,37℃孵育15min。加入50μL/孔2mol/L H2SO4终止反应,在酶标仪上读取OD450值。结果如图7所示:在ELISA-结合水平,B7G10-CHI、B12E9-CHI结合活性高于阳性参照MOR6654-hG1。
5.2ELISA-阻断活性比较
BAFF-hFc包被液稀释到2μg/mL,包被50μL/孔量加入酶标板孔中,37℃孵育2小时。弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加200μL封闭液4℃过夜。弃去孔内的液体,用洗板机,洗涤液200μl//孔洗5次。每孔加入25μLBAFFR-mFc(4μg/mL)+25μL的7G10-CHI、12E9-CHI或MOR6654-hG1浓度为首孔20μg/mL,依次5倍稀释,7个梯度的抗体,同时设置空白对照;37℃孵育120min;弃去孔内的液体,用洗板机,洗涤液200μl/次,洗5次。每孔加入50μL的Goat-anti-Mouse-IgG-Fc-Secondary-Antibody(1:10000稀释)的第二抗体,37℃孵育60min;弃去孔内的液体,用洗板机,洗涤液200μl/次,洗5次。加显色液50μL/孔,37℃孵育15min,加入50μL/孔2mol/L H2SO4终止反应,在酶标仪上读取OD450值。结果如图8所示:在ELISA-结合水平,B7G10-CHI、B12E9-CHI阻断活性高于阳性参照MOR6654-hG1。
5.3FACS结合活性比较
Raji细胞计数,每孔加入3E5细胞,PBS洗两次;孔内加入B7G10-CHI、B12E9-CHI或MOR6654-hG1浓度为20μg/mL,5倍稀释,7个梯度的抗体,同时设置空白对照;4℃孵育30min;1000rpm离心2min,弃去孔内的液体,PBS洗液,200μl/孔洗2次。每孔加入50μL的PE-anti-Mouse-IgG-Fc-Secondary-Antibody(1:200稀释)的第二抗体,4℃孵育30min;1000rpm离心2min,弃去孔内的液体,PBS洗液,200μl/孔洗2次,1000rpm离心2min;加入200μL/孔PBS液,重悬细胞,流式细胞仪读数。结果如图9所示:在FACS-结合水平,B7G10-CHI、B12E9-CHI结合活性高于阳性参照MOR6654-hG1。
实施例6B7G10、B12E9人源化抗体表达载体构建、纯化
收集5×106B7G10、B12E9杂交瘤细胞,PBS清洗2次,按照RNAprep Pure培养细胞/细菌总RNA提取试剂盒(天根,DP430)进行RNA提取。采用Nanodrop进行定量。按照HighCapacity RNA-to-cDNA Kit(Thermo fisher,4387406)说明书进行反转录,PCR扩增B7G10、B12E9细胞系H、K链可变区,测序。通过限制性内切酶连接到真核表达载体PHR-X-K和PHR-X-G中,采用expiCHO S细胞(Thermo Fisher)表达系统进行蛋白表达,采用Hitrap MabSelectSuRe层析柱用于蛋白纯化。
Nanodrop检测Hu-7G10-02蛋白浓度为0.8811mg/ml,12%SDS-PAGE检测蛋白纯度,纯度大于95%;Nanodrop检测Hu-7G10-22蛋白浓度为1.2911mg/ml,12%SDS-PAGE检测蛋白纯度,纯度大于95%;Nanodrop检测Hu-7G10-32蛋白浓度为1.1859mg/ml,12%SDS-PAGE检测蛋白纯度,纯度大于95%;Nanodrop检测Hu-7G10-42蛋白浓度为1.7346mg/ml,12%SDS-PAGE检测蛋白纯度,纯度大于95%;Nanodrop检测Hu-7G10-42蛋白浓度为0.6432mg/ml,12%SDS-PAGE检测蛋白纯度,纯度大于95%。
Nanodrop检测Hu-12E9-04蛋白浓度为1.1189mg/ml,12%SDS-PAGE检测蛋白纯度,纯度大于95%;Nanodrop检测Hu-12E9-20蛋白浓度为1.5504mg/ml,12%SDS-PAGE检测蛋白纯度,纯度大于95%;Nanodrop检测Hu-12E9-22蛋白浓度为1.4660mg/ml,12%SDS-PAGE检测蛋白纯度,纯度大于95%;Nanodrop检测Hu-12E9-23蛋白浓度为1.5578mg/ml,12%SDS-PAGE检测蛋白纯度,纯度大于95%;Nanodrop检测Hu-12E9-24蛋白浓度为1.6026mg/ml,12%SDS-PAGE检测蛋白纯度,纯度大于95%;Nanodrop检测Hu-12E9-30蛋白浓度为1.4539mg/ml,12%SDS-PAGE检测蛋白纯度,纯度大于95%;Nanodrop检测Hu-12E9-32蛋白浓度为1.1169mg/ml,12%SDS-PAGE检测蛋白纯度,纯度大于95%;Nanodrop检测Hu-12E9-33蛋白浓度为0.9420mg/ml,12%SDS-PAGE检测蛋白纯度,纯度大于95%Nanodrop检测Hu-12E9-34蛋白浓度为1.3293mg/ml,12%SDS-PAGE检测蛋白纯度,纯度大于95%。
实施例7B7G10、B12E9人源化改造和筛选
采用同源序列建模-抗体互补结构区(complementary determining region,CDRs)移植-框架区(framework region,FR)关键氨基酸回突变(back mutation)技术对鼠源抗体B7G10和B12E9分别进行人源化设计。首先通过序列比对,在已知数据库中发现与B7G10和B12E9轻重链最为相似的抗体种系序列(germline sequence),如表2所示。
表2
将鼠源抗体的轻重链基因分别移植到序列同源度最高的人抗体种系序列,然后在PDB数据库中搜索结构最为相似的已知抗体,并进行结构建模分析,找到FR区关键氨基酸,这些关键氨基酸参与轻重链相互作用,影响结构稳定性,进而影响抗原结合,故需与母本(鼠源)抗体的FR相应位置保持一致,仔细挑选氨基酸位点回突变为母本氨基酸残基。回突变位点越多,人源化程度便会相应的降低,因此有必要测试不同程度回突变序列抗体的活性,挑选活性最好,同时回突变位点最少的抗体作为优选。通过CDR移植和结构建模确定了回突变位点,备选的抗体轻重链序列如下表3所示。
表3:备选的抗体轻重链序列
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备选的轻重链可变区序列分别进行反向翻译成DNA序列,重链与人IgG1恒定区、轻链与人κ恒定区编码序列接续在一起,然后进行基因合成,完整的抗体轻重链编码基因构建到pHr载体。然后瞬时转染ExpiCHO细胞进行抗体表达,其中,转染时,不同的轻重链备选序列两两配对共同导入表达细胞,如下表4A,B所示。
表4A:B7G10人源化抗体组合及编号
VH0 | VH1 | VH2 | VH3 | VH4 | |
VL0 | Hu-7G10-00 | Hu-7G10-10 | Hu-7G10-20 | Hu-7G10-30 | Hu-7G10-40 |
VL1 | Hu-7G10-01 | 7G10-CHI | Hu-7G10-21 | Hu-7G10-31 | Hu-7G10-41 |
VL2 | Hu-7G10-02 | Hu-7G10-12 | Hu-7G10-22 | Hu-7G10-32 | Hu-7G10-42 |
VL3 | Hu-7G10-03 | Hu-7G10-13 | Hu-7G10-23 | Hu-7G10-33 | Hu-7G10-43 |
VL4 | Hu-7G10-04 | Hu-7G10-14 | Hu-7G10-24 | Hu-7G10-34 | Hu-7G10-44 |
表4B:B12E9人源化抗体组合及编号
VH0 | VH1 | VH2 | VH3 | |
VL0 | Hu-12E9-00 | Hu-12E9-10 | Hu-12E9-20 | Hu-12E9-30 |
VL1 | Hu-12E9-01 | 12E9-CHI | Hu-12E9-21 | Hu-12E9-31 |
VL2 | Hu-12E9-02 | Hu-12E9-12 | Hu-12E9-22 | Hu-12E9-32 |
VL3 | Hu-12E9-03 | Hu-12E9-13 | Hu-12E9-23 | Hu-12E9-33 |
VL4 | Hu-12E9-04 | Hu-12E9-14 | Hu-12E9-24 | Hu-12E9-34 |
7.1ELISA-结合活性测评
7.1.1 7G10人源化抗体结合活性测评(ELISA)
