CN108251431B - 双载体系统及其用途 - Google Patents
双载体系统及其用途 Download PDFInfo
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- CN108251431B CN108251431B CN201810041670.6A CN201810041670A CN108251431B CN 108251431 B CN108251431 B CN 108251431B CN 201810041670 A CN201810041670 A CN 201810041670A CN 108251431 B CN108251431 B CN 108251431B
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Abstract
本申请公开了一种用于在细菌中表达Fab抗体片段的双质粒系统,包含第一质粒和第二质粒,其中所述第一质粒包含抗体轻链(VL‑CL)表达单元,所述第二质粒包含抗体重链VH‑CH1表达单元;所述第一质粒和第二质粒包含在所述细菌中相容的不同复制原点;并且所述抗体轻链表达单元和抗体重链VH‑CH1表达单元使用相同的原核启动子。本申请还公开了所述双质粒系统的用途。
Description
技术领域
本发明为基因工程抗体药物领域,特别是抗人IL-17的单克隆抗体领域。本发明涉及人源性功能性抗人IL-17单克隆抗体,以及这类抗体在治疗人IL-17介导的疾病中的用途。
背景技术
白细胞介素17(IL-17)家族目前包括IL-17A、IL-17B、IL-17C、IL-17D、IL-17E和IL-17F六种细胞因子。IL-17家族的成员与任何其它已知的细胞因子没有序列相似性,而且家族成员之间的序列相似性也比较低(Gaffen SL,Nat.Rev.Immunol.2009Aug;9(8):556-67)。IL-17家族成员的功能主要是参与免疫应答的调节。白细胞介素IL-17A(以下简称IL-17)是20-30kD的同源二聚体糖蛋白,其主要由活化的CD4+T细胞产生并作为促炎细胞因子起作用。IL-17由活化的T细胞在炎性位点分泌,而不在体循环中分泌。IL17具有多种生物学特性,包括上调黏附分子并在多种细胞类型包括滑膜细胞、软骨细胞、成纤维细胞、内皮细胞、上皮细胞、角质形成细胞和巨噬细胞中诱导产生大量炎性细胞因子和趋化因子。同样,IL-17通过诱导趋化因子的释放诱导嗜中性粒细胞聚集到炎性位点上,刺激前列腺素和金属蛋白酶的产生,并抑制蛋聚糖的合成。此外,IL-17在造血祖细胞的成熟中起重要作用。IL-17在不同的器宫和组织包括肺、关节软骨、骨、脑、造血细胞、肾、皮肤和肠中具有信号转导功能。因此,由IL-17A/Th17介导的免疫反应是全身性的,由此引发的炎症反应主要表现为中性粒细胞浸润。
大量的研究已经证实IL-17的增加与多种疾病有关,包括呼吸道炎症、类风湿性关节炎(RA)、骨关节炎、骨侵蚀、腹膜内脓肿与粘连炎症(IBD)、同种异体移植排斥、牛皮癣、某些类型的癌、血管发生、动脉粥样硬化和多发性硬化(MS)等(Witkowski等人,Cell.Mol.Life Sci.61:567-579,2004)。而且,IL-17在胶原基质分解、炎症及关节损伤等方面与IL-1b具有相对独立的效应,而且IL-17具有与TNF-a协同扩大炎症的生物学效应。进一步的研究证实,通过结合IL-17的特异性抗体或可溶性IL17受体阻断IL-17的体内生物学活性时,可以有效减少了多种动物关节炎模型中的炎症和骨侵蚀。因此,IL-17成为治疗RA和其它自身免疫性疾病的新靶标,而且由于IL17主要集中于炎症部位,因而靶向IL17的药物可能较靶向其它参与体循环的促炎细胞因子(如TNF)等具有潜在的更高安全性。
目前欧盟和美国FDA都已经批准用Novartis公司的Cosentyx治疗中重度斑块状银屑病成人患者,而Cosentyx的活性成份是secukinumab,是一种IL-17的单抗。但是本领域仍然需要更多适于治疗患者的改善的抗IL-17抗体。
发明内容
本发明的目的在于提供一种新型抗人IL-17的单克隆抗体或其片段,编码该单克隆抗体或其片段的多核苷酸的载体、宿主细胞、制备和纯化该抗体的方法及临床应用。由本发明涉及的抗体基因可变区的序列,可构建全长的抗体分子作为药物用于临床上由人IL-17介导的自身免疫系统疾病使用。这些适应症包括但不局限于下列:银屑病、类风湿性关节炎或强直性脊柱炎。
本发明构建了大容量的天然人源噬菌体抗体库,从中筛选得到了全人源抗IL-17单克隆抗体。
本发明的抗体为全人源的单克隆抗体,拮抗至少一种与IL-17或其部分相关的体外或体内生物活性。
在一个实施例中,本发明抗体的特征在于对人IL-17具有强结合亲和力。
在另一实施例中,本发明的抗体特征在于以高于背景的水平特异性结合人IL-17、猕猴IL-17和食蟹猴IL-17,而不结合小鼠IL-17。
在一个实施例中,本发明抗IL-17单克隆抗体含有重链可变区多肽,该多肽含有3个HCDR,其特征在于:所述HCDR1序列为GX1X2X3X4X5Y;所述HCDR2序列为NQDGX6E;所述HCDR3序列为DYYDX7ISDYYIHYWYFDL。其中X1X2X3X4X5序列为FTIDN,MSMSD或者ITMDD;X6为N或者D;X7为V或者L。而且其中HCDRs序列根据Chothia定义。优选地,本发明抗IL-17单克隆抗体包含重链可变区多肽,该多肽具有选自SEQ ID NO:24-26的氨基酸序列。
在另一个实施例中,本发明抗IL-17单克隆抗体含有轻链可变区多肽,该多肽含有3个LCDR序列,其特征在于:所述轻链可变区LCDR1序列为RASQNVHNRLT;所述轻链可变区LCDR2序列为GASNLES;所述轻链可变区LCDR3序列为QQYNGSPTT。而且其中LCDRs定义根据Chothia定义。优选地,本发明抗IL-17单克隆抗体包含轻链可变区多肽,该多肽具有选自SEQ ID NO:21的氨基酸序列。
在优选的实施例中,本发明抗IL-17单克隆抗体含有(i):含HCDR1、HCDR2、和HCDR3序列的重链可变区,其特征在于:所述HCDR1序列为GX1X2X3X4X5Y;所述HCDR2序列为NQDGX6E;所述HCDR3序列为DYYDX7ISDYYIHYWYFDL。而且其中HCDRs序列根据Chothia定义。(ii):含LCDR1、LCDR2、和LCDR3序列的轻链可变区,其特征在于:所述轻链可变区LCDR1序列为RASQNVHNRLT;所述轻链可变区LCDR2序列为GASNLES;所述轻链可变区LCDR3序列为QQYNGSPTT。而且其中LCDRs定义根据Chothia定义。
在更优选的实施例中,本发明抗IL-17单克隆抗体的重链可变区序列为SEQ IDNO:24,轻链可变区序列为SEQ ID NO:21;或重链可变区序列为SEQ ID NO:25,轻链可变区序列为SEQ ID NO:21;或重链可变区序列为SEQ ID NO:26,轻链可变区序列为SEQ ID NO:21。
本发明抗IL-17单克隆抗体可包含或由完整的抗体(即全长)、基本上完整的抗体或其抗原结合部分,例如Fab片段、F(ab')2片段或单链Fv片段组成。
本发明抗IL-17单克隆抗体包括可变区和恒定区,其中抗体重链恒定区可以是IgG1亚型(Seq ID 29)或者IgG4亚型(SeqID30),轻链恒定区可以是kappa亚型(Seq ID 31)或者Lambda亚型(seqID32)。
本发明所述的单克隆抗体或其片段是全人源的。
本发明提供了转染上述载体的宿主细胞,所述的宿主细胞为CHO细胞或HEK293细胞。
本发明抗体的药理学活性可以在标准测试方法,例如以下文献中公开的方法中进行证明:
Hwang SY,Kim JY,Kim KW,Park MK,Moon Y,Kim WU,Kim HY:IL-17inducesproduction of IL-6and IL-8in rheumatoid arthritis synovial fibroblasts viaNF-kappaB-and PI3-kinase/Akt-dependent pathways.Arthritis research&therapy2004,6(2):R120-128.简言之,在多种浓度的本发明抗体存在下,采用重组IL-17刺激成人真皮成纤维细胞(HDFa细胞)。在刺激24小时之后取上清,并通过ELISA检测IL-6。当如上检测时,优选地,针对如上定义的对IL-6产生的抑制,本发明抗体具有大约0.22nM或者更小,更优选大约0.12nM或者更小,更优选大约0.07nM或者更小的IC50。
本发明抗体在人血清中的稳定性可以在标准测试方法中进行证明。简言之,取过滤去菌的单抗样品,分别稀释于200ul无菌的正常人混合血清或PBS至终浓度30ug/ml,混匀后置37℃水浴放置8天(192小时)。8天后,利用ELISA分析血清样品、PBS样品和冻存的单抗样品与人IL17的结合,并分别比较各单抗样品结合IL17能力的变化。当如上检测时,优选地,本发明抗体具有大约87%,更优选大约91%,更优选大约97%的结合IL17能力。
本发明抗体分子在小鼠体内的代谢可以在标准测试方法中进行证明。简言之,单抗样品都制备于PBS缓冲系统(pH7.0),0.5mg/ml,给药剂量为5mg/kg,尾静脉单次给药,每组8只BALB/c小鼠,雌雄各半。然后分别在给药后4,24,48,96,168,240,336小时取血清样品(眼眶采血),保存于-70℃。在取样结束后进行单抗药物的浓度定量分析。血药浓度的定量分析基于包被的IL17的定量ELISA方法。根据一级反应模型,将抗体药物浓度的自然对数(ln C)对时间(t)作图,求出斜率常数k,然后根据公式t1/2=0.693/k,计算得到抗IL17单抗在小鼠体内的半衰期(t1/2)。当如上检测时,优选地,本发明抗体的小鼠体内的半衰期(t1/2)为大约6.7小时,更优选的为大约7.4小时,更优选的为大约8.5小时。
本发明还提供编码本发明抗体或其轻链或重链的分离的核酸分子;包含所述核酸的载体,任选地所述核酸有效连接到调控序列,该调控序列可以被用所述载体转化过的宿主细胞识别;包含那个载体的宿主细胞;产生本发明抗体的方法,该方法包括培养宿主细胞以便于表达核酸并任选地,从宿主细胞培养基中回收抗体。
本发明还提供编码小鼠IL-17(SEQ ID NO:9)、猕猴IL-17(SEQ ID NO:10)或食蟹猴IL-17(SEQ ID NO:11)的分离的核酸分子;小鼠、猕猴或食蟹猴核酸编码的IL-17蛋白质(分别为SEQ ID NO:9-11);包含所述核酸分子的载体;包含所述载体的宿主细胞;和产生小鼠IL-17、猕猴IL-17或食蟹猴IL-17的方法。
附图说明
图1:新型噬菌体呈现载体pADSCFV-S结构示意图(Para:阿拉伯糖启动子,PelBleader:PelB蛋白信号肽基因,NcoI:NcoI酶切位点,Stuff:750bp无关序列,NotI:NotI酶切位点,gIII:M13噬菌体的gIII蛋白基因;f1ori:M13噬菌体复制原点,Ampr:氨苄抗性基因,pBRori:pBR322复制原点,AraC:AraC基因)。
图2:单克隆phage和IL17R竞争结合IL17。
