CN103209994B - 可用于被动流感免疫的抗体 - Google Patents
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Abstract
本发明揭示与包括1组和2组代表在内的多种流感病毒分化枝交叉反应的单克隆抗体和其片段。这些抗体可用于控制流感的流行和大范围流行以及提供针对季节性流感的预防性或治疗性保护。
Description
相关申请案交叉参考
本申请案主张2011年2月22日提出申请的美国临时专利申请案第61/445,455号、2011年2月15日提出申请的美国临时专利申请案第61/443,103号和2010年6月17日提出申请的美国临时专利申请案第61/355,978号的优先权,所述案件的全部内容以引用的方式并入本文中。
经由EFS-WEB提交的序列表参考
如MPEP§1730II.B.2(a)(C)中所审定和阐述,经由USPTO EFS-WEB服务器电子提交的以下序列表的全部内容出于所有目的全文以引用的方式并入本文中。在电子申请的文本文件上序列表鉴别如下:
文件名称 | 创建日期 | 大小(字节) |
388512012840seqlist.txt | 2011年6月17日 | 85,437个字节 |
技术领域
本发明涉及被动免疫以对抗流感的领域。更具体来说,涉及与流感血凝素A的HA0成熟裂解位点共有序列附近结合的抗体,包括由人类细胞分泌的抗体。
背景技术
流感病毒的血凝素蛋白具有在流感株之间高度异质的球形头结构域和含有为进入细胞中所需要的融合位点的茎部区域。血凝素蛋白(HA0)经激活以容许融合位点通过裂解成仍然使用二硫键保持偶合但经历构象变化的HA1和HA2部分而实现毒力。这个裂解位点含有流感A和流感B以及流感A和B的多个株所共有的共有序列。
比安奇E.(Bianchi,E.)等人,病毒学期刊(J.Virol.)(2005)79:7380-7388阐述基于这个裂解位点的共有序列的“通用”流感B疫苗,其在偶联到脑膜炎奈瑟球菌(Neisseriameningitidis)的外膜蛋白复合物时能够在小鼠中引发抗体。还阐述似乎与所述共有序列结合的单克隆抗体。另外,在小鼠中观察到抗血清的成功被动转移。包含衍生自流感的M2和/或HA蛋白质的肽的先前疫苗(例如阐述于WO2004/080403中的那些)易诱导具有弱功效或在株间无效的抗体。
发明内容
本发明提供结合多种流感株所共有的表位且更具体来说结合1组和2组A型流感中的任一者或二者的代表的单克隆抗体。所述抗体能够在由(例如)先前未经识别的流感株或市售季节性疫苗不赋予对抗保护的株引起的大范围流行事件中赋予被动免疫。由于抗体结合许多株,此指示靶向基本位点且因此可能甚至包括先前未遇到的株,因此所述疫苗将在所述情况下有效。所述抗体还可用于改善或预防个体感染,对于所述个体,接种疫苗不能产生完全保护性反应,或所述个体由于免疫系统较弱而处于高风险(例如,非常年幼者、老年人、移植患者、经癌症或HIV化学疗法治疗的患者)。
因此,在一个方面中,本发明涉及与作为模式标本(type specimen)的1组(包括H1、H2、H5、H6、H8、H9、H11、H13、H16)或2组(包括H3和H7)A型流感病毒广泛交叉反应且显示群组交叉反应性的单克隆抗体或其免疫反应性片段。所述抗体与流感病毒的HA0蛋白质中含有的表位特异性结合且识别HA的天然三聚形式。如业内所充分了解,基于非免疫球蛋白的蛋白质可具有与抗体类似的表位识别性质,且还可提供适宜的实施例,包括基于纤维连接蛋白、转铁蛋白、脂质运载蛋白的结合剂或基于核酸的适体。
在其它方面中,本发明涉及使用本发明的抗体和片段被动地抑制个体的病毒感染的方法。本发明还涉及用于产生这些抗体或片段的重组材料和方法。
附图说明
图1A和1B显示通过酶联免疫吸附分析(ELISA)测试的MAB53和MAB8对各种流感分化枝的HA0蛋白质的结合的结果。图1C显示MAB53结合HEK293细胞中表达的天然三聚体。
图2A和2B显示由福特生物生物传感器测试的MAB53和MAB8对各种分化枝的HA0蛋白质的结合的结果。
图3A显示通过酶联免疫吸附分析测试的MAB53对作为完整蛋白质的HA0和裂解片段HA1的结合程度。图3B显示MAB53对来自HA2的表示为CP的肽的结合程度。
图4A和4B显示福特生分析的结果,其表明MAB53与MAB8竞争,但不与MAB30竞争。
图5A和5B显示根据卡百特(Kabat)编号MAB53重链和轻链可变区的CDR作图。IGHV1-69*01是SEQ ID NO:83,且IGKV3-20*01是SEQ ID NO:84。
图6显示通过活体外噬斑分析所测量的各种量的MAB53对H1N1的中和。
图7A和7B显示用H1N1(图A)或H5N1(图B)攻击的小鼠的存活时间随投与各种量的MAB53的变化。
图8显示在感染H5N1后用MAB53治疗的效果。
具体实施方式
本发明提供有用的抗体,包括提供有效的方式以识别分泌所述抗体的细胞,以便可获取相关的编码序列并储存以在随后容易地重组产生所述抗体。所述方法包括基于二进制逻辑(binary logic)的筛选程序设计。
所述程序可特定地使用阐述于美国专利7,413,868中的细胞斑点(CellSpot)TM方法容易地应用于人类细胞,所述专利的内容以引用的方式并入本文中。简单来说,所述方法能够利用以微粒标记进行标记和显微镜观察在高通量分析中筛选从人类(或其它)个体获得的个别细胞。在一个例示性实施例中,通过使所分泌的抗体吸附于表面上或偶合到表面并随后用期望抗原(各抗原偶合到不同的微粒标记)处理表面,甚至可针对单一细胞所分泌的抗体对单一细胞进行分析。因此,可借助于显微镜识别细胞的印迹。使用这种技术,可针对期望的抗体分泌筛选数百万个细胞,且甚至可回收稀有抗体,例如在本文中期望用于株间被动流感免疫的那些。由于人类个体具有针对至少一些流感株的现有抗体,且由于通过本发明方法获得的抗体结合保守序列,因此,这些抗体用以达到解决新颖病毒株以及人类群体已经经历过的病毒株的目的。
本发明提供一种识别与血凝素(HA0)裂解位点共有序列附近的位置结合的单克隆抗体的方法。所述方法包含使候选单克隆抗体或片段与以下接触:i)基本上由所述共有序列上游或下游的氨基酸序列组成但缺少所述共有序列的肽:ii)基本上由所述共有序列上游的氨基酸序列组成且包括所述共有序列的肽:和iii)基本上由所述共有序列下游的氨基酸序列组成且包括所述共有序列的肽;其中将结合ii)和iii)的肽但不结合i)的肽的单克隆抗体鉴定为与HA0裂解位点共有序列特异性结合的肽。如所属领域的技术人员所了解,还可使用其它组合,只要遵循二进制逻辑(binary logic)即可。例如,i)可为基本上由第一株的共有序列上游的氨基酸组成且缺少共有序列的肽,且ii)是来自第一株的完整HA0序列,且iii)是来自第二株的完整HA0序列。还可使用较短的部分。为进一步证实,还可使用从保守区分离的肽,但是认为从较大的蛋白质结构域获得的信息将提供更多关于完整抗原识别的信息。
这种方法既不限于使用细胞斑点TM技术,也不限于人类抗体。这种方法的二进制逻辑可用于任一替代性筛选方法中。同样,其可应用于除天然免疫球蛋白以外的其它多样性库。
本发明方法依赖于二进制逻辑,其中使用含有期望共有序列和额外上游和/或下游部分的肽作为测试肽,且评估其与缺少共有序列的区域相比与抗体复合的能力。因此,获得图谱(pattern),从而可即刻识别分泌合适抗体的细胞。