BAFFR-mFc包被液稀释到2μg/mL,包被50μL/孔量加入酶标板孔中,37℃孵育2小时。弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加200μL封闭液4℃过夜。弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加入50μL的Hu-7G10-02、Hu-7G10-22、Hu-7G10-32、Hu-7G10-42、Hu-7G10-44、或7G10-CHI浓度为首孔20μg/mL,5倍稀释,7个梯度的抗体,同时设置空白对照;37℃孵育60min;弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加入50μL的Goat-anti-human-IgG-Fc-Secondary-Antibody(1:10000稀释)的第二抗体,37℃孵育60min;弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。加显色液50μL/孔,37℃孵育15min。加入50μL/孔2mol/L H2SO4终止反应,在酶标仪上读取OD450值。结果如图10A所示。
7.1.2 12E9人源化抗体结合活性测评(ELISA)
BAFFR-mFc包被液稀释到2μg/mL,包被50μL/孔量加入酶标板孔中,37℃孵育2小时。弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加200μL封闭液4℃过夜。弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加入50μL的Hu-12E9-04、Hu-12E9-20、Hu-12E9-22、Hu-12E9-23、Hu-12E9-24、Hu-12E9-30、Hu-12E9-32、Hu-12E9-33、Hu-12E9-34或12E9-CHI浓度为首孔20μg/mL,5倍稀释,7个梯度的抗体,同时设置空白对照;37℃孵育60min;弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加入50μL的Goat-anti-human-IgG-Fc-Secondary-Antibody(1:10000稀释)的第二抗体,37℃孵育60min;弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。加显色液50μL/孔,37℃孵育15min。加入50μL/孔2mol/L H2SO4终止反应,在酶标仪上读取OD450值。结果如图10B所示。
7.2ELISA-阻断活性测评
7.2.1 7G10人源化抗体阻断活性测评(ELISA)
BAFF-hFc包被液稀释到2μg/mL,包被50μL/孔量加入酶标板孔中,37℃孵育2小时。弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加200μL封闭液4℃过夜。弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加入25μLBAFFR-mFc(4μg/mL)+25μL的Hu-7G10-02、Hu-7G10-22、Hu-7G10-32、Hu-7G10-42、Hu-7G10-44、或7G10-CHI浓度为首孔20μg/mL,依次5倍稀释,7个梯度的抗体,同时设置空白对照;37℃孵育120min;弃去孔内的液体,用洗板机,洗涤液200μl/次,洗5次。每孔加入50μL的Goat-anti-Mouse-IgG-Fc-Secondary-Antibody(1:10000稀释)的第二抗体,37℃孵育60min;弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。加显色液50μL/孔,37℃孵育15min,加入50μL/孔2mol/L H2SO4终止反应,在酶标仪上读取OD450值。结果如图11A所示。
7.2.2 12E9人源化抗体阻断活性测评(ELISA)
BAFF-hFc包被液稀释到2μg/mL,包被50μL/孔量加入酶标板孔中,37℃孵育2小时。弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加200μL封闭液4℃过夜。弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加入25μLBAFFR-mFc(4μg/mL)+25μL的Hu-12E9-04、Hu-12E9-20、Hu-12E9-22、Hu-12E9-23、Hu-12E9-24、Hu-12E9-30、Hu-12E9-32、Hu-12E9-33、Hu-12E9-34或12E9-CHI浓度为首孔20μg/mL,依次5倍稀释,7个梯度的抗体,同时设置空白对照;37℃孵育120min;弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。每孔加入50μL的Goat-anti-Mouse-IgG-Fc-Secondary-Antibody(1:10000稀释)的第二抗体,37℃孵育60min;弃去孔内的液体,用洗板机,洗涤液200μl/孔洗5次。加显色液50μL/孔,37℃孵育15min,加入50μL/孔2mol/L H2SO4终止反应,在酶标仪上读取OD450值。结果如图11B所示。
实施例8B7G10、B12E9抗体体外药效评价(ADCC)
8.1基于PBMC的ADCC活性方法筛选B7G10CHI
抗体通过Fab区识别靶点,并通过Fc段与效应细胞受体相互作用介导特异性的靶向杀伤(ADCC)是此类抗体药物的作用机制之一。我们采取新鲜制备或冻存的PBMC与靶细胞孵育,并加入不同浓度抗体的方法测试了优选的抗体分子的ADCC活性。实验中,提前一天将冻存的PBMC复苏,过夜培养。次日,收集处于对数生长期的Raji细胞,用培养基清洗细胞1次,将细胞密度调整到1×106/ml,向2ml细胞悬液中加入1.5μl DELFIA BATDA,37℃孵育20min。用培养基清洗细胞3次,重悬,调整细胞密度到5×104/ml,100μl每孔加入到96孔细胞培养板中。将待测抗体B7G10CHI和B12E9CHI,以及对照抗体MOR6654-hG1用培养基稀释到200g/ml、40μg/ml和8μg/ml,各加入50μl到相应孔中。将50μl 1×107/ml浓度的淋巴细胞(E:T=100:1)加到各孔中,自发释放量和最大释放量孔用培养基补到200μl,同时靶细胞最大释放量孔再加入10μl裂解液,37℃孵育2h。孔板放进孔板离心机中离心500rpm 5min,每孔取20μl上清转至另一个96不透明平底白板,并加入200μl铕溶液,室温在摇板机上振动孵育15min后测量荧光强度(TRF),结果如图12所示。
8.2报告基因法测定ADCC活性筛选B7G10CHI
ADCC杀伤发生来源于效应细胞的激活,人工改造的Jurkat细胞可以作为效应细胞激活的模型,这种Jurkat细胞内转入了Fc的受体CD16A亚基以及受体激活后启动基因转录的DNA作用元件NFAT,此元件控制荧光素酶的转录。在此测试中,以改造的Jurkat细胞与靶细胞孵育,加入不同浓度的测试对象(抗体),收集不同浓度下的荧光信号,拟合的曲线可以区分抗体激活效应细胞的活性强弱。具体操作如下:收集处于对数生长期的Raji细胞离心去上清,重悬计数,将细胞密度调整到6×106/ml,25μl每孔铺到96孔不透明细胞培养板中。将待测抗体和对照抗体用培养基稀释到60μg/ml作为起始浓度,5倍梯度稀释8个浓度点,取各浓度点25μl加入到96孔板中,设置复孔。37℃、5%CO2培养箱孵育45min。收集Jurkat细胞,按照效靶比1:6取25μl 1×106/ml密度的细胞加入孔板中。37℃、5%CO2培养箱孵育6h后,室温平衡15min。每孔加入荧光检测试剂75μl,室温避光孵育5min,检测荧光信号,结果如图13所示。
8.3报告基因法测定ADCC活性筛选Hu7G10分子
B7G10作为母本抗体,其人源化分子有多种,其中至少5种分子的ELISA结合、阻断活性较为接近,需要进一步采用ADCC报告基因法进行区分。具体操作如下:收集处于对数生长期的Raji细胞离心去上清,重悬计数,将细胞密度调整到6×106个/ml,25μl每孔铺到96孔不透明细胞培养板中。将待测抗体和对照抗体用培养基稀释到60μg/ml作为起始浓度,5倍梯度稀释8个浓度点,取各浓度点25μl加入到96孔板中,设置复孔。37℃5%CO2培养箱孵育45min。收集ADCC Report Cell,按照效靶比1:6取25μl 1×106/ml密度的细胞加入孔板中,37℃、5%CO2培养箱孵育6h后,室温平衡15min。每孔加入荧光检测试剂75μl,室温避光孵育5min,检测荧光信号,结果如图14所示。
8.4报告基因法测定Hu7G10-22AF的ADCC活性
Hu7G10在FUT8双等位基因敲除的CHO-K1细胞中表达,获得无岩藻糖修饰的分子Hu7G10AF。无岩藻糖修饰的抗体一般会提高与Fc受体的亲和力,从而以更高的效率激活效应细胞。本实施例采用报告基因法测试Hu7G10-22AF的ADCC活性。操作如下:收集处于对数生长期的Raji细胞离心去上清,重悬计数,将细胞密度调整到6×106/ml,25μl每孔铺到96孔不透明细胞培养板中。将待测抗体和对照抗体用培养基稀释到15μg/ml作为起始浓度,5倍梯度稀释8个浓度点,取各浓度点25μl加入到96孔板中,设置复孔。37℃5%CO2培养箱孵育45min。收集ADCC Report Cell,按照效靶比1:6取25μl 1×106/ml密度的细胞加入孔板中。37℃5%CO2培养箱孵育6h后,室温平衡15min。每孔加入荧光检测试剂75μl,室温避光孵育5min,检测荧光信号,结果如图15所示。