图3:质粒pADK-S和pAK-S结构示意图(Para:阿拉伯糖启动子,leader:PelB蛋白信号肽基因,NcoI:NcoI酶切位点,Stuff:750bp无关序列,PmlI:PmlI酶切位点,CK:人抗体kappa轻链恒定区基因;f1ori:M13噬菌体复制原点,Ampr:氨苄抗性基因,pBRori:pBR322复制原点,AraC:AraC基因,CmR:氯霉素抗体基因,CDFori:CDF质粒复制原点)。
图4:phage ELISA鉴定phage-Abs的相对亲和力。
图5:ELISA检测抗IL17抗体和人IL17结合能力。
图6:ELISA分析抗IL17单抗与不同种属IL17蛋白的结合能力。
图7:抗huIL17单克隆抗体竞争IL17R结合IL17。
图8:抗IL17单抗抑制IL17诱导DHFa细胞释放IL6的比较分析。
图9:不同抗IL17单抗在人血清中的稳定性分析。
图10:四种抗IL17单抗在小鼠体内浓度变化趋势图。
具体实施方式
以下实施例仅仅对本发明进行进一步的说明,不应理解为对本发明的限制。
实施例1:高质量噬菌体呈现抗体库的构建。
抗体库技术是制备人单克隆抗体的一个重要方法,而且基于噬菌体呈现的抗体库技术则是目前最成熟的抗体库技术,已经成功地应用于人单抗药物的制备。本实施例描述利用当今比较成熟的多种基因工程技术构建噬菌体呈现抗体库的策略和方法。
1.1制备抗体重链和轻链可变区基因(VH和VL)。
为构建人抗体库,首先需要获得人抗体的重链可变区(VH)和轻链可变区(VL)基因。抗体可变区基因可以来自正常人外周血淋巴细胞或者全合成。
1.1.1天然人抗体可变区基因的制备。
采集19个正常志愿者的血液(各50ml),然后用淋巴细胞分离液(MP Biomedicals公司,Cat#:0850494)分离淋巴细胞,利用Omega公司的总RNA提取试剂盒(Cat#:R6834-01)制备RNA,然后用TransGen Biotech公司的反转录试剂盒(Cat#:AT301-03)制备cDNA。最后用下表1所列的引物组进行PCR,分别扩增抗体的重链可变区基因(VH)和轻链可变区基因(VL,包括Vk和Vl)。利用常规的琼脂糖凝胶电泳方法纯化并回收扩增的PCR产物(VH,VK或Vl),置-20℃保存备用。
表1:扩增天然人抗体重链和轻链基因所用引物。
1.1.2全合成人抗体可变区基因的制备。
全合成抗体基因制备的基本策略是利用兼并引物(degenerate primers)在选定的模板抗体基因的CDRs中引入设计的突变。为构建全合成人抗体库,本实施例中选择了3种人抗体重链可变区模板(VH1;VH3和VH5),两种人抗体轻链可变区模板(VK1和Vl3)构建人全合成抗体库。
设计并委托明琛志远生物技术公司合成5种抗体可变区基因VH1(Seq ID NO:1),VH3(Seq ID NO:2),VH5(Seq IDNO:3),VK1(Seq ID NO:4),Vl3(Seq ID NO:5)。设计并合成表2所列的引物,分别用于在5种可变区基因的CDR1,CDR2和CDR3中引入设计的各种突变。利用常规PCR技术及各组含有设计突变的兼并引物,分别在对应的CDR中引入设计的突变,然后再利用2-3轮重叠延伸PCR(overlapping PCR),构建得到完整的重链可变区(VH1.VH3,VH5)或者轻链可变区(VK1,VL3)基因。琼脂糖凝胶电泳回收扩增的最终的可变区基因的PCR产物,置-20℃保存备用。
表2.扩增全合成人抗体可变区基因所用引物。
1.2构建单链抗体(single chain Fv,ScFv)基因
为构建单链抗体基因(ScFv),在重链可变区(VH)和轻链可变区(VL)之间添加常用的由15个氨基酸组成的柔性连接肽(linker),该连接肽的序列为GGGGSGGGGSGGGGS,编码基为ggtggaggcggttct ggcggaggtgggagc ggaggcggaggttca。且设计的单链抗体的结构为VH–linker-VL。
基于此实施例第一部分的方法,共获得如下表3所示的多种重链和轻链可变区基因,即四种不同的重链可变区基因和3种轻链可变区基因。
表3:各种不同重链和轻链可变区基因。
基于上述单链抗体的设计以及目前已经成熟重叠延伸PCR技术,可以很方便的将此表所示的不同重链和轻链进行组合,共构建获得12种不同的单链抗体基因。利用琼脂糖凝胶电泳方法纯化并回收PCR扩增获得的12种单链抗体基因,置-20℃保存备用。
1.3构建基于阿拉伯糖启动子的噬菌体呈现载体。
常用的噬菌体呈现载体都是基于乳糖启动子(Plac),而乳糖启动子由于其渗漏表达等特性,影响抗体库的容量和多样性。以常用的噬菌体呈现载体pCANTAB5E(AmershamBiosciences/GE公司)为基础,利用常规的分子生物学技术,对pCANTAB5E进行了如下改造。
利用AflIII和NotI双酶切,将pCANTAB5E载体上的Plac启动子及g3蛋白信号肽部分更换为包含AraC基因,阿拉伯糖启动子(Para)及PelB信号肽(PelB leader)的片段。其中AraC基因和ParaC来自invitrogen公司的pBADhis载体,而PelB leader序列(Seq ID NO:6)为人工合成序列。然后再利用NcoI和NotI双酶切,将一段约750bp的无关序列(stuffsequence,Seq ID NO:7)克隆在NcoI和NotI位点之间,构建得到最终的新型噬菌体呈现载体pADSCFV-S(图1)。该载体中的NcoI位点和NotI位点,可以方便的用于克隆单链抗体(ScFv)基因。
1.4人单链抗体库及噬菌体呈现抗体库的制备。
基于常规的分子生物学技术,利用NcoI和NotI双酶切的策略,将1.2中制备的12种ScFv分别克隆至载体pADSCFV-S,将连接产物分别电转TG1电转感受态,每个子库约20个电转,总共约240次电转。利用稀释法对每个子库的库容量进行推算,随机从每个子库中取30-40个克隆进行序列分析,以推算每个子库的正确率,汇总12个子库的库容量及正确率见表4。此12个子库的总库容量达到1.0*10E9,平均正确率超过75%。
表4:12个子库的库容量及正确率。
将构建的12个子库分别接种于2YTAG液体培养基(A:氨苄青霉素,100ug/ml;G:葡萄糖,2%),37℃,220rpm震荡培养至对数生长期(OD600=0.8),感染M13辅助噬菌体(M13KO7,NEB公司),感染结束后置换2YTAKA液体培养基(A:氨苄青霉素,100ug/ml;K:卡那霉素,70ug/ml;A:阿拉伯糖,0.001%),28℃,220rpm震荡培养过夜进行噬菌体扩增,然后利用PEG/Nacl沉淀方法制备纯化噬菌体(phage-ScFv),并进行滴度测定。然后参照库容量的比例将制备的12个子库的phage-ScFv进行混合,制备噬菌体呈现的人抗体库,噬菌体的最终滴度为6*10E12cfu/ml,冻存于-70℃。此噬菌体呈现抗体库可以用于筛选针对各种目的抗原的特异性人抗体。
实施例2:各种重组蛋白抗原的制备。
制备抗IL17单抗的过程中需要用到多种不同的重组蛋白,包括人IL17(huIL17,Seq ID NO:8),小鼠IL17(moIL17,Seq ID NO:9)、猕猴IL17(mmIL17,Seq ID NO:10)和食蟹猴IL17(mfIL17,Seq ID NO:11),人IL17R胞外区(IL17R,Seq ID NO:12)。而这些蛋白都有糖基化修饰,因而利用哺乳动物细胞表达系统将更有利于保持重组蛋白的结构和功能。此外,为了方便纯化,在这些重组蛋白的C端添加了His-tag(SeqID NO:13)或者人抗体的Fc段(Seq ID NO:14)。
根据Uniprot数据库的各种目的重组蛋白的氨基酸序列,设计并合成上述各种重组蛋白的基因(包含His-tag或者Fc编码基因)。利用常规的分子生物学技术将合成的各种重组蛋白基因克隆至合适的真核表达载体(如invitrogen公司的pcDNA3.1等),然后利用脂质体(如invitrogen公司的293fectin等)或其它转染试剂(如PEI等)将制备的重组蛋白表达质粒转染入HEK293细胞(如invitrogen公司的HEK293F),在无血清悬浮培养条件下培养3-4天。然后通过离心等方式收获培养上清。
His-tag融合表达的重组蛋白利用金属螯合亲和层析柱(如GE公司的HisTrap FF等)对培养上清中的重组蛋白进行一步纯化。而Fc融合表达的重组蛋白用ProteinA/G亲和层析柱(如GE公司的Mabselect SURE等)进行一步纯化。然后利用脱盐柱(如GE公司的Hitrap desaulting等)将重组蛋白保存缓冲液置换为PBS(pH7.0)或者其它合适的缓冲液。必要时,可以对抗体样品进行过滤除菌,然后分装保存于-20℃。
实施例3利用噬菌体呈现抗体库技术制备抗人IL17单抗。
3.1噬菌体抗体库中抗人IL17单抗的富集。
以huIL17-his(以下简写为IL17-His)为抗原包被ELISA板,5ug/ml,150ul/well,共包被4孔,4℃过夜。PBST-1%BSA封闭ELISA板,37℃封闭1h,同时将实施例1中制备的噬菌体呈现抗体库(phage-scFv)用PBST-1%BSA室温封闭1h,噬菌体的投入量约为1012。封闭后的噬菌体抗体库加入ELISA板中进行抗体抗原结合,37℃结合1h。PBST/PBS洗去未结合的噬菌体,最后用pH2.2,0.1M Glycine-HCl洗脱结合的噬菌体,用pH8.8,1.5M Tris-HCl中和洗脱下来的噬菌体。
将中和后的噬菌体感染生长至对数生长期的TG1菌液,37℃静置感染30min,37℃150rpm震荡培养30min。取1%菌液涂板计数,剩下的菌液4000rpm,离心5min,弃上清,菌体涂布于2YTAG(A:氨苄青霉素,100ug/ml;G:葡萄糖,2%)固体大平皿上,33℃过夜培养,为下一轮筛选做准备。
收集大平皿上菌体,取适量接种2YTAG液体培养基(A:氨苄青霉素,100ug/ml;G:葡萄糖,2%)震荡培养至对数生长期,感染M13KO7,感染结束后置换2YTAKA(A:氨苄青霉素,100ug/ml;K:卡那霉素,70ug/ml;A:阿拉伯糖,0.001%)液体培养基,28℃,220rpm震荡培养过夜进行噬菌体扩增,PEG/NaCl沉淀纯化噬菌体(phage)用于下一轮筛选。共进行三轮噬菌体库富集筛选。
3.2抗IL17单克隆的鉴定。
挑取经过三轮筛选后产出的分隔良好的单克隆菌落,接种于装有2YTAG培养基的96孔板中,37℃,220rpm培养至其对数生长期,每孔加入约1010的辅助噬菌体M13K07,37℃静止感染30min,37℃150rpm震荡培养30min。2000rpm,室温离心10min,弃去上清,菌体用2YTAKA培养基(A:氨苄青霉素,100ug/ml;K:卡那霉素,70ug/ml;A:阿拉伯糖,0.001%)重悬,28℃,220rpm震荡培养过夜。
用pH9.6的碳酸盐缓冲液包被IL17-Fc,4℃包被过夜。PBST洗涤三次,PBST-4%milk 37℃封闭1h。将培养过夜的单克隆phage上清按比例稀释于PBST-4%milk中,100ul/well加到封闭好的ELISA板中,37℃结合1h。PBST洗涤ELISA板,将HRP-anti-M13抗体1:5000稀释,100ul/well加入ELISA板中,37℃放置1h。OPD显色液显色5-20min,1M H2SO4 50ml/well终止显色,酶标仪492nm/630nm双波长测定光密度值。