在一个例示性实施例中,使用三种抗原来评估所分泌的抗体群体。第一种肽是HA0中所含有共有序列上游的所有或实质上所有氨基酸序列,且偶合到(比方说)红色的微粒标记。第二种测试抗原含有这些上游序列,但还含有共有序列,且用不同颜色(例如,蓝色)的颗粒标记。第三种测试肽含有共有序列和HA0蛋白质的所有或实质上所有下游区域,且用第三颜色(例如,绿色)的微粒标记。(所谓上游部分意指从共有序列朝向N端,且所谓下游部分意指从共有序列朝向C端的氨基酸序列延长部分。所谓“实质上所有”意指仅缺少一种或数种非必需氨基酸。)结合共有序列的抗体将结合经绿色和蓝色微粒标记的肽二者,但不结合缺少共有序列的经红色标记的上游序列。如果需要,可通过添加结合(例如)黄色微粒标记的仅代表下游部分而不含共有序列的第四种肽来证实特异性,其中所述黄色微粒标记将不结合抗体。当然,选择上游还是下游部分作为阴性对照无关紧要。
已知A型流感和B型流感的多种株的裂解位点。例如,上文引用的比安奇等人的文章在表1中显示若干所述株的裂解位点附近的序列:
表1A型和B型流感病毒成熟裂解位点的溶剂暴露区域的共有序列
aHA1与HA2之间的裂解位置由箭头表示。
b对于维多利亚(Victoria)和山形(Yamagata)谱系二者,共有序列是相同的。
如所述,严格共有序列开始于裂解位点上游的精氨酸残基,且因此包括于本发明测试肽中的优选共有序列具有序列RGI/L/F FGAIAGFLE(SEQ ID NO:7)。在测试肽中可使用此序列的仅一部分。
在识别分泌期望抗体的细胞之后,直接获取编码其的核苷酸序列并以大规模重组产生期望抗体。此还能够实现抗体的处理,以便其可作为(例如)单链抗体或仅可变区产生。
可将获取的核酸物理储存并回收用于以后的重组产生,和/或可获取关于抗体的编码序列的序列信息并储存以容许随后合成合适的核酸。编码序列中所含信息的可利用性和快速合成和克隆技术以及已知的重组产生方法容许在大范围流行或其它紧急情况事件中快速产生所需要的抗体。
申请者已回收多种与多种流感分化枝的HA0蛋白质免疫反应的单克隆抗体(SEQIDNO:9到23、26到40、42到56和59到73)。其它序列包括人类IgG l重链恒定区的氨基酸序列(SEQ ID NO:8)、人类轻链恒定κ区的氨基酸序列(SEQ ID NO:24)、人类轻链恒定λ区的氨基酸序列(SEQ ID NO:25)、人类重链恒定区的核苷酸序列(SEQ ID NO:41)、人类轻链恒定κ区的核苷酸序列(SEQ ID NO:57)和人类轻链恒定λ区的核苷酸序列(SEQID NO:58)。
这些mAb中的两者MAB53和MAB8在重要的关系较远的流感分化枝之间具有实质交叉反应性。如图1A和B中所显示,这些mAb中的每一者以适当的或高的亲和力结合三种不同的分化枝。MAB53结合H1、H9和H7分化枝的HA0,且MAB8结合H1、H7和H3分化枝的HA0蛋白质。图1中所显示的结果是通过ELISA分析针对HA0蛋白质获得,且表明亲和力在纳摩尔范围内。对所有1组分化枝的HA的天然三聚体的反应性是使用在HEK293细胞中表达的HA利用通过流式细胞术测量的抗体结合来验证。
使用替代的分析系统(基于生物水平干涉测量的结合分析,称为福特生生物传感器)来证实这些结果,如图2A和2B中所显示。如通过这种更准确的分析所测量,亲和力如下:
MAB53/H1=60pM,H5=6nM,H7=70pM,H9=30pM;
MAB8/H1=9nM,H3=16nM,H5=0.2nM。
MAB53和MAB8二者均为完全人类抗体,但其它物种所特有的类似抗体也包括在本发明内。在本发明的上下文中,“抗体”和其片段包括分子的那些与结合相关的部分;因此,片段将仅包括可变区,且“抗体”作为一般术语还应视为包括所述片段。因此,包括Fab片段、和Fv片段以及重组产生的单链抗体,和用以产生双特异性试剂的所述构建体融合物。嵌合抗体、人源化抗体和人类抗体全部在本发明的范围内,因为其是基于其它蛋白质支架(例如纤维连接蛋白、转铁蛋白或脂质运载蛋白)的抗体模拟物。同样,现存在多种用于制造并入来自两种单独抗体的抗原特异性结构域的单一抗体样分子(双特异性抗体)的技术。因此,可使用分别对1组和2组具有广泛反应性的个别抗体的Fab结构域来构建具有非常广泛的株反应性的单一抗体。适宜技术已由宏观基因(Macrogenics)(罗克维尔(Rockville),马里兰州(MD))、微麦特(Micromet)(贝塞斯达(Bethesda),马里兰州)和梅里麦克(Merrimac)(剑桥市(Cambridge),马萨诸塞州(MA))阐述。(参见,例如,奥卡特KD(Orcutt KD),阿克曼ME(Ackerman ME),西埃里维兹M(Cieslewicz M),奎罗兹E(Quiroz E),史拉萨斯基AL(Slusarczyk AL),弗兰焦尼JV(Frangioni JV),维特如普KD(Wittrup KD)。模块化IgG-scFv双特异性抗体拓扑学(Amodular IgG-scFv bispecific antibody topology),蛋白质工程设计与选择(Protein Eng Des Sel.)(2010)23:221-228;菲茨杰拉德J(FitzgeraldJ),卢戈夫斯基A(Lugovskoy A).靶向多种致癌基因途径的抗体治疗剂的合理工程改造(Rational engineering of antibody therapeutics targeting multiple oncogenepathways).单克隆抗体(MAbs.)(2011)1:3(3);贝耶乐PA(Baeuerle PA),莱因霍尔德C(Reinhardt C).用于癌症疗法的双特异性T细胞结合抗体(Bispecific T-cell engagingantibodies for cancer therapy).癌症研究(Cancer Res.)(2009)69:4941-4944。)
为识别MAB53结合的表位,对于未裂解的HA0蛋白质、HA1片段和HA2片段实施酶联免疫吸附分析。如图3A和B中所显示,尽管MAB53以高亲和力结合HA0,但其不结合HA1,此表明结合互补的HA2片段。为证实此假设,使用C端生物素将衍生自HA2的肽固定在经抗生蛋白链菌素涂布的板上。具体来说,所测试的序列是RGLFGAIAGFIENGW(SEQ ID NO:74)。还使用不相关的侧翼部分。经证实MAB53能够结合此肽。由于通过蛋白质印迹法(Western blot)测试时MAB53不结合HA0,因此假定优势表位在性质上至少部分是构象表位。
还已发现,MAB8和MAB53结合相同或邻近的表位,如通过其彼此竞争结合H1分化枝的HA0蛋白质的能力所展示。使用福特生分析使用2μg/ml抗体和50nM来自H1的HA0来显示此。如图4A中所显示,当添加50nM HA0溶液时,从MAB53获得的与福特生表面结合的信号增强。然而,当随后添加MAB8时,未出现其它信号。因此,MAB53阻断MAB8所结合的表位。然而,如图4B中所显示,与HA0免疫反应的另一抗体MAB30明显结合不同的表位,因为当将其添加到偶合的MAB53-HA0中时,信号增强。
重要的是,MAB53与MAB8的不同之处在于,MAB8是在pH降低到6时从HA0蛋白质释放,而MAB53不是。此差异是重要的,因为其似乎预示中和能力。在针对MAB8中和H1N1病毒感染的能力的测试中在噬斑减少分析中在MDCK靶细胞中,1-5μg/ml的低剂量MAB53中和H1N1、H7N3、HSN1和H9N2的感染。然而,MAB8不中和这些株的感染。因此,可通过以下优先选择中和株:在初级筛选期间在pH6下洗涤结合的MAB或片段,由此从HA0移除在抗体-病毒复合物经由胞内体腔进入细胞中时不可能保持结合的MAB,且由此预期会具有降低的中和病毒的能力。
例如,在细胞斑点方法中,HA0可与固体载体(荧光珠粒)结合且由MAB或MAB的混合物捕获,随后在pH6下洗涤。