将Hu7G10-22AF与Hu7G10-22按不同比例混合稀释,按照上述方法进行检测,结果如图16所示。
本发明不局限于上述最佳实施方式,任何人在本发明的启示下都可得出其他各种形式的产品,但不论在其形状或结构上作任何变化,凡是具有与本申请相同或相近似的技术方案,均落在本发明的保护范围之内。
序列表
<110> 白先宏
<120> BAFF-R结合分子及其应用
<140> 2020109247382
<160> 49
<170> SIPOSequenceListing 1.0
<210> 1
<211> 78
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Met Arg Arg Gly Pro Arg Ser Leu Arg Gly Arg Asp Ala Pro Ala Pro
1 5 10 15
Thr Pro Cys Val Pro Ala Glu Cys Phe Asp Leu Leu Val Arg His Cys
20 25 30
Val Ala Cys Gly Leu Leu Arg Thr Pro Arg Pro Lys Pro Ala Gly Ala
35 40 45
Ser Ser Pro Ala Pro Arg Thr Ala Leu Gln Pro Gln Glu Ser Val Gly
50 55 60
Ala Gly Ala Gly Glu Ala Ala Leu Pro Leu Pro Gly Leu Leu
65 70 75
<210> 2
<211> 84
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Met Arg Arg Gly Pro Arg Ser Leu Arg Gly Arg Asp Ala Pro Ala Pro
1 5 10 15
Thr Pro Cys Val Pro Ala Glu Cys Phe Asp Leu Leu Val Arg His Cys
20 25 30
Val Ala Cys Gly Leu Leu Arg Thr Pro Arg Pro Lys Pro Ala Gly Ala
35 40 45
Ser Ser Pro Ala Pro Arg Thr Ala Leu Gln Pro Gln Glu Ser Val Gly
50 55 60
Ala Gly Ala Gly Glu Ala Ala Leu Pro Leu Pro Gly Leu Leu His His
65 70 75 80
His His His His
<210> 3
<211> 311
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Met Arg Arg Gly Pro Arg Ser Leu Arg Gly Arg Asp Ala Pro Ala Pro
1 5 10 15
Thr Pro Cys Val Pro Ala Glu Cys Phe Asp Leu Leu Val Arg His Cys
20 25 30
Val Ala Cys Gly Leu Leu Arg Thr Pro Arg Pro Lys Pro Ala Gly Ala
35 40 45
Ser Ser Pro Ala Pro Arg Thr Ala Leu Gln Pro Gln Glu Ser Val Gly
50 55 60
Ala Gly Ala Gly Glu Ala Ala Leu Pro Leu Pro Gly Leu Leu Glu Pro
65 70 75 80
Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro
85 90 95
Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys
100 105 110
Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val
115 120 125
Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn
130 135 140
Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr
145 150 155 160
Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp
165 170 175
Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu
180 185 190
Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg
195 200 205
Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys
210 215 220
Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp
225 230 235 240
Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys
245 250 255
Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser
260 265 270
Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser
275 280 285
Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser
290 295 300
Phe Ser Arg Thr Pro Gly Lys
305 310
<210> 4
<211> 310
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Met Arg Arg Gly Pro Arg Ser Leu Arg Gly Arg Asp Ala Pro Ala Pro
1 5 10 15
Thr Pro Cys Val Pro Ala Glu Cys Phe Asp Leu Leu Val Arg His Cys
20 25 30
Val Ala Cys Gly Leu Leu Arg Thr Pro Arg Pro Lys Pro Ala Gly Ala
35 40 45
Ser Ser Pro Ala Pro Arg Thr Ala Leu Gln Pro Gln Glu Ser Val Gly
50 55 60
Ala Gly Ala Gly Glu Ala Ala Leu Pro Leu Pro Gly Leu Leu Glu Pro
65 70 75 80
Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
85 90 95
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
100 105 110
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
115 120 125
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
130 135 140
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
145 150 155 160
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
165 170 175
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
180 185 190
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
195 200 205
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
210 215 220
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
225 230 235 240
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
245 250 255
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
260 265 270