参照上述方法,筛选约300个单克隆,最终挑选到4株序列不同且与IL17亲和力较高的scFv单链抗体,分别为11A,9G,3E,6D。
3.3抗IL17单抗的初步功能分析。
接种四种单克隆菌株(11A,9G,3E,6D)于2YTAG液体培养基中,培养至对数生长期,加入细菌数约20倍的辅助噬菌体M13KO7进行感染,感染结束后置换2YTAKA培养基,28℃,220rpm培养过夜进行噬菌体扩增,PEG/Nacl沉淀纯化噬菌体。
用pH9.6的碳酸盐包被IL17-his,4℃包被过夜。PBST洗涤三次,PBST-4% milk37℃封闭1h。稀释四种phage滴度至5*10E11cfu/ml,用四种phage稀释液分别稀释IL17R-his,IL17R-his起始浓度为20ug/ml,3倍梯度稀释,每个样品做7个稀释度,100ul/well加到ELISA板中,37℃孵育1h。PBST洗涤ELISA板,HRP-anti-M13二抗1:5000稀释,100ul/well加入ELISA板中,37℃放置1h。OPD显色液显色5-20min,1M H2SO4 50ml/well终止显色,酶标仪492nm/630nm双波长测定光密度值。
结果(图2)显示,IL17R-his可以和单链抗体11A及9G竞争结合IL17-his,说明11A(Seq ID NO:15)和9G(Seq ID NO:16)与IL17R有相同的IL17结合位点,而单链抗体3E和6D跟IL17R-his不产生竞争,为无功能抗体。
实施例4基于轻链置换的策略对抗IL17单抗进行亲和力成熟。
4.1构建抗体亲和力成熟研究所需的双载体呈现系统。
为了方便对抗体的轻链和重链进行突变研究,构建了三组(共6个)能够在同一E.coli细胞内共存的原核表达载体,具体如下:
以实施例1中的质粒pADSCFV-S为基础,利用PmlI和XbaI双酶切,将合成的人抗体kappa轻链恒定区基因(Seq ID NO:17)克隆至pADSCFV-S载体,替换原载体上的gIII基因,构建得到载体pADK-S(图3)。该载体可以用于克隆和表达人抗体的kappa轻链基因。
类似地,以实施例1中的质粒pADSCFV-S为基础,利用PmlI和XbaI双酶切,将合成的人抗体重链恒定区CH1和gIII蛋白C端结构域融合基因(Seq ID NO:18)或者人抗体lambda轻链恒定区(Seq ID NO:19)克隆至pADSCFV-S载体,替换原载体上的gIII基因,构建得到载体pADG-S和pADL-S。
利用PCR自pACYC184质粒(NEB公司)质粒上扩增氯霉素抗性基因(CmR),人工合成CDF质粒复制原点基因(CDFori,Seq ID NO:20),然后利用常规的重叠延伸PCR方法构建CmR-CDoriF融合基因(两端分别添加XbaI和AflIII位点)。然后利用XbaI和AflIII双酶切,将CmR-CDFori融合基因分别克隆至载体pADK-S、pADG-S和pADL-S,替换其中的f1ori-Ampr-pBRori部分,构建三个新质粒pAK-S(图3)、pAG-S和pAL-S。
4.2构建适合轻链置换研究的人抗体轻链库。
为了方便开展抗体的轻链置换突变研究,以质粒pADK-S和pADL-S为基础,构建了高质量的人轻链抗体库,具体如下:
基于常规PCR技术,以实施例1中构建的四个含有VK1可变区基因的子库DNA为模板,以表5所列的引物,扩增VK1基因。然后利用NcoI和PmlI双酶切,将扩增的VK1基因克隆至载体pADK-S中(替换其中的stuff序列)。将连接产物电转TG1感受态细胞,构建人VK1轻链库。利用稀释法对库容量进行推算,随机挑取30个克隆进行序列分析,以推算每个VK1轻链库的正确率,结果见表6。
与上类似,以实施例1中构建的四个含有VL3可变区基因子库的DNA为模板,以表5所列的引物,扩增VL3基因。然后利用NcoI和PmlI双酶切,将扩增的VL3基因克隆至载体pADL-S中(替换其中的stuff序列)。将连接产物电转TG1感受态细胞,构建人VL3轻链库。利用稀释法对库容量进行推算,随机挑取30个克隆进行序列分析,以推算每个VL3轻链库的正确率,结果见表6。两个轻链库的总容量达到1.0*10E8,平均正确率超过90%。
然后将构建的2个轻链子库分别接种于2YTAG(A:氨苄青霉素,100ug/ml;G:葡萄糖,2%)液体培养基培养至对数生长期,感染M13辅助噬菌体(M13KO7),感染结束后置换2YTAKG(A:氨苄青霉素,100ug/ml;K:卡那霉素,70ug/ml;G:葡萄糖,2%)液体培养基,28℃,220rpm培养过夜进行噬菌体扩增,然后利用PEG/Nacl沉淀方法制备纯化噬菌体,并进行滴度测定。然后参照库容量的比例将制备的2个子库的phage进行混合,制备包装人抗体轻链的噬菌体库(phage-VK1+VL3),噬菌体库的最终滴度为5.4*10E11cfu/ml,冻存于-70℃,可以用于各种抗体的轻链置换研究。
表5:构建VK1和VL3轻链库所用引物。
表6:VK1和VL3轻链库的库容量及正确率。
子库 | 库容量 | 正确率 |
pADK-VK1 | 7.2*10E7 | 95% |
pADL-VL3 | 3.7*10E7 | 90% |
4.3抗IL17抗体的轻链置换研究。
将从人抗体库中筛选到的两种单链抗体11A和9G的轻链(11AVK,9GVK)和重链(11AVH,9GVH)分别克隆至原核表达载体pADK-s和pAG-s上,获得各自的轻、重链表达质粒pADK-11AVK,pADK-9GVK,pAG-11AVH,pAG-9GVH。将重链质粒(pAG-11AVH,pAG-9GVH)分别转化TG1细胞,然后利用包装有轻链库的噬菌体(phage-VK1+VL3)感染,获得两种抗体的轻链突变库库(11AVH-VK1+VL3和9GVH-VK1+VL3)。
然后将2个轻链突变库(11AVH-VK1+VL3和9GVH-VK1+VL3)分别接种于2YTACG液体培养基(A:氨苄青霉素,100ug/ml;C:氯霉素,34ug/ml;G:葡萄糖,2%)培养至对数生长期,感染M13辅助噬菌体(M13KO7),感染结束后置换2YTACKA(A:氨苄青霉素,100ug/ml;C:氯霉素,34ug/ml;K:卡那霉素,70ug/ml;A:阿拉伯糖,0.001%)液体培养基,28℃,220rpm培养过夜进行噬菌体扩增,然后利用PEG/Nacl沉淀方法制备纯化噬菌体库(phage-11AVH-VK1+VL3和phage-9GVH-VK1+VL3),并进行滴度测定。然后将两个噬菌体库进行等比例混合,噬菌体库的最终滴度为1.9*10E13cfu/ml,冻存于-70℃。
参照常规的噬菌体呈现方法和技术,利用IL17-His对phage-11AVH-VK1+VL3和phage-9GVH-VK1+VL3混合库进行2轮富集,并利用噬菌体ELISA方法对富集获得的单克隆进行鉴定(约400个克隆),挑选ELISA信号值较高的克隆送测,将测序正确的克隆制备纯化phage。同时将此两种抗体(11A和9G)的轻、重链表达质粒共转化TG1,并制备纯化的phage作为阳性对照。
4.4纯化phage ELISA比较抗IL17单抗突变体的相对亲和力。
将纯化后的多个单克隆phage调整滴度为1*10E11/cfu,用PBST-4%milk进行3倍梯度稀释,利用包被的IL17-Fc(2ug/ml)和常规的噬菌体ELISA方法分析各个稀释度的噬菌体抗体结合IL17的能力。Phage-ELISA结果显示,对11A和9G分别进行轻链置换后筛选出的几株不同的噬菌体抗体均能与IL17进行结合,而且C2(Seq ID NO:21)和D5(Seq ID NO:22)的相对亲和力明显高于其它克隆(图4),而且C2和D5的重链均为9GVH。
实施例5 9G重链可变区(9GVH)突变库的构建及筛选。
为进一步提高抗IL17单抗的亲和力,构建了9G重链可变区的突变库,并利用双载体呈现系统对重链突变库进行了筛选。
以9G重链可变区基因(9GVH,Seq ID NO:23)为模板,利用常规的PCR技术,分别以表7所列的兼并引物在9GVH的CDRs中引入各种设计的突变,然后利用重叠延伸PCR技术组装得到完整的9G重链可变区突变基因。利用NcoI和PmlI双酶切,将9GVH突变基因克隆至载体pADG-S,并利用电击转化的方式将连接产物转化TG1感受态细胞,构建得到库容量约4*10E6的9GVH突变库。随机挑取20个单克隆进行序列分析,显示此突变库的正确率为70%(14/20)。
然后将构建的9GVH突变库(TG1菌)接种于2YTAG液体培养基(A:氨苄青霉素,100ug/ml;G:葡萄糖,2%)培养至对数生长期,感染M13辅助噬菌体(M13KO7),感染结束后置换2YTAKG(A:氨苄青霉素,100ug/ml;K:卡那霉素,70ug/ml;G:葡萄糖,2%)液体培养基,28℃,220rpm培养过夜进行噬菌体扩增,然后利用PEG/Nacl沉淀方法制备纯化的包装9GVH突变库的噬菌体(phage-9GVH),并进行滴度测定,噬菌体库的最终滴度为1.4*10E13cfu/ml,冻存于-70℃。
表7:9G重链(9GVH)各个CDR引入突变所用引物。
同时利用常规PCR技术,将实施例4中筛选得到的2个轻链基因C2和D5分别克隆至载体pAK-S,并转化TG1菌,得到pAK-C2/TG1和pAK-D5/TG1两种菌株。然后分别利用噬菌体库(phage-9GVH)感染对数生长期的pAK-C2/TG1和pAK-D5/TG1,获得两种9GVH突变库(轻链分别为C2和D5)。
然后参照常规的噬菌体呈现方法,利用M13KO7进行感染,将两种含有9GVH突变的Fab库分别呈现到噬菌体的表面,制备两个Fab噬菌体呈现库(phage-C2-9GVH和phage-D5-9GVH)。将两个噬菌体呈现库等比例混合,利用IL17-his对phage-C2-9GVH和phage-D5-9GVH混合库进行两轮筛选,挑选约300个克隆进行单克隆phage ELISA鉴定,最终挑选三株9GVH的突变体进行后续试验鉴定,分别命名为9GA3(Seq ID NO:24),9GC2(Seq ID NO:25),9GC5(Seq ID NO:26),而且此三个9GVH突变体的最优匹配轻链为C2(seq ID NO:21)。
实施例6单克隆抗体的表达和纯化。
由于抗体为含有复杂翻译后修饰的大分子蛋白质,因而重组全抗体的表达通常选用哺乳动物细胞表达系统。而且利用Protein A/G亲和层析方法可以方便的将抗体纯化至95%以上的纯度。本实施例简述常规的重组抗体制备方法和技术。
利用常规的分子生物学技术将目的抗体的重链和轻链基因分别克隆至合适的真核表达载体(如invitrogen公司的pcDNA3.1等),其中抗体重链恒定区可以是IgG1亚型(SeqID NO:29)或者IgG4亚型(Seq ID NO:30),轻链恒定区可以是kappa亚型(Seq ID NO:31)或者Lambda亚型(seq ID NO:32)。
然后利用脂质体(如invitrogen公司的293fectin等)或其它转染试剂(如PEI等)将制备的重轻链表达质粒共转染入HEK293细胞(如invitrogen公司的HEK293F)或者CHO细胞(如invitrogen公司的CHO-S)等,在无血清悬浮培养条件下培养3-4天。通过离心等方式收获培养上清,利用Protein A/G亲和层析柱(如GE公司的Mabselect SURE等)对培养上清中的重组抗体进行一步纯化,然后利用脱盐柱(如GE公司的Hitrap desaulting等)将抗体保存缓冲液置换为PBS(pH7.0)或者其它合适的缓冲液(如:0.1NaCl,0.01M sodiumcitrate,pH6.0等)。必要时,可以对制备的抗体样品进行过滤除菌,然后分装保存于-20℃。