MAB53重组产生且已经测序。重链和轻链的全长序列如下:
重链: ASTKGPSVFPLVPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKYDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:75);且
轻链: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:76)。
粗体序列是可变结构域,且非粗体序列代表重链的IgG1恒定区和轻链的κ恒定区。
另外,已根据卡百特CDR评估基于匹配框架区来分析这些可变区。如图5A中所显示,IGHV1-69*01重链(SEQ ID NO:83)的CDR1、CDR2和CDR3分别是GGIIRKYAIN(SEQ ID NO:77)、GGIIAIFNTANYAQKFQG(SEQ ID NO:78)和ARGMNYYSDYFDY(SEQ ID NO:79)。如图5B中所显示,IGKV3-20*01轻链(SEQ ID NO:84)的CDR1、CDR2和CDR3分别是RASQSVRSNNLA(SEQ IDNO:80)、GASSRAT(SEQ ID NO:81)和QQYGSSPALT(SEQ ID NO:82)。
如图6中所显示,MAB53在噬斑分析中在活体外中和H1N1。
还已显示,用分等级剂量的MAB53预处理的小鼠经受得住原本致死效价的H1N1和H5N1病毒的攻击,且提供100%的对抗H1N1攻击的保护,如图7中所显示。效能与科茹塞尔(Crucell)阐述的现有技术抗体相当,所述现有技术抗体不显示对抗2组株的活性。斯罗西比M.(Throsby M.)等人,公共科学图书馆1(PLoS One).(2008)3:e3942。电子版2008年12月16日。这些是从人类IgM+记忆B细胞回收的对抗H5N1和H1N1提供交叉保护的异源亚型中和单克隆抗体。
如图7A中所显示,MAB53在10mg/kg下提供完全保护;在2mg/kg下存活90%,且在0.4mg/kg下存活50%。相比之下,来自科茹塞尔的现有技术抗体在2mg/kg下提供完全保护,但在投与0.7mg/kg时仅存活20%。尽管病毒剂量的致死性低于图7A中所显示的实验;仅90%的小鼠在感染后死亡,然而在图7A中所显示的实验中,在第6天所有小鼠都死亡。这表明,MAB53高度强效。
当H5N1攻击代替H1N1攻击时,对于图7B中所显示的MAB53,10mg/kg达成80%存活;2mg/kg达成60%存活,且0.4mg/kg达成50%存活。相比之下,对于现有技术抗体,在5mg/kg下达成100%存活,且在1.7mg/kg下达成60%存活。因此,1.7mg/kg和2mg/kg下的存活率相当。在这种情况下,在用MAB53测试的小鼠中病毒剂量本身略微较不强效。
如图8中所显示,在第+3天作为感染后治疗投与MAB53(10mg/kg)以对抗高致病性H5N1株。对照抗体是匹配但不识别任何流感抗原的同种型。感染和治疗方案与图7A中相同,但在第+3天而不是第-1天给与。
实施肽扫描分析(pepscan analysis),从而确立MAB53和CR6261结合HA的类似区域,但不同表位(数据未显示)。这与两种抗体的不同活性一致。
因此,MAB53和在相同条件下结合相同表位的抗体可有效地作为被动疫苗适于保护群体对抗流行和大范围流行,以及预防性或治疗性地用于为具有减弱的免疫系统的患者对抗季节性流感。
序列表
NVPEKQTR(SEQ ID NO:1)
GIFGAIAGFIE(SEQ ID NO:2)
NIPSIQSR(SEQ ID NO:3)
GLFGAIAGFIE(SEQ ID NO:4)
PAKLLKER(SEQ ID NO:5)
GFFGAIAGFLE(SEQ ID NO:6)
RGI/L/FFGAIAGFLE(SEQ ID NO:7).
人类IgG1HC恒定区的氨基酸序列(SEQ ID NO:8)
ASTKGPSVFPLVPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
MAB1HC可变结构域的氨基酸序列(SEQ ID NO:9)
QVQLQESGPGLVKPSETLSLICRVSGGSISSHYWSWIRQPPGKGLEWIGYISYRGRSNHNPSLGRRVSMSIDTSENQFSLNLSSVIAADTAVYYCARDATGIREINALDIWGQGTTVTVSS
MAB8HC可变结构域的氨基酸序列(SEQ ID NO:10)
EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYTMSWVRQAPGQGLEWVSSITRTSSNIYYADSVEGRFTISRDNAKNSLYLQMHSLRVEDTAVYYCARISGVVGPVPFDYWGQGTLITVSS
MAB30HC可变结构域的氨基酸序列(SEQ ID NO:11)
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDHYMDWVRQAPGKGLEWVGRIRNKAAIYTTEYAASVKGRFTISRDDLKSSVYLQMNSLKTDDTAIYYCARSYGYFDYWGQGTLVTVSS
MAB42HC可变结构域的氨基酸序列(SEQ ID NO:12)
QVQLVQSGAEVKKPGASVKVSCKASGYSFNGYYMHWVRQAPGQGLEWMGWINLSSGGTDYAQKFQGWVTLTRDTSITTAYMELSSLRSNDTAVYYCARIRPRTGGLDSWGQGTLVIVSS
MAB48HC可变结构域的氨基酸序列(SEQ ID NO:13)
QVQLVQSGAEVKKPGSSVKVSCKASGVTFTAYAISWVRQAPGRGLEWMGGISPLFGIVNFGQNFQGRVTITADKSTGAAYMELSSLSSEDTAMYYCARGPYYYDRSHLDYWGQGTLVTVSS
MAB49HC可变结构域的氨基酸序列(SEQ ID NO:14)
QVQLVQSGAEVKRPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIGMFGTTNYAQKFQGRVTITADEFTSTAYMELTSLRSDDTAMYYCARDRNYYASGTYDHWGQGTLVTVSS
MAB52HC可变结构域的氨基酸序列(SEQ ID NO:15)
QVLLVQSGAEVKKPGSSVNISCKASGGTFSNYAISWVRQAPGQGLDWMGRIIPIFGTANYAQKFQGRLTITADESTSTAYMELSSLRSEDTAVFYCAITKPGSVYALDVWGQGTTVTVSS
MAB53HC可变结构域的氨基酸序列(SEQ ID NO:16)
QVQLVQSGAEVRKPGSSVKVSCKVSGGIIRKYAINWVRQAPGQGLEWMGGIIAIFNTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTALYYCARGMNYYSDYFDYWGQGSLVTVSP
MAB285HC可变结构域的氨基酸序列(SEQ ID NO:17)
QVQLVQSGAEVKKPGASVKVSCRASGYTFTGYYMQWVRQAPGQGLEWMGFINANTGVTNFAQKFQGRVTLTRDTSISTAYMELRRLTSADTAVYYCARAPQWLSYSFDIWGQGTMVTVSS
MAB321HC可变结构域的氨基酸序列(SEQ ID NO:18)