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
275 280 285
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
290 295 300
Ser Leu Ser Pro Gly Lys
305 310
<210> 5
<211> 451
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Gln Val Ala Ala Leu Gln Gly Asp Leu Ala Ser Leu Arg Ala Glu Leu
1 5 10 15
Gln Gly His His Ala Glu Lys Leu Pro Ala Gly Ala Gly Ala Pro Lys
20 25 30
Ala Gly Leu Glu Glu Ala Pro Ala Val Thr Ala Gly Leu Lys Ile Phe
35 40 45
Glu Pro Pro Ala Pro Gly Glu Gly Asn Ser Ser Gln Asn Ser Arg Asn
50 55 60
Lys Arg Ala Val Gln Gly Pro Glu Glu Thr Val Thr Gln Asp Cys Leu
65 70 75 80
Gln Leu Ile Ala Asp Ser Glu Thr Pro Thr Ile Gln Lys Gly Ser Tyr
85 90 95
Thr Phe Val Pro Trp Leu Leu Ser Phe Lys Arg Gly Ser Ala Leu Glu
100 105 110
Glu Lys Glu Asn Lys Ile Leu Val Lys Glu Thr Gly Tyr Phe Phe Ile
115 120 125
Tyr Gly Gln Val Leu Tyr Thr Asp Lys Thr Tyr Ala Met Gly His Leu
130 135 140
Ile Gln Arg Lys Lys Val His Val Phe Gly Asp Glu Leu Ser Leu Val
145 150 155 160
Thr Leu Phe Arg Cys Ile Gln Asn Met Pro Glu Thr Leu Pro Asn Asn
165 170 175
Ser Cys Tyr Ser Ala Gly Ile Ala Lys Leu Glu Glu Gly Asp Glu Leu
180 185 190
Gln Leu Ala Ile Pro Arg Glu Asn Ala Gln Ile Ser Leu Asp Gly Asp
195 200 205
Val Thr Phe Phe Gly Ala Leu Lys Leu Leu Glu Pro Arg Gly Pro Thr
210 215 220
Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met
245 250 255
Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu
260 265 270
Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val
275 280 285
His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu
290 295 300
Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly
305 310 315 320
Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile
325 330 335
Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val
340 345 350
Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr
355 360 365
Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu
370 375 380
Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val
405 410 415
Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val
420 425 430
His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr
435 440 445
Pro Gly Lys
450
<210> 6
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Gln Val Ala Ala Leu Gln Gly Asp Leu Ala Ser Leu Arg Ala Glu Leu
1 5 10 15
Gln Gly His His Ala Glu Lys Leu Pro Ala Gly Ala Gly Ala Pro Lys
20 25 30
Ala Gly Leu Glu Glu Ala Pro Ala Val Thr Ala Gly Leu Lys Ile Phe
35 40 45
Glu Pro Pro Ala Pro Gly Glu Gly Asn Ser Ser Gln Asn Ser Arg Asn
50 55 60
Lys Arg Ala Val Gln Gly Pro Glu Glu Thr Val Thr Gln Asp Cys Leu
65 70 75 80
Gln Leu Ile Ala Asp Ser Glu Thr Pro Thr Ile Gln Lys Gly Ser Tyr
85 90 95
Thr Phe Val Pro Trp Leu Leu Ser Phe Lys Arg Gly Ser Ala Leu Glu
100 105 110
Glu Lys Glu Asn Lys Ile Leu Val Lys Glu Thr Gly Tyr Phe Phe Ile
115 120 125
Tyr Gly Gln Val Leu Tyr Thr Asp Lys Thr Tyr Ala Met Gly His Leu
130 135 140
Ile Gln Arg Lys Lys Val His Val Phe Gly Asp Glu Leu Ser Leu Val
145 150 155 160
Thr Leu Phe Arg Cys Ile Gln Asn Met Pro Glu Thr Leu Pro Asn Asn
165 170 175
Ser Cys Tyr Ser Ala Gly Ile Ala Lys Leu Glu Glu Gly Asp Glu Leu
180 185 190
Gln Leu Ala Ile Pro Arg Glu Asn Ala Gln Ile Ser Leu Asp Gly Asp
195 200 205
Val Thr Phe Phe Gly Ala Leu Lys Leu Leu Glu Pro Lys Ser Ser Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 7
<211> 557
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 7
ggagcttctg gctctgatag cccttgacca ggcatcccag ggtcaccatg gagttagttt 60
gggcagcaga tccaggggcc agtggataga cagatggggg tgtcgttttg gctgaggaga 120
ctgtgagagt ggtgccttgg ccccagtagt caaagtagta caagatgtag acactattgt 180
agtccagtcg atctcttcca cagtaataca tggctgtgtc ctcagacttc agatggctca 240
tttgcaggta taaattgttc ttggcattgt ctctggagat ggtgaatcgg ccctttacat 300
tgtctggata gtaggtgtaa tcaccaccat cactaatggt tgcgacccat tccagtctct 360
tttcaggagt ctggcgaacc caagacatgg catagctact gaaagtgaat ccagaggctg 420
cacaggagag tttcagggac cctccaggct ccactaagcc tcccccagac tccaccagct 480
gcacttcaca ctggacacct tttaaaacaa ggacaaggaa aatcaaatta aaccccactt 540