实施例7抗IL17单抗和人IL17的结合实验。
利用ELISA方法对四种抗IL17单抗:9GA3,9GC2,9GC5和对照抗体Secukinumab(VH:seq ID NO:27,VK:Seq ID NO:28)结合IL17-His的能力进行了分析。
包被IL17-his(0.5ug/ml,100ul/孔,4℃包被过夜),各单克隆抗体的起始浓度为300nM,并分别进行3倍梯度稀释,每个单抗样品设置11个稀释度。利用HRP-goat-anti-human IgG检测各个稀释度的单克隆抗体结合IL17的能力(图5)。
实施例8:抗IL17单抗与不同种属IL17的结合。
将制备的四种IL17(huIL17,mIL17,mmIL17,mfIL17)分别包被于96孔ELISA板,1ug/ml,100ul/well,4℃包被过夜。利用封闭液(2%milk-PBST)在37℃封闭1小时后,分别加入各种抗IL17单抗,包括9GA3,9GC2,9GC5,secukinumab和Ixekizumab(VH:Seq ID NO:33,VK:Seq ID NO:34),37℃结合1小时,然后用PBST洗涤4次,加入HRP-anti-human IgG(二抗),37℃结合1小时,然后用PBST洗涤4次,加入OPD底物显色液,5-10分钟后用1M H2SO4终止显色,用Molecular Device的酶标仪(Spectra Max190)测定OD492。结果如图6,本发明的抗IL17单抗及对照抗体都不结合鼠IL17,但都识别人,猕猴和食蟹猴IL17。
实施例9抗人IL17单克隆抗体竞争IL17受体(IL17R)结合IL17。
功能性的抗IL17单抗应该在蛋白水平上阻断IL17R和IL17之间的结合,本实施例分析了四种不同抗IL17单抗(9GA3,9GC2,9GC5,secukinumab)抑制IL17R与IL17结合的能力。
包被IL17-Fc(0.5ug/ml,100ul/well),4℃包被过夜,用2ug/ml的IL17R-his对各单克隆抗体进行3倍梯度稀释,各抗体起始浓度调整为200ug/ml,共10个稀释梯度。利用HRP-mouse-anti-his单抗检测IL17R-his和IL17-Fc的结合信号,然后利用GraphPad Prism6进行数据分析和作图(图7)。
HDFa细胞(成人真皮成纤维细胞)购自Sciencell公司(Cat#:2320),常规培养传代按照Sciencell公司的产品说明书进行。
利用HDFa细胞进行抗IL17单抗活性分析时,将HDFa细胞接种于96孔细胞板,细胞密度1*10E4cells/well,培养基FM中添加1%FBS,其它同FM完全培养基,37度培养过夜。第二天,将培养基更换为含有2nM IL17-His及不同浓度(0.01-10nM)抗IL17单抗(9GA3,9GC2,9GC5,secukinumab)的培养基(FM+1%FBS),培养24小时。然后收集培养上清,利用ExcellBiology公司的IL6定量试剂盒(Cat#:EHoo4-96)对各个培养上清中的IL6分别进行定量分析。然后利用GraphPad Prism 6进行数据分析和作图(图8),各种抗IL17单抗抑制IL6释放的IL50见表8。
表8:四种抗IL17单抗抑制IL17诱导HDFa细胞释放IL6的IC50。
mAb | 9GA3 | 9GC2 | 9GC5 | secukinumab |
IC50(nM) | 0.12 | 0.22 | 0.07 | 0.48 |
实施例11:抗IL17单抗在人血清中的稳定性分析。
为了初步分析不同抗IL17单抗分子的特异性及血清稳定性,进行了抗IL17单抗在人血清中的稳定性分析。此研究包括四种不同抗IL17单抗,分别为9GA3,9GC2,9GC5和secukinumab。纯化的单抗样品都制备于0.01M sodium citrate,0.1M NaCl,pH6.0。取过滤去菌的单抗样品,分别稀释于200ul无菌的正常人混合血清或PBS至终浓度30ug/ml,混匀后置37℃水浴放置8天(192小时)。8天后,利用ELISA分析血清样品(A),PBS样品(B)和冻存的单抗样品(C)与人IL17的结合(图9),并分别比较各单抗样品结合IL17能力的变化(A/C)。结果见下表9,表明四种抗IL17单抗具有较好的血清稳定性。
表9:不同处理条件下单抗样品结合IL17能力的变化。
单抗 | 9GA3 | 9GC2 | 9GC5 | Secukinumab |
A/C | 87% | 91% | 97% | 91% |
实施例12:小鼠体内PK研究。
为了研究不同抗IL17单抗分子在小鼠体内的代谢规律,开展了多种抗IL17单抗的单次剂量尾静脉给药的PK研究。研究中包括4种不同抗IL17单抗(IgG4亚型),分别为9GA3,9GC2,9GC5和Ixekizumab,单抗样品都制备于PBS缓冲系统(pH7.0),0.5mg/ml,给药剂量为5mg/kg,尾静脉单次给药,每组8只BALB/c小鼠,雌雄各半。然后分别在给药后4,24,48,96,168,240,336小时取血清样品(眼眶采血),保存于-70℃。在取样结束后进行单抗药物的浓度定量分析。
血药浓度的定量分析基于包被的IL17的定量ELISA方法,而且分别用9GA3,9GC2,9GC5和Ixekizumab四种纯化的抗IL17单抗样品作为定量标准品,分别制作标准曲线,用于不同单抗的血药浓度分析。四种单抗在小鼠体内浓度变化趋势如图10。
根据一级反应模型,将抗体药物浓度的自然对数(ln C)对时间(t)作图,求出斜率常数k,然后根据公式t1/2=0.693/k,计算得到四种抗IL17单抗在小鼠体内的半衰期(t1/2),具体见表10。
表10:四种抗IL17单抗在小鼠体内半衰期(t1/2)。
单抗 | 9GA3 | 9GC2 | 9GC5 | Ixekizumab |
t1/2(h) | 8.5 | 6.7 | 7.4 | 4.0 |
序列表
<110>北京百特美博生物科技有限公司
北京智仁美博生物科技有限公司
<120> 双载体系统及其用途
<160>34
<170> SIPOSequenceListing 1.0
<210>1
<211>357
<212>DNA
<213>智人(Homo sapiens)
<220>
<221> gene
<222> ()..()
<223>VH1
<400>1
caggtgcagt tagtgcagag cggtgcggaa gtgaaaaaac cgggcagcag cgtgaaagtg 60
agctgcaaag cgagtggcgg cacctttagc agctatgcga ttagctgggt gcgtcaggca 120
ccgggacagg gcctggaatg gatgggccgt ataattccga ttctgggcat tgcgaactat 180
gcgcagaaat tccaaggccg cgtgaccatt accgcggaca aatctaccag caccgcgtat 240
atggaactga gcagcctgcg tagcgaggat accgctgtgt attattgcgc ccgtgcgcgt 300
gatttttgga gcggctgggg ctattggggc cagggcaccc tggtgactgt gtcatct 357
<210>2
<211>354
<212>DNA
<213>智人(Homo sapiens)
<220>
<221> gene
<222> ()..()
<223>VH3
<400>2
gaagtgcaat tggtggaaag cggtggcggt ctggtgcagc cgggtggcag cctgcgtctg 60
agctgcgcag cgagcggctt cacctttagc agctacgcga tgagctgggt gcgccaggca 120
ccgggtaaag gtctggaatg ggtgagcgcg attagcggta gcggcggcag cacctactat 180
gcggatagcg tgaaaggccg ttttaccatc tcgcgtgata actcgaaaaa caccctgtac 240
ctgcagatga acagcctgcg tgcggaagat accgcggtgt attattgcgc acgtgggtgg 300
agttataatg gggttgatcc ctggggtcag ggcactctgg tgaccgtgtc gagc 354
<210>3
<211>354
<212>DNA
<213>智人(Homo sapiens)
<220>
<221> gene
<222> ()..()
<223>VH5
<400>3
gaagttcaac tggttcaaag cggtgccgaa gtcaagaaac caggcgaaag cctcaaaatc 60
agctgcaaag gctctggtta taswttcacc avctactgga tcrgttgggt tcgccagatg 120
ccaggcaaag gtctggaatg gatgggtaka attdacccar gtgacagcda caccavwtat 180
tctccaagct tccagggtca ggttactatc agcgcagaca aaagcatcag caccgcctat 240
ctgcagtgga gctctctcaa agccagcgat actgctatgt actattgtgc acgcgtttct 300
tcggtcgact acttcgatta ctggggtcaa ggtactctgg tcaccgtctc gagc 354
<210>4
<211>321
<212>DNA
<213>智人(Homo sapiens)
<220>
<221> gene
<222> ()..()
<223>VK1
<400>4
gatatccaga tgacccagag cccgagcagc ctgagcgcga gcgtgggtga tcgcgtgacc 60
attacctgcc gcgcgagcca gggcattagc agctatctgg cgtggtatca gcagaaaccg 120
ggtaaagcgc cgaaactgtt aatttatgcg gccagcagct tgcagagcgg cgtgccgtcg 180
cgttttagcg gctcgggttc gggcaccgat tttaccctga ccatctcgag cttgcagccg 240
gaggacttcg ccacctacta ttgccagaat gctgagctta ttttaacctt cggccagggc 300
accaaagtgg agatcaaacg c 321
<210>5
<211>330
<212>DNA
<213>智人(Homo sapiens)
<220>
<221> gene
<222> ()..()
<223>VL3
<400>5