EVQLVESGAEVRSPGASVKLSCKASAYTFINYYLHWVRQAPGQRLEWMGWINPDSGVTEYAQTFQGRVTMTRDTSINTAYLDLERLTSDDTAVYYCARGFIPWGGKYFYLDYWGQGTLVTVSS
M AB322HC可变结构域的氨基酸序列(SEQ ID NO:19)
QVQLQQSGPGLVKPSQTLSLTCSVSGSFIRSGDYNWSWIRQPPGKGLEWIGYIDNSGSTHYNPSLKSRVSISVDTSKNHLSLKLSFVTDADTGVYYCAGEQASDSRGNYYYYAMDVWGQGTPVTVS S
MAB375HC可变结构域的氨基酸序列(SEQ ID NO:20)
QVQLQQSGPGLMKPSETLSLSCTVSGDSVSSFYWSWIRQSPGKGLEWIGYLLYSGNTKYNPSLKSRATISRDTSKNQLSLELTSLTAADTAVYYCARVVRWRHGGDLDVWGQGTMVTVSS
MAB376HC可变结构域的氨基酸序列(SEQ ID NO:21)
QVQLVQSGGDLVQPGGSLRLSCAVSGFIFRKYIMSWVRQAPGKGPEWVAVISSSGDRTFYADgVEGRFIVSRDNSKDTLFLQMNSLRTEDTAMYYCAKDLLGFCSGGDCLKVFDLWGRGTMVTVS S
MAB377HC可变结构域的氨基酸序列(SEQ ID NO:22)
QVQLLQSGPGLIKASETLSLSCSVSNDSVSNYYWSWIRQSPEKGLEWIGYLLYSGNTKYNPSLKSRAIISRDMSKNQLSLRVTSVTAADTAIYYCARVVRWRFGGDMDVWGQGTAVTVST
MAB378HC可变结构域的氨基酸序列(SEQ ID NO:23)
QVQLQQSGPGLIKPSETLSLSCSVSGDSVNNYYWSWIRQPPEKGLEWIGYLQYSGSTKYNPSLKSRVTISRDTSKNQLSLKLTSVTAADTAIYYCARVVRWRHGGDMDVWGQGTAVTVSS
人类LC恒定κ区的氨基酸序列(SEQ ID NO:24)
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
人类LC恒定λ区的氨基酸序列(SEQ ID NO:25)
GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVVPAECS
MAB1LC氨基酸序列(SEQ ID NO:26)
DIQMTQSPSSLSASGGDRVTITCRASQSVSTYLNWYQQKPGKAPNLLVYAVSNLQRGVPSRFSGSGSGTHFTLTISSLQPEDFATYYCQQSYSDPLTFGGGTKVEIKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
MAB8LC氨基酸序列(SEQ ID NO:27)
DIQMTQSPSSLSASVGDRVTITCRASQTISKYLNWYQQKPGRAPKLLIYSASSLQSGVPSRFTGSGSGTDFTLTITSLQPEDFATYYCQQSYRPSQITFGPGTKVDIKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
MAB30LC氨基酸序列(SEQ ID NO:28)
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGNAPNLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYDTYSPTFGQGTKVEIKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
MAB42LC氨基酸序列(SEQ ID NO:29)
QSALTQPASVSGSAGQSITISCTGTSSDVGAYNFVSWYQHHPGKAPKLMIYDVDNRPSGVSNRFSGSKSGDTASLTISGLQAEDEADYYCSSYRRNGPWVFGGGTKLTVLGQPKAAPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVVPAECS
MAB48LC氨基酸序列(SEQ ID NO:30)
EIVLTQSPGTLSLSPGERATLSCRASQSVGSSDLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYVSSPLTFGGGTKVEIKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
MAB49LC氨基酸序列(SEQ ID NO:31)
DIQMTQSPSSLSASVGDRVTITCRASQSISRYLNWYQQKPGKAPKLLIYSASSLQSGVPSRFGGSGSGTDFTLTISSLQPEDFALYYCQQTYSIPITFGQGTRLDFKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
MAB52LC氨基酸序列(SEQ ID NO:32)
DIQMTQSPSSLSASVGDRVTITCRASQTISTYLNWYQQKPGKAPNLLIYTASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYDAPTWTFGPGTKVEIKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
MAB53LC氨基酸序列(SEQ ID NO:33)
EIVLTQSPGTLSLSPGERATLSCRASQSVRSNNLAWYQHKPGQAPRLLIFGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPALTFGGGTKVEIKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
MAB285LC氨基酸序列(SEQ ID NO:34)
QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNPVNWYQQLPGTAPRLLIYSNNQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCTSWDDSLNAWVFGGGTRLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVVPAECS
MAB321LC氨基酸序列(SEQ ID NO:35)
DIVLTQSPPSLSASVGDRVTITCRASQSINNYLNWYQQKPGNAPRILIYGASSLVSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYRPLYTFGPGTQLDVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
MAB322LC氨基酸序列(SEQ ID NO:36)
DIVMTQSPSSLSASVGDRVTITCRASESISAYLNWYQHTPGRAPKLLIYAASSLETGVPSRFSGSGSGTEFTLTISGLQPEDFVTYYCQQTYNTPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