ttccatacaa tcggggc 557
<210> 8
<211> 496
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
gggggggggt aggaagttgt tcaagaagca cacgactgag gcacctccag atgttaactg 60
ctcactggat ggtgggaaga tggatacagt tggtgcagca tcagcccgtt tcagctccag 120
cttggtccca gcaccgaacg tgagcggaac atgtgaacct tgaaagcagt aataaactcc 180
cagatcctca gcctccactc tgctgatctt gagtgtgaaa tctgttcctg atccactgcc 240
actgaacctg tctgggaccc cagaaaatcg gttggaaact gtgaagatca ggagctttgg 300
agactggcct ggtttctgta ggaaccattg taaataggtg tttccatcac tatgtacaat 360
gctctgacta gatctgcaag agatggaggc ttgatctcca agactgacag gcagggagag 420
tggagtttgg gtcatcaaaa catcactggt ggaagcagga atccagaaca gcagtgaaag 480
gaggacaccc gctccg 496
<210> 9
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Glu Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asp Gly Gly Asp Tyr Thr Tyr Tyr Pro Asp Asn Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Asn Leu Tyr
65 70 75 80
Leu Gln Met Ser His Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Gly Arg Asp Arg Leu Asp Tyr Asn Ser Val Tyr Ile Leu Tyr Tyr Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120 125
<210> 10
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Gln Trp Phe Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Phe Thr Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 11
<211> 549
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
gagctctggc tctgtatacc cttgaccagg catcctagag tcaccgagga gccagttgta 60
cctccacaca caggggccag tggatagacc gatggggctg ttgttttggc tgaggagact 120
gtgagagagg tgccttggcc ccagtagtca aagtagtaca agatgtagac actatcgtag 180
tccaatcgat ctcttgcaca gtaatacatg gctgtgtcct cagacctcag atggctcatt 240
tgcaggtaca ggttgttctt ggcattgtct ctggagatgg tgaatcggcc ccttacattg 300
tctggatagt agatgtaact accaccatca ctaatggttg cgacccactc cagcctcttt 360
tccggagtct ggcgaaccca agacatggca tagttactga aagtgaatcc agaggctgca 420
caggagagtt tcagggaccc tccaggcttc actaagcctc ccccagactc caccagctgc 480
acttcacact ggacaccttt taaaacaagg acaaggaaaa tcaaactgaa ccagaagttc 540
catacatcg 549
<210> 12
<211> 505
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
gtacttgatg attgatgtct ctggggtaga gttgttcaga agcacacgac tgaggcacct 60
ccagatgtta actgctcact ggatggtggg aagatggata cagttggtgc agcatcagcc 120
cgtttcagct ccagcttggt cccagcaccg aacgtgagcg gagcatgtga accttgaaag 180
cagtaataaa gtcccagatc ctcagcctcc actctgctga tcttgagtgt gaaatctgtc 240
cctgatccac tgccactgaa cctgtctggg accccagaaa atcggttgga aactttgtag 300
atcaggagct ttggagactg gcctggtctc tgcaggtacc attgtaaata ggtgattcca 360
tcactatgta caaggctctg actagatctg caagagatgg aggcttgatc tccaagactg 420
acagacaggg agagtggagt ttgggtcatc aaaacatcac tgctggaagc tgaaaatctg 480
cacctgaaaa tccatcatct gggac 505
<210> 13
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asp Gly Gly Ser Tyr Ile Tyr Tyr Pro Asp Asn Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Asn Leu Tyr
65 70 75 80
Leu Gln Met Ser His Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Leu Asp Tyr Asp Ser Val Tyr Ile Leu Tyr Tyr Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Ser Leu Thr Val Ser Ser
115 120 125
<210> 14
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Ser Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Ile Thr Tyr Leu Gln Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Leu Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Ala Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 15
<211> 455
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Glu Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asp Gly Gly Asp Tyr Thr Tyr Tyr Pro Asp Asn Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Asn Leu Tyr
65 70 75 80
Leu Gln Met Ser His Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Gly Arg Asp Arg Leu Asp Tyr Asn Ser Val Tyr Ile Leu Tyr Tyr Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr
115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu
210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