gatatcgttc tgactcaatc tccggcaact ctgtctctgt ctccgggtga acgtgcaact 60
ctgtcttgtc gtgcatctca gtctgtgagc tctagttatc tggcatggta tcagcaaaaa 120
ccgggtcagg caccgcgtct gctgatttat ggtgcaagct ctcgtgcaac tggtgttccg 180
gcacgtttta gtggtagtgg tagcggcacc gattttactc tgactatctc gagtctggaa 240
ccggaggact tcgccgtgta ctattgccag cagttgatcg ataagctgta taccaccttc 300
ggccagggca ccaaagtgga gatcaaacgc 330
<210>6
<211>66
<212>DNA
<213>Pectobacterium carotovorum
<220>
<221> misc_feature
<222> ()..()
<223>pelB leader
<400>6
atgaaatacc tattgcctac ggcagccgct ggattgttat tactcgctgc ccaaccagcc 60
atggcg 66
<210>7
<211>696
<212>DNA
<213>人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223>stuff sequence
<400>7
cgtttaaggg caccaataac tgccttaaaa aaattacgcc ccgccctgcc actcatcgca 60
gtactgttgt aattcattaa gcattctgcc gacatggaag ccatcacaaa cggcatgatg 120
aacctgaatc gccagcggca tcagcacctt gtcgccttgc gtataatatt tgcccatagt 180
gaaaacgggg gcgaagaagt tgtccatatt ggccacgttt aaatcaaaac tggtgaaact 240
cacccaggga ttggctgaga cgaaaaacat attctcaata aaccctttag ggaaataggc 300
caggttttca ccgtaacacg ccacatcttg cgaatatatg tgtagaaact gccggaaatc 360
gtcgtggtat tcactccaga gcgatgaaaa cgtttcagtt tgctcatgga aaacggtgta 420
acaagggtga acactatccc atatcaccag ctcaccgtct ttcattgcca tacggaattc 480
cggatgagca ttcatcaggc gggcaagaat gtgaataaag gccggataaa acttgtgctt 540
atttttcttt acggtcttta aaaaggccgt aatatccagc tgaacggtct ggttataggt 600
acattgagca actgactgaa atgcctcaaa atgttcttta cgatgccatt gggatatatc 660
aacggtggta tatccagtga tttttttctc cacgtg 696
<210>8
<211>132
<212>PRT
<213>智人(Homo sapiens)
<220>
<221> PEPTIDE
<222> ()..()
<223>人IL17
<400>8
Gly Ile Thr Ile Pro Arg Asn Pro Gly Cys Pro Asn Ser Glu Asp Lys
1 5 10 15
Asn Phe Pro Arg Thr Val Met Val Asn Leu Asn Ile His Asn Arg Asn
20 25 30
Thr Asn Thr Asn Pro Lys Arg Ser Ser Asp Tyr Tyr Asn Arg Ser Thr
35 40 45
Ser Pro Trp Asn Leu His Arg Asn Glu Asp Pro Glu Arg Tyr Pro Ser
50 55 60
Val Ile Trp Glu Ala Lys Cys Arg His Leu Gly Cys Ile Asn Ala Asp
65 70 75 80
Gly Asn Val Asp Tyr His Met Asn Ser Val Pro Ile Gln Gln Glu Ile
85 90 95
Leu Val Leu Arg Arg Glu Pro Pro His Cys Pro Asn Ser Phe Arg Leu
100 105 110
Glu Lys Ile Leu Val Ser Val Gly Cys Thr Cys Val Thr Pro Ile Val
115 120 125
His His Val Ala
130
<210>9
<211>133
<212>PRT
<213>小鼠(Mus musculus)
<220>
<221> PEPTIDE
<222> ()..()
<223>小鼠IL17
<400>9
Ala Ala Ile Ile Pro Gln Ser Ser Ala Cys Pro Asn Thr Glu Ala Lys
1 5 10 15
Asp Phe Leu Gln Asn Val Lys Val Asn Leu Lys Val Phe Asn Ser Leu
20 25 30
Gly Ala Lys Val Ser Ser Arg Arg Pro Ser Asp Tyr Leu Asn Arg Ser
35 40 45
Thr Ser Pro Trp Thr Leu His Arg Asn Glu Asp Pro Asp Arg Tyr Pro
50 55 60
Ser Val Ile Trp Glu Ala Gln Cys Arg His Gln Arg Cys Val Asn Ala
65 70 75 80
Glu Gly Lys Leu Asp His His Met Asn Ser Val Leu Ile Gln Gln Glu
85 90 95
Ile Leu Val Leu Lys Arg Glu Pro Glu Ser Cys Pro Phe Thr Phe Arg
100 105 110
Val Glu Lys Met Leu Val Gly Val Gly Cys Thr Cys Val Ala Ser Ile
115 120 125
Val Arg Gln Ala Ala
130
<210>10
<211>132
<212>PRT
<213>猕猴(Macaca mulatta)
<220>
<221> PEPTIDE
<222> ()..()
<223>猕猴IL17
<400>10
Gly Ile Ala Ile Pro Arg Asn Pro Gly Cys Pro Asn Ser Glu Asp Lys
1 5 10 15
Thr Phe Pro Arg Thr Val Met Val Asn Leu Asn Ile His Asn Arg Asn
20 25 30
Thr Asn Thr Asn Pro Lys Arg Ser Ser Asp Tyr Tyr Asn Arg Ser Thr
35 40 45
Ser Pro Trp Asn Leu His Arg Asn Glu Asp Pro Glu Arg Tyr Pro Ser
50 55 60
Val Ile Trp Glu Ala Lys Cys Arg His Leu Gly Cys Val Asn Ala Asp
65 70 75 80
Gly Asn Val Asp Tyr His Met Asn Ser Val Pro Ile Gln Gln Glu Ile
85 90 95
Leu Val Leu Arg Arg Glu Pro Arg His Cys Pro Asn Ser Phe Arg Leu
100 105 110
Glu Lys Ile Leu Val Ser Val Gly Cys Thr Cys Val Thr Pro Ile Val
115 120 125
His His Val Ala
130
<210>11
<211>132
<212>PRT
<213>食蟹猴(Macaca fascicularis)
<220>
<221> PEPTIDE
<222> ()..()
<223>食蟹猴IL17
<400>11
Gly Ile Ala Ile Pro Arg Asn Ser Gly Cys Pro Asn Ser Glu Asp Lys
1 5 10 15
Asn Phe Pro Arg Thr Val Met Val Asn Leu Asn Ile His Asn Arg Asn
20 25 30
Thr Ser Thr Asn Pro Lys Arg Ser Ser Asp Tyr Tyr Asn Arg Ser Thr
35 40 45
Ser Pro Trp Asn Leu His Arg Asn Glu Asp Pro Glu Arg Tyr Pro Ser
50 55 60
Val Ile Trp Glu Ala Lys Cys Arg His Leu Gly Cys Val Lys Ala Asp
65 70 75 80
Gly Asn Val Asp Tyr His Met Asn Ser Val Pro Ile Gln Gln Glu Ile
85 90 95
Leu Val Leu Arg Arg Glu Pro Arg His Cys Pro Asn Ser Phe Arg Leu
100 105 110
Glu Lys Ile Leu Val Ser Val Gly Cys Thr Cys Val Thr Pro Ile Val
115 120 125
His His Val Ala
130
<210>12
<211>288
<212>PRT
<213>智人(Homo sapiens)
<220>
<221> PEPTIDE
<222> ()..()
<223>人IL17受体胞外区
<400>12
Leu Arg Leu Leu Asp His Arg Ala Leu Val Cys Ser Gln Pro Gly Leu
1 5 10 15
Asn Cys Thr Val Lys Asn Ser Thr Cys Leu Asp Asp Ser Trp Ile His
20 25 30
Pro Arg Asn Leu Thr Pro Ser Ser Pro Lys Asp Leu Gln Ile Gln Leu
35 40 45
His Phe Ala His Thr Gln Gln Gly Asp Leu Phe Pro Val Ala His Ile
50 55 60
Glu Trp Thr Leu Gln Thr Asp Ala Ser Ile Leu Tyr Leu Glu Gly Ala
65 70 75 80
Glu Leu Ser Val Leu Gln Leu Asn Thr Asn Glu Arg Leu Cys Val Arg
85 90 95