MAB375LC氨基酸序列(SEQ ID NO:37)
DIQMTQSPSFLSASVGDRVTFTCRASQGIASSLAWYQQKAGKAPKLLIYAASTLEDGVPSRFSGSGFGTEFTLTITSLQPEDFATYYCHQVNSYPRTFGPGTTVDINR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
MAB376LC氨基酸序列(SEQ ID NO:38)
DIQMTQSPSTLSASVGDTVTITCRASQSISTWLAWFQQKPGRAPKLLIYQASSLEGGVPSRFSGSGSGTDFNLTISGLQPDDFATYYCLQYNTYSKSFGQGTKVEIKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
MAB377LC氨基酸序列(SEQ ID NO:39)
DIQMTQSPSFLSASVGDRVTITCRASQGIATSLAWYQQKPGKAPRLLIYAASTLESGVPSRFSGGGSGTDFTLTISSLQPEDFAVYYCQQVNSYPRTFGPGTKLDVKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
MAB378LC氨基酸序列(SEQ ID NO:40)
DIQMTQSPSFLSASVGDRVTMTCRASQGISSYLAWYQQKPGKAPKLLIYAASTLESGVPSRFSGSGSGTEFTLTISSLQPEDFAIYYCQQVNGYPRTFGPGTKVDIKR
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS S PVTKSFNRGEC
人类IgG1HC恒定区的核苷酸序列(内含子加下划线)(SEQ ID NO:41)
GCCTCCACCAAGGGCCCATCAGTCTTCCCCCTGGCACCCTCTACCAAGAGCACCTCTGGGGGCACAACGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGGTGAGAGGCCAGC ACAGGGAGGGAGGGTGTCTGCTGGAAGCCAGGCTCAGCGCTCCTGCCTGGACGCATCCCGGCTATGCAGTCCCAGTC CAGGGCAGCAAGGCAGGCCCCGTCTGCCTCTTCACCCGGAGGCCTCTGCCCGCCCCACTCATGCTCAGGGAGAGGGT CTTCTGGCTTTTTCCCCAGGCTCTGGGCAGGCACAGGCTAGGTGCCCCTAACCCAGGCCCTGCACACAAAGGGGCAG GTGCTGGGCTCAGACCTGCCAAGAGCCATATCCGGGAGGACCCTGCCCCTGACCTAAGCCCACCCCAAAGGCCAAAC TCTCCACTCCCTCAGCTCGGACACCTTCTCTCCTCCCAGATTCCAGTAACTCCCAATCTTCTCTCTGCAGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGGTAAGCCAGCCCAGGCCTCGCCCTCCAGCTCAAGGCGGG ACAGGTGCCCTAGAGTAGCCTGCATCCAGGGACAGGCCCCAGCCGGGTGCTGACACGTCCACCTCCATCTCTTCCTC AGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGTGGGACCCGTGGGGTGCGAGGGCCACATGGACAGAGGCCGGCTCGGCCCACC CTCTGCCCTGAGAGTGACCGCTGTACCAACCTCTGTCCCTACAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA
MAB1HC可变结构域的核苷酸序列(SEQ ID NO:42)
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCATCTGCAGAGTCTCTGGTGGCTCGATCAGTAGTCATTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGATATATTTCTTATAGGGGGAGAAGCAACCACAATCCTTCCCTTGGGAGACGAGTCTCTATGTCAATAGACACGTCGGAGAACCAGTTCTCCCTGAACCTGAGCTCTGTGATCGCTGCGGACACGGCCGTATATTACTGTGCGAGAGATGCTACTGGGATCAGAGAAATCAATGCTCTTGATATCTGGGGCCAAGGGACAACGGTCACCGTCTCTTCA
MAB8HC可变结构域的核苷酸序列(SEQ ID NO:43)
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGTTTCACTTTCAGTACCTATACTATGAGTTGGGTCCGCCAGGCTCCAGGGCAGGGGCTAGAGTGGGTCTCGTCCATTACTAGGACTAGTAGTAATATATACTACGCAGACTCAGTGGAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAGATGCATAGCCTGAGAGTCGAAGACACGGCTGTGTATTACTGTGCGAGAATCAGCGGGGTAGTGGGACCTGTCCCCTTTGACTACTGGGGCCAGGGAACCCTGATCACCGTCTCCTCT
MAB30HC可变结构域的核苷酸序列(SEQ ID NO:44)
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACCACTACATGGACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTGGCCGTATTAGAAATAAAGCTGCCATTTACACCACAGAATACGCCGCGTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTTAAAGAGCTCAGTGTATCTGCAAATGAACAGTCTGAAAACCGACGACACGGCCATATATTACTGTGCTAGGAGCTATGGATACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
MAB42HC可变结构域的核苷酸序列(SEQ ID NO:45)
CAGGTGCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATATTCCTTCAACGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATCAACCTGAGCAGTGGTGGCACAGATTATGCACAGAAATTTCAGGGGTGGGTCACTTTGACCAGGGACACGTCCATCACCACAGCCTACATGGAGTTGAGCAGCCTGAGATCGAACGACACGGCCGTGTATTACTGTGCGAGAATTAGACCTCGCACTGGTGGACTTGACTCCTGGGGCCAGGGAACCCTGGTCATCGTCTCCTCA
MAB48HC可变结构域的核苷酸序列(SEQ ID NO:46)