325 330 335
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 16
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Gln Trp Phe Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Phe Thr Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 17
<211> 455
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asp Gly Gly Ser Tyr Ile Tyr Tyr Pro Asp Asn Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Asn Leu Tyr
65 70 75 80
Leu Gln Met Ser His Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Leu Asp Tyr Asp Ser Val Tyr Ile Leu Tyr Tyr Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Ser Leu Thr Val Ser Ser Ala Ser Thr
115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
130 135 140
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
195 200 205
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu
210 215 220
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
325 330 335
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 18
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Ser Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Ile Thr Tyr Leu Gln Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Leu Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Ala Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 19
<211> 1368
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 19
gaggtgcagc tggtggagag cggaggcggg cttgtggagc ctggcggcag cctgaagctg 60
agctgcgccg caagcggctt caccttcagc agctacgcca tgagctgggt gaggcagacc 120
cctgagaaga ggcttgagtg ggtggctacc atcagcgacg gcggtgacta cacctactac 180
cctgacaacg tgaagggcag gttcaccatc tcccgagaca acgccaagaa caacctgtac 240
ctgcagatga gccacctgaa gagcgaggac accgccatgt attattgcgg cagggacagg 300
ctggattaca acagcgtgta catcctgtac tattttgact actggggcca gggcaccaca 360
ctgacggtgt caagcgcttc gaccaagggc ccatcggtct tccccctggc accctcctcc 420
aagagcacct ctgggggcac agcggccctg ggctgcctgg tcaaggacta cttccccgaa 480
ccggtgacgg tgtcgtggaa ctcaggcgcc ctgaccagcg gcgtgcacac cttcccggct 540
gtcctacagt cctcaggact ctactccctc agcagcgtgg tgaccgtgcc ctccagcagc 600
ttgggcaccc agacctacat ctgcaacgtg aatcacaagc ccagcaacac caaggtggac 660
aagaaagttg agcccaaatc ttgtgacaaa actcacacat gcccaccgtg cccagcacct 720
gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 780
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 840
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 900
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 960
tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 1020
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1080
ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1140
tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1200
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1260
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1320
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 1368
<210> 20
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 20
gacgtgctga tgacccagac ccctctgagc ctgcctgtga gcctcggcga ccaggccagt 60
atcagttgca ggagcagcca gagcatcgtg cacagcgacg gcaacaccta cctgcagtgg 120
ttcctgcaga agcctggcca aagccctaag ctgctgatct tcaccgtgag caacaggttt 180
agcggcgtgc ctgacaggtt cagcgggagc ggcagcggaa ccgacttcac cctcaaaatc 240
agtagggtgg aggccgagga cctgggcgtg tactactgct tccagggcag ccacgtgcct 300
ctgaccttcg gtgccgggac caagctggag ctgaagcgta cggtggctgc accatctgtc 360
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttga 660
<210> 21
<211> 1368
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 21
gaggtgcagc tggtggagag cggaggcggc ctggtgaaac ctggcggcag ccttaagctg 60
agctgcgccg cttcaggctt caccttcagc aactacgcca tgagctgggt gaggcagacc 120
cctgagaaga ggctggagtg ggtggctacc atctcagacg gaggcagcta tatctactat 180
cctgacaacg tgaggggcag gttcactatc agcagggaca acgccaagaa caacctgtac 240
ctgcagatga gccacctgag gagcgaggac accgccatgt actactgtgc ccgggacaga 300
ctggactacg acagcgtgta catcctgtac tatttcgact actggggcca gggcaccagc 360
ctgactgtga gcagcgcttc gaccaagggc ccatcggtct tccccctggc accctcctcc 420