Phe Glu Phe Leu Ser Lys Leu Arg His His His Arg Arg Trp Arg Phe
100 105 110
Thr Phe Ser His Phe Val Val Asp Pro Asp Gln Glu Tyr Glu Val Thr
115 120 125
Val His His Leu Pro Lys Pro Ile Pro Asp Gly Asp Pro Asn His Gln
130 135 140
Ser Lys Asn Phe Leu Val Pro Asp Cys Glu His Ala Arg Met Lys Val
145 150 155 160
Thr Thr Pro Cys Met Ser Ser Gly Ser Leu Trp Asp Pro Asn Ile Thr
165 170 175
Val Glu Thr Leu Glu Ala His Gln Leu Arg Val Ser Phe Thr Leu Trp
180 185 190
Asn Glu Ser Thr His Tyr Gln Ile Leu Leu Thr Ser Phe Pro His Met
195 200 205
Glu Asn His Ser Cys Phe Glu His Met His His Ile Pro Ala Pro Arg
210 215 220
Pro Glu Glu Phe His Gln Arg Ser Asn Val Thr Leu Thr Leu Arg Asn
225 230 235 240
Leu Lys Gly Cys Cys Arg His Gln Val Gln Ile Gln Pro Phe Phe Ser
245 250 255
Ser Cys Leu Asn Asp Cys Leu Arg His Ser Ala Thr Val Ser Cys Pro
260 265 270
Glu Met Pro Asp Thr Pro Glu Pro Ile Pro Asp Tyr Met Pro Leu Trp
275 280 285
<210>13
<211>11
<212>PRT
<213>人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223>his标签
<400>13
Ala Ser Gly Ala Ala His His His His His His
1 5 10
<210>14
<211>234
<212>PRT
<213>智人(Homo sapiens)
<220>
<221> PEPTIDE
<222> ()..()
<223>Fc标签
<400>14
Ala Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys
1 5 10 15
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
20 25 30
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
35 40 45
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
50 55 60
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
65 70 75 80
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
85 90 95
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
100 105 110
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
115 120 125
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
130 135 140
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
145 150 155 160
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
165 170 175
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
180 185 190
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
195 200 205
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
210 215 220
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210>15
<211>747
<212>DNA
<213>人工序列(Artificial Sequence)
<220>
<221> gene
<222> ()..()
<223>单链抗体11A
<400>15
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt gattactgga tgaattgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccgca attaaccaaa gcggcgatga gaaatactat 180
gtgggctctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agtcgaggac acggctgtgt attactgtgt gagagactat 300
tacacttttc tgagcgatta ttacatacac tactggtact tcgatctctg gggccgtggc 360
accctggtca ctgtgtcctc aggtggtggt ggtagcggcg gcggcggctc tggtggtggt 420
ggatccgata tccagatgac ccagagcccg agcagcctga gcgcgagcgt gggtgatcgc 480
gtgaccatta cctgccgcgc gagccagagt atccgtaact acctgacttg gtatcagcag 540
aaaccgggta aagcgccgaa actgttaatt tatggggcca gcagccggca gtctggcgtg 600
ccgtcgcgtt ttagcggctc gggttcgggc accgatttta ccctgaccat ctcgagcttg 660
cagccggagg acttcgccac ctactattgc cagcaatacg ccgggtcccc aatcaccttc 720
ggtcagggca ccaaagtgga gatcaaa 747
<210>16
<211>747
<212>DNA
<213>人工序列(Artificial Sequence)
<220>
<221> gene
<222> ()..()
<223>单链抗体9G
<400>16
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt gattactgga tgaattgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccgca attaaccaag acggcaatga gaaatactat 180
gtgggctctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agtcgaggac acggctgtgt attactgtgt gagagactat 300
tacgatgtga ttagcgatta ttacatacac tactggtact tcgatctctg gggccgtggc 360
accctggtca ctgtgtcctc aggtggtggt ggtagcggcg gcggcggctc tggtggtggt 420
ggatccgata tccagatgac ccagagcccg agcagcctga gcgcgagcgt gggtgatcgc 480
gtgaccatta cctgccgcgc gagccaggat atccatagct acctgacttg gtatcagcag 540
aaaccgggta aagcgccgaa actgttaatt tatggtgcca gcacccggga gactggcgtg 600
ccgtcgcgtt ttagcggctc gggttcgggc accgatttta ccctgaccat ctcgagcttg 660
cagccggagg acttcgccac ctactattgc cagcaatacc gcggcacgcc aacgaccttc 720
ggtcagggca ccaaagtgga gatcaaa 747
<210>17
<211>318
<212>DNA
<213>智人(Homo sapiens)
<220>
<221> gene
<222> ()..()
<223>人抗体kappa轻链恒定区
<400>17
gtggcggcgc catctgtctt catcttcccg ccatctgatg agcagttgaa atctggtacc 60
gctagcgttg tgtgcctgct gaataacttc tatcccagag aggccaaagt acagtggaag 120
gtggataacg ccctccaatc gggtaactcc caggagagtg tcacagagca ggacagcaag 180
gacagcacct acagcctcag cagcaccctg acgctgagca aagcagacta cgagaaacac 240
aaagtctacg cctgcgaagt cacccatcag ggcctgagct cgcccgtcac aaagagcttc 300
aacaggggag agtgttag 318
<210>18
<211>804
<212>DNA
<213>人工序列(Artificial Sequence)
<220>
<221> gene
<222> ()..()
<223>人抗体重链恒定区CH1和gIII蛋白C端结构域融合基因
<400>18
gtgtcctcag cgtcgaccaa gggcccatcg gtcttccccc tggcaccctc ctccaagagc 60
acctctgggg gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 120
acggtgtcgt ggaactcagg cgccctgacc agcggcgtgc acaccttccc ggctgtccta 180
cagtcctcag gactctactc cctcagcagc gtggtgaccg tgccctccag cagcttgggc 240
acccagacct acatctgcaa cgtgaatcac aagcccagca acaccaaggt ggacaagaga 300