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAAGTCTCCTGCAAGGCTTCTGGAGTCACCTTCACCGCCTATGCTATCAGTTGGGTGCGACAGGCCCCTGGACGAGGGCTTGAGTGGATGGGAGGGATCAGCCCTTTGTTTGGAATAGTAAATTTCGGACAGAACTTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGGGCGCAGCCTACATGGAGCTGAGCAGCCTGAGCTCTGAGGACACGGCCATGTATTACTGTGCGAGAGGACCCTATTATTACGATAGAAGTCACCTAGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
MAB49HC可变结构域的核苷酸序列(SEQ ID NO:47)
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAGGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGTTATGCTATTAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCGGTATGTTTGGAACAACAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATTCACGAGCACAGCCTACATGGAGCTGACCAGCCTGAGATCTGACGACACGGCCATGTATTACTGTGCGAGAGACCGAAATTACTATGCTTCGGGGACTTATGACCACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
MAB52HC可变结构域的核苷酸序列(SEQ ID NO:48)
CAAGTGCTGCTGGTGCAGTCTGGGGCTGAAGTGAAGAAGCCTGGGTCCTCGGTGAATATCTCTTGCAAGGCTTCTGGAGGCACTTTCAGCAACTATGCTATCTCCTGGGTGCGACAGGCCCCTGGACAAGGTCTTGACTGGATGGGAAGGATCATCCCTATCTTTGGAACAGCAAACTACGCACAGAAATTCCAGGGCAGACTCACCATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAACTGAGCAGCCTGAGATCTGAAGACACGGCCGTGTTTTACTGTGCGATTACTAAACCGGGGTCTGTCTACGCTTTGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
MAB53HC可变结构域的核苷酸序列(SEQ ID NO:49)
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAGGAAGCCGGGGTCCTCGGTGAAGGTCTCCTGCAAGGTTTCTGGAGGCATCATTAGGAAATATGCTATCAACTGGGTGCGACAGGCCCCCGGACAAGGGCTTGAGTGGATGGGAGGGATCATCGCTATCTTTAATACAGCAAACTATGCACAGAAATTCCAGGGCAGAGTCACGATTACCGCGGACGAGTCCACGAGCACAGTCTACATGGAGCTGAGCAGCCTGAGATCTGAAGACACGGCCCTTTATTACTGTGCGAGAGGAATGAATTACTACAGTGACTACTTTGACTACTGGGGCCAGGGAAGCCTTGTCACCGTCTCCCCA
MAB285HC可变结构域的核苷酸序列(SEQ ID NO:50)
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCCGGGCTTCTGGATACACCTTCACCGGCTACTATATGCAGTGGGTGCGGCAGGCCCCTGGCCAAGGGCTTGAGTGGATGGGATTCATCAATGCTAACACTGGTGTCACAAACTTTGCTCAGAAGTTTCAGGGCAGGGTCACCTTGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAGGAGGCTGACATCTGCCGACACGGCCGTGTATTACTGTGCGAGAGCGCCCCAGTGGTTATCGTATTCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCCTCA
MAB321HC可变结构域的核苷酸序列(SEQ ID NO:51)
GAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAGGAGCCCTGGGGCCTCAGTGAAGCTCTCCTGCAAGGCTTCTGCATACACCTTCATCAACTACTATCTGCACTGGGTGCGACAGGCCCCTGGACAAAGGCTTGAGTGGATGGGATGGATCAACCCTGACAGTGGTGTCACAGAATATGCACAGACATTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAATACAGCCTACCTGGACCTGGAGAGACTGACATCTGACGACACGGCCGTATATTACTGTGCGAGAGGTTTTATTCCTTGGGGTGGGAAGTACTTCTACCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
MAB322HC可变结构域的核营酸序列(SEQ ID NO:52)
CAGGTACAGCTGCAGCAGTCAGGGCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCAGTGTATCTGGTAGTTTCATCAGAAGTGGAGATTATAATTGGAGTTGGATCCGCCAGCCCCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCGATAATAGCGGGAGCACCCACTACAACCCGTCCCTCAAGAGTCGAGTTAGCATATCAGTGGACACGTCCAAGAACCACTTGTCCCTGAAGCTGAGTTTTGTGACTGACGCAGACACGGGCGTGTATTACTGTGCCGGAGAACAAGCGTCTGATAGTCGTGGTAATTACTACTACTACGCTATGGACGTCTGGGGCCAAGGGACCCCGGTCACCGTCTCCTCA
MAB375HC可变结构域的核苷酸序列(SEQ ID NO:53)
CAGGTGCAGCTGCAGCAGTCGGGCCCCGGACTGATGAAGCCTTCGGAGACCCTGTCCCTCAGCTGCACTGTCTCTGGTGACTCCGTCAGTAGTTTTTATTGGAGTTGGATTCGGCAGTCTCCAGGAAAGGGACTGGAGTGGATTGGGTATTTGCTTTACAGTGGGAATACCAAGTATAATCCGTCCCTCAAGAGTCGAGCCACCATATCAAGAGACACGTCCAAGAACCAGTTGTCCCTGGAGTTGACCTCTCTGACCGCTGCGGACACGGCCGTCTACTATTGTGCGAGAGTGGTGAGATGGCGACATGGTGGCGATTTGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