aagagcacct ctgggggcac agcggccctg ggctgcctgg tcaaggacta cttccccgaa 480
ccggtgacgg tgtcgtggaa ctcaggcgcc ctgaccagcg gcgtgcacac cttcccggct 540
gtcctacagt cctcaggact ctactccctc agcagcgtgg tgaccgtgcc ctccagcagc 600
ttgggcaccc agacctacat ctgcaacgtg aatcacaagc ccagcaacac caaggtggac 660
aagaaagttg agcccaaatc ttgtgacaaa actcacacat gcccaccgtg cccagcacct 720
gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 780
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 840
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 900
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 960
tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 1020
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1080
ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1140
tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1200
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1260
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1320
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 1368
<210> 22
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 22
gacgtgctga tgacccagac acctctgagt ctgagcgtga gcctgggcga ccaggccagc 60
atcagctgca ggagcagcca gagcctcgtg cacagcgacg gcatcaccta tctgcagtgg 120
tacctgcaga ggcctggaca gagtcctaag ctgctgattt acaaggtgag caataggttc 180
agcggcgtgc ctgacaggtt tagcggcagc ggctccggca ccgacttcac cctgaagatc 240
tctagggtgg aggccgaaga cctgggcctg tactactgct tccagggcag ccacgcccct 300
ctgaccttcg gcgctgggac caagctggag ctgaaacgta cggtggctgc accatctgtc 360
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttga 660
<210> 23
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Asp Gly Gly Asp Tyr Thr Tyr Tyr Pro Asp Asn Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Leu Asp Tyr Asn Ser Val Tyr Ile Leu Tyr Tyr Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 24
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asp Gly Gly Asp Tyr Thr Tyr Tyr Pro Asp Asn Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Leu Asp Tyr Asn Ser Val Tyr Ile Leu Tyr Tyr Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 25
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asp Gly Gly Asp Tyr Thr Tyr Tyr Pro Asp Asn Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Gly Arg Asp Arg Leu Asp Tyr Asn Ser Val Tyr Ile Leu Tyr Tyr Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 26
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asp Gly Gly Asp Tyr Thr Tyr Tyr Pro Asp Asn Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Gly Arg Asp Arg Leu Asp Tyr Asn Ser Val Tyr Ile Leu Tyr Tyr Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 27
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Gln Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 28
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Gln Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 29
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Gln Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Phe Thr Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 30
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Asp Val Leu Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Gln Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Phe Thr Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 31
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Asp Gly Gly Ser Tyr Ile Tyr Tyr Pro Asp Asn Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Leu Asp Tyr Asp Ser Val Tyr Ile Leu Tyr Tyr Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 32
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asp Gly Gly Ser Tyr Ile Tyr Tyr Pro Asp Asn Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Leu Asp Tyr Asp Ser Val Tyr Ile Leu Tyr Tyr Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 33
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asp Gly Gly Ser Tyr Ile Tyr Tyr Pro Asp Asn Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Leu Asp Tyr Asp Ser Val Tyr Ile Leu Tyr Tyr Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 34