gttgagccca aatcttgtgc ggccgcaggt ggcggctccg gttccggtga ttttgattat 360
gaaaaaatgg caaacgctaa taagggggct atgaccgaaa atgccgatga aaacgcgcta 420
cagtctgacg ctaaaggcaa acttgattct gtcgctactg attacggtgc tgctatcgat 480
ggtttcattg gtgacgtttc cggccttgct aatggtaatg gtgctactgg tgattttgct 540
ggctctaatt cccaaatggc tcaagtcggt gacggtgata attcaccttt aatgaataat 600
ttccgtcaat atttaccttc cctccctcaa tcggttgaat gtcgcccttt tgtctttggc 660
gctggtaaac catatgaatt ttctattgat tgtgacaaaa taaacttatt ccgtggtgtc 720
tttgcgtttc ttttatatgt tgccaccttt atgtatgtat tttctacgtt tgctaacata 780
ctgcgtaata aggagtcttg ataa 804
<210>19
<211>354
<212>DNA
<213>智人(Homo sapiens)
<220>
<221> gene
<222> ()..()
<223>人抗体lambda轻链恒定区
<400>19
gtgctaggtc agcccaaggc tgccccctcg gtcactctgt tcccgccctc ctctgaggag 60
cttcaagcca acaaggccac actggtgtgt ctcataagtg acttctaccc gggagccgtg 120
acagtggcct ggaaggcaga tagcagcccc gtcaaggcgg gagtggagac caccacaccc 180
tccaaacaaa gcaacaacaa gtacgcggcc agcagctatc tgagcctgac gcctgagcag 240
tggaagtccc acagaagcta cagctgccag gtcacgcatg aagggagcac cgtggagaag 300
acagtggccc ctacagaatg ttcaggtgca gctcatcacc accatcacca ttaa 354
<210>20
<211>739
<212>DNA
<213>人工序列(Artificial Sequence)
<220>
<221> misc_feature
<222> ()..()
<223>CDF ori
<400>20
gcgctgcgga cacatacaaa gttacccaca gattccgtgg ataagcaggg gactaacatg 60
tgaggcaaaa cagcagggcc gcgccggtgg cgtttttcca taggctccgc cctcctgcca 120
gagttcacat aaacagacgc ttttccggtg catctgtggg agccgtgagg ctcaaccatg 180
aatctgacag tacgggcgaa acccgacagg acttaaagat ccccaccgtt tccggcgggt 240
cgctccctct tgcgctctcc tgttccgacc ctgccgttta ccggatacct gttccgcctt 300
tctcccttac gggaagtgtg gcgctttctc atagctcaca cactggtatc tcggctcggt 360
gtaggtcgtt cgctccaagc tgggctgtaa gcaagaactc cccgttcagc ccgactgctg 420
cgccttatcc ggtaactgtt cacttgagtc caacccggaa aagcacggta aaacgccact 480
ggcagcagcc attggtaact gggagttcgc agaggatttg tttagctaaa cacgcggttg 540
ctcttgaagt gtgcgccaaa gtccggctac actggaagga cagatttggt tgctgtgctc 600
tgcgaaaacc agttaccacg gttaagcagt tccccaactg acttaacctt cgatcaaacc 660
acctccccag gtggtttttt cgtttacagg gcaaaagatt acgcgcagaa aaaaaggatc 720
tcaagaagat cctttgatc 739
<210>21
<211>107
<212>PRT
<213>人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223>抗体轻链
<400>21
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val His Asn Arg
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Gly Ser Pro Thr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210>22
<211>107
<212>PRT
<213>人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223>抗体轻链
<400>22
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Asn Asn Tyr
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Arg Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Gly Ser Pro Thr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210>23
<211>381
<212>DNA
<213>人工序列(Artificial Sequence)
<220>
<221> gene
<222> ()..()
<223>抗体重链9G
<400>23
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt gattactgga tgaattgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccgca attaaccaag acggcaatga gaaatactat 180
gtgggctctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agtcgaggac acggctgtgt attactgtgt gagagactat 300
tacgatgtga ttagcgatta ttacatacac tactggtact tcgatctctg gggccgtggc 360
accctggtca ctgtgtcctc a 381
<210>24
<211>127
<212>PRT
<213>人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223>抗体重链
<400>24
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 Ile Thr Met Asp Asp Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Asn Gln Asp Gly Asn Glu Lys Tyr Tyr Val Gly Ser 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 Val Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Asp Tyr Tyr Asp Leu Ile Ser Asp Tyr Tyr Ile His Tyr Trp
100 105 110
Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210>25
<211>127
<212>PRT
<213>人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223>抗体重链
<400>25
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 Ile Asp Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Asn Gln Asp Gly Asn Glu Lys Tyr Tyr Val Gly Ser 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 Val Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Asp Tyr Tyr Asp Val Ile Ser Asp Tyr Tyr Ile His Tyr Trp
100 105 110
Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210>26
<211>127
<212>PRT
<213>人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223>抗体重链
<400>26
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 Met Ser Met Ser Asp Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Asn Gln Asp Gly Asp Glu Lys Tyr Tyr Val Gly Ser 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 Val Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Asp Tyr Tyr Asp Leu Ile Ser Asp Tyr Tyr Ile His Tyr Trp
100 105 110
Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210>27
<211>127
<212>PRT
<213>人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223>VH
<400>27