MAB376HC可变结构域的核苷酸序列(SEQ ID NO:54)
CAGGTGCAGCTGGTGCAGTCCGGGGGGGACTTGGTCCAGCCGGGGGGGTCCCTGAGACTGTCATGTGCAGTCTCTGGATTCATCTTTAGAAAATATATCATGAGTTGGGTCCGGCAGGCTCCAGGGAAGGGGCCGGAGTGGGTCGCAGTTATTAGTTCTAGTGGTGACCGGACATTCTACGCCGACTCCGTGGAGGGCCGCTTCATCGTCTCCAGAGACAATTCCAAGGACACACTGTTTCTGCAAATGAACAGCCTGAGAACCGAGGACACGGCCATGTATTACTGTGCGAAAGACCTTTTGGGATTTTGTAGTGGTGGTGATTGCCTGAAGGTCTTCGATCTCTGGGGCCGAGGCACCATGGTCACTGTCTCCTCA
MAB377HC可变结构域的核苷酸序列(SEQ ID NO:55)
CAGGTGCAGCTGCTGCAGTCGGGCCCAGGACTGATAAAGGCTTCGGAGACCCTGTCTCTCAGCTGCAGTGTCTCTAATGACTCCGTCAGTAATTATTATTGGAGTTGGATCCGGCAGTCCCCAGAGAAGGGACTGGAGTGGATTGGGTATTTGCTTTATAGTGGGAATACCAAGTACAATCCCTCCCTCAAGAGTCGAGCCATCATATCAAGAGACATGTCCAAAAATCAGTTGTCCCTCAGAGTGACTTCTGTGACCGCTGCGGACACGGCCATATATTATTGTGCGCGAGTGGTGAGATGGCGATTTGGTGGTGATATGGACGTCTGGGGTCAAGGGACCGCGGTCACCGTCTCCACA
MAB378HC可变结构域的核苷酸序列(SEQ ID NO:56)
CAGGTGCAGCTGCAGCAGTCGGGCCCAGGACTGATAAAGCCTTCGGAGACCCTGTCTCTCAGCTGCTCTGTCTCTGGTGACTCCGTCAATAATTATTATTGGAGTTGGATCCGGCAGCCCCCAGAGAAGGGACTGGAGTGGATTGGGTATCTGCAGTATAGTGGGAGTACAAAGTACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAAGAGACACGTCCAAAAACCAGTTGTCCCTGAAGCTGACCTCTGTGACCGCTGCGGACACGGCCATATATTATTGTGCGAGAGTGGTGAGATGGCGACATGGTGGGGATATGGACGTCTGGGGCCAAGGGACCGCGGTCACCGTCTCCTCT
人类LC恒定κ区的核苷酸序列(SEQ ID NO:57)
CGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCTAGCGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
人类LC恒定λ区的核苷酸序列(SEQ ID NO:58)
GGTCAGCCCAAGGCTGCCCCCTCTGTCACTCTGTTCCCGCCCTCTAGCGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGTCCCTGCAGAATGCTCT
MAB1LC可变结构域的核苷酸序列(SEQ ID NO:59)
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGGAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGTGTTAGTACGTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGGTCTATGCTGTATCCAATTTACAACGTGGCGTGCCATCAAGGTTCAGTGGCAGTGGATCTGGGACACATTTCACTCTCACAATCAGCAGTCTGCAACCTGAGGATTTCGCAACTTACTACTGTCAACAGAGTTACAGTGACCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
MAB8LC可变结构域的核苷酸序列(SEQ ID NO:60)
GACATCCAGATGACCCAGTCTCCATCTTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGACCATTAGCAAGTATTTAAATTGGTATCAGCAGAAGCCAGGGAGAGCCCCTAAACTCCTGATCTACTCTGCGTCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCACTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCACCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGACCCTCCCAGATCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA
MAB30LC可变结构域的核苷酸序列(SEQ ID NO:61)
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGTTGGTTGGCCTGGTATCAGCAGAAACCAGGGAACGCCCCTAACCTCCTGATCTATAAGGCGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATGATACTTATTCTCCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA
MAB42LC可变结构域的核苷酸序列(SEQ ID NO:62)
CAGTCTGCCCTGACTCAGCCTGCCTCCGGGTCTGGGTCTGCTGGACAGGCGATCACCATCTCCTGCACTGGAACCGGCACTGACGTCTGTGCTTATAACTTTGTCTCCTGGTACCAACACCACCCCGGCGAAGCCCCCAAACTCATGATTTATGATGTCGATAATCGGCCCTCATGGGTTTCTAATCGCTTCTCTGGCTCCAAGTCTGGTAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTACTACTGCAGCTCATATAGAAGGAACGGCCCTTGCTTGTTCGGCGGAGGGACCAAGCTGACCGTCCTG
MAB48LC可变结构域的核苷酸序列(SEQ ID NO:63)
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTGGCAGCAGCGACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATATATGGTGCATCCAGCCGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGTCAGTTCACCCCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAG
MAB49LC可变结构域的核苷酸序列(SEQ ID NO:64)
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGGTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATTCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCGGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCACTTTACTACTGTCAACAGACTTACAGTATCCCGATCACCTTCGGCCAAGGGACACGACTGGACTTTAAA
MAB52LC可变结构域的核苷酸序列(SEQ ID NO:65)
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACTATCACTTGCCGGGCAAGTCAGACCATTAGCACCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATACTGCATCCAGTTTGCAAAGCGGGGTCCCATCAAGATTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTATTACTGTCAACAGAGTTACGATGCCCCCACGTGGACCTTCGGCCCAGGGACCAAGGTGGAAATCAAA
MAB53LC可变结构域的核苷酸序列(SEQ ID NO:66)
GAAATTGTGTTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGAAGCAACAACTTAGCCTGGTACCAGCACAAACCTGGCCAGGCTCCCAGGCTCCTCATCTTTGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTATATTACTGTCAGCAGTATGGTAGCTCACCTGCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
MAB285LC可变结构域的核苷酸序列(SEQ ID NO:67)
CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAGTAATCCTGTAAACTGGTACCAGCAGCTCCCAGGAACGGCCCCCAGACTTCTCATCTATAGTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTACTACTGTACATCATGGGATGACAGCCTGAATGCTTGGGTGTTCGGCGGGGGGACCAGGCTGACCGTCCTA
MAB321LC可变结构域的核苷酸序列(SEQ ID NO:68)
GATATCGTGTTGACTCAGTCTCCACCCTCCCTGTCTGCATCTGTGGGGGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAATAACTACTTAAATTGGTATCAACAGAAACCAGGGAACGCCCCAAGAATACTAATCTATGGTGCATCCAGTTTGGTAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACCGGCCCCTGTACACTTTTGGCCCGGGGACCCAGCTGGATGTCAAA
MAB322LC可变结构域的核苷酸序列(SEQ ID NO:69)
GATATCGTGATGACCCAGTCTCCATCTTCCCTGTCTGCATCTGTGGGAGACAGAGTCACCATCACTTGCCGGGCAAGTGAGAGCATTAGCGCTTATTTAAATTGGTATCAGCACACACCAGGGAGAGCCCCTAAGCTCCTGATCTATGCTGCCTCCAGTTTGGAAACTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGCACAGAATTCACTCTCACCATCAGCGGTCTGCAACCTGAAGATTTTGTCACTTACTACTGTCAACAGACTTACAATACCCCTCGGACCTTCGGCCAAGGGACCAAGGTGGAAATCAAA
MAB375LC可变结构域的核苷酸序列(SEQ ID NO:70)
GATATCCAGATGACCCAGTCTCCATCCTTCTTGTCTGCATCTGTGGGAGACAGAGTCACCTTCACTTGCCGGGCCAGTCAGGGCATTGCCAGTTCTTTAGCCTGGTATCAGCAAAAAGCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCTTCTACTTTGGAAGATGGGGTCCCATCAAGGTTCAGCGGCAGTGGATTTGGGACAGAATTCACTCTCACAATCACCAGCCTGCAGCCTGAAGATTTTGCAACCTATTACTGTCATCAGGTGAATAGTTACCCTCGGACTTTCGGCCCTGGGACCACAGTGGATATCAAC
MAB376LC可变结构域的核苷酸序列(SEQ ID NO:71)
GATATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTGGGAGACACAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTACTTGGTTGGCCTGGTTTCAGCAGAAACCAGGGAGAGCCCCTAAACTCCTGATCTATCAGGCGTCTAGTTTGGAAGGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGGTCTGGGACAGACTTCAACCTCACCATCAGCGGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCTACAATATAACACTTATTCGAAGTCATTCGGCCAAGGGACCAAGGTGGAAATCAAAC
MAB377LC可变结构域的核苷酸序列(SEQ ID NO:72)
GATATCCAGATGACCCAGTCTCCATCCTTCTTGTCTGCATCTGTCGGAGACAGAGTCACCATCACCTGCCGGGCCAGTCAGGGCATTGCCACTTCTTTAGCCTGGTATCAGCAAAAACCTGGGAAAGCCCCGAGGCTCCTGATCTATGCTGCATCCACTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCGGTGGATCTGGGACAGACTTCACTCTCACAATCAGCAGTCTGCAGCCCGAAGATTTTGCTGTTTATTACTGTCAACAGGTTAACTCCTATCCTCGGACTTTCGGCCCTGGGACCAAACTGGATGTCAAAC