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Ile Thr Tyr Leu Gln Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 35
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Ile Thr Tyr Leu Gln Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 36
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 36
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Ile Thr Tyr Leu Gln Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 37
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 37
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Ile Thr Tyr Leu Gln Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Leu Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Ala Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 38
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
Gly Phe Thr Phe Ser Ser Tyr Ala
1 5
<210> 39
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
Ile Ser Asp Gly Gly Asp Tyr Thr
1 5
<210> 40
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 40
Gly Arg Asp Arg Leu Asp Tyr Asn Ser Val Tyr Ile Leu Tyr Tyr Phe
1 5 10 15
Asp Tyr
<210> 41
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 41
Gln Ser Ile Val His Ser Asp Gly Asn Thr Tyr
1 5 10
<210> 42
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 42
Thr Val Ser
1
<210> 43
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 43
Phe Gln Gly Ser His Val Pro Leu Thr
1 5
<210> 44
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 44
Gly Phe Thr Phe Ser Asn Tyr Ala
1 5
<210> 45
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 45
Ile Ser Asp Gly Gly Ser Tyr Ile
1 5
<210> 46
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 46
Ala Arg Asp Arg Leu Asp Tyr Asp Ser Val Tyr Ile Leu Tyr Tyr Phe
1 5 10 15
Asp Tyr
<210> 47
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 47
Gln Ser Leu Val His Ser Asp Gly Ile Thr Tyr
1 5 10
<210> 48
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 48
Lys Val Ser
1
<210> 49
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 49
Phe Gln Gly Ser His Ala Pro Leu Thr
1 5
Claims (10)
1.特异性结合BAFF-R的抗体或其抗原结合片段,其包含重链可变区和轻链可变区,其中,
所述重链可变区包含分别如:SEQ ID NO:38、39、40所示的HCDR1、HCDR2、HCDR3,
所述轻链可变区包含分别如:SEQ ID NO:41、42、43所示的LCDR1、LCDR2、LCDR3。
2.特异性结合BAFF-R的抗体或其抗原结合片段,其包含重链可变区和轻链可变区,其中,
所述重链可变区序列选自:SEQ ID NO:9、23、24、25、26任一项所示的氨基酸序列,
所述轻链可变区序列选自:SEQ ID NO:10、27、28、29、30任一项所示的氨基酸序列。
3.如权利要求1所述的抗体或抗原结合片段,其特征在于,该抗体或抗原结合片段是鼠源抗体或其片段、嵌合抗体或其片段、人源化抗体或其片段。
4.如权利要求2所述的抗体或抗原结合片段,其特征在于,所述的抗原结合片段为Fab、Fab’、Fv、sFv、F(ab’)2的一种或其任意组合。
5.编码如权利要求1-4任一项所述的抗体或抗原结合片段的核酸序列。
6.含有如权利要求5所述的核苷酸序列的表达载体。
7.根据权利要求6所述的表达载体转化的宿主细胞,所述宿主细胞选自原核细胞、酵母细胞、昆虫细胞或哺乳动物细胞。
8.如权利要求7所述的宿主细胞,其中,所述宿主细胞选自HEK293F细胞、ExpiCHO S细胞或CHO-K1细胞,其中所述CHO-K1细胞为FUT8双等位基因敲除的。
9.一种药物或药物组合物,其含有如权利要求1-4任一项所述的抗体或抗原结合片段以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
10.一种如权利要求1-4任一项所述的抗体或抗原结合片段,或如权利要求9所述的药物组合物,或如权利要求5所述的核苷酸序列在制备治疗癌症和/或自身免疫性疾病的药物中的用途,其中,所述癌症疾病选自非霍奇金淋巴瘤(B-NHL),各型慢性淋巴细胞白血病(CLL)原发性急性淋巴细胞白血病(ALL),多发性骨髓瘤;所述自身免疫性疾病选自系统性红斑狼疮、特发性肺纤维化、类风湿性关节炎(RA)、原发性干燥综合征(PSS)、自身免疫性肝炎、多发性硬化症、重症肌无力、IgA肾病、视神经脊髓炎、肉芽肿病合并多血管炎、显微多血管炎、免疫性血小板减少性紫癜中的一种。
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Citations (2)
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CN102119174A (zh) * | 2008-07-17 | 2011-07-06 | 诺瓦提斯公司 | 使用治疗性抗体的组合物和方法 |
CN109641957A (zh) * | 2016-06-06 | 2019-04-16 | 希望之城 | Baff-r抗体及其用途 |
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CN102119174A (zh) * | 2008-07-17 | 2011-07-06 | 诺瓦提斯公司 | 使用治疗性抗体的组合物和方法 |
CN109641957A (zh) * | 2016-06-06 | 2019-04-16 | 希望之城 | Baff-r抗体及其用途 |
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Anti–BAFF-R antibody VAY-736 demonstrates promising preclinical activity in CLL and enhances effectiveness of ibrutinib;Mcwilliams E M 等;Blood Advances;第3卷(第3期);447-460 * |
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原发性干燥综合征患者 B 细胞活化因子受体的表达;宋淑菊等;中国基层医药;第19卷(第5期);651-653 * |
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