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 Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr Val Gly Ser 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 Val Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Asp Tyr Tyr Asp Ile Leu Thr Asp Tyr Tyr Ile His Tyr Trp
100 105 110
Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210>28
<211>108
<212>PRT
<213>人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223>VK
<400>28
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Cys Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210>29
<211>330
<212>PRT
<213>智人(Homo sapiens)
<220>
<221> PEPTIDE
<222> ()..()
<223>抗体重链恒定区IgG1亚型
<400>29
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210>30
<211>327
<212>PRT
<213>智人(Homo sapiens)
<220>
<221> PEPTIDE
<222> ()..()
<223>抗体重链恒定区IgG4亚型
<400>30
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210>31
<211>107
<212>PRT
<213>智人(Homo sapiens)
<220>
<221> PEPTIDE
<222> ()..()
<223>kappa亚型轻链恒定区
<400>31
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210>32
<211>105
<212>PRT
<213>智人(Homo sapiens)
<220>
<221> PEPTIDE
<222> ()..()
<223>lambda亚型轻链恒定区
<400>32
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
1 5 10 15
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
20 25 30
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
35 40 45
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys
50 55 60
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
65 70 75 80
His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
85 90 95
Lys Thr Val Ala Pro Thr Glu Cys Ser
100 105
<210>33
<211>119
<212>PRT
<213>人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223>VH
<400>33
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asp Tyr
20 25 30
His Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Asn Pro Met Tyr Gly Thr Thr Asp Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Asp Tyr Phe Thr Gly Thr Gly Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210>34
<211>112
<212>PRT
<213>人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> ()..()
<223>VK
<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 Arg Ser Leu Val His Ser
20 25 30
Arg Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ile 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 Ser Gln Ser
85 90 95
Thr His Leu Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Claims (14)
1.一种用于在细菌中表达Fab抗体片段的双质粒系统,包含第一质粒和第二质粒,其中:
所述第一质粒包含抗体轻链(VL-CL)表达单元,所述第二质粒包含抗体重链VH-CH1表达单元;
所述第一质粒和第二质粒包含在所述细菌中相容的不同复制原点,其中所述不同复制原点分别为pBR ori和SEQ ID NO:20所示的CDF ori;并且
所述抗体轻链表达单元和抗体重链VH-CH1表达单元使用相同的原核启动子。
2.如权利要求1所述的双质粒系统,其中所述细菌为大肠杆菌。
3.如权利要求1所述的双质粒系统,其中所述启动子为可诱导启动子。
4.如权利要求3所述的双质粒系统,其中所述启动子为阿拉伯糖启动子(Para)或者乳糖启动子(Plac)。
5.如权利要求1所述的双质粒系统,其中所述抗体轻链恒定区为SEQ ID NO:17所示的kappa轻链恒定区或者SEQ ID NO:19所示的lambda轻链恒定区。
6.如权利要求1所述的双质粒系统,其中所述重链恒定区CH1段选自IgG1、IgG2、IgG3或者IgG4亚型。
7.如权利要求1所述的双质粒系统,其中所述第一质粒和第二质粒包含不同抗生素抗性基因。
8.如权利要求7所述的双质粒系统,其中所述抗生素抗性基因选自氨苄青霉素抗性基因(Ampr)、氯霉素抗性基因(CmR)、卡那霉素抗性基因(KaR)或者四环素抗性基因(TetR)。
9.如权利要求1所述的双质粒系统,其中所述第一质粒和第二质粒包含相同的编码信号肽的核酸分子。
10.如权利要求9所述的双质粒系统,其中所述信号肽为SEQ ID NO:6所示的PelB信号肽。
11.如权利要求1所述的双质粒系统,其中所述第一质粒包含氯霉素抗体基因(CmR)和SEQ ID NO:20所示的CDF ori,第二质粒包含氨苄青霉素抗性(Ampr)和pBR ori。
12.如权利要求1所述的双质粒系统,其包含SEQ ID NO:18所示的融合基因。
13.权利要求1-12中任一项所述的双质粒系统在制备Fab抗体片段中的用途。
14.权利要求1-12中任一项所述的双质粒系统在噬菌体呈现Fab抗体或Fab抗体库中的用途。
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CN108251431B (zh) | 2015-03-05 | 2020-12-08 | 北京百特美博生物科技有限公司 | 双载体系统及其用途 |
CN107236041B (zh) * | 2016-03-29 | 2020-07-24 | 舒泰神(北京)生物制药股份有限公司 | Il-17抗体 |
CN109715660A (zh) * | 2016-09-14 | 2019-05-03 | 北京韩美药品有限公司 | 一种能够特异性地结合il-17a的抗体及其功能片段 |
CN107698679B (zh) * | 2017-01-22 | 2019-03-01 | 北京东方百泰生物科技有限公司 | 抗pcsk9单克隆抗体 |
CN109796534B (zh) * | 2017-11-16 | 2021-08-10 | 北京比洋生物技术有限公司 | 抗il-17抗体/tnfr ecd融合蛋白及其用途 |
CN110551215A (zh) * | 2018-05-30 | 2019-12-10 | 中山康方生物医药有限公司 | 抗白细胞介素-17a抗体、其药物组合物及其用途 |
CN109679920B (zh) * | 2018-12-26 | 2019-11-22 | 北京贝来生物科技有限公司 | 一种表达il-17a信号通路阻断剂的间充质干细胞 |
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CN112142841B (zh) * | 2020-09-27 | 2022-03-22 | 江苏荃信生物医药股份有限公司 | 一种新的抗人il-17a单克隆抗体、包含其的试剂盒及其检测方法 |
CN112300285B (zh) * | 2020-11-06 | 2022-08-02 | 江苏荃信生物医药股份有限公司 | 一种定量检测血清中抗人白介素17单克隆抗体含量的酶联免疫分析方法 |
WO2022144023A1 (zh) * | 2021-01-04 | 2022-07-07 | 江苏恒瑞医药股份有限公司 | 抗il-17抗体治疗自身免疫性疾病和炎症的方法 |
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2015
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2016
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CN101970655A (zh) * | 2008-01-15 | 2011-02-09 | 雅培制药有限公司 | 改良哺乳动物表达载体及其用途 |
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CN105315371B (zh) | 2018-05-29 |
ZA201701920B (en) | 2018-07-25 |
US10392436B2 (en) | 2019-08-27 |
US20170327571A1 (en) | 2017-11-16 |
EP3181587A4 (en) | 2017-12-06 |
EP3181587B1 (en) | 2019-08-28 |
WO2016138842A1 (zh) | 2016-09-09 |
CN108251431A (zh) | 2018-07-06 |
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EP3181587A1 (en) | 2017-06-21 |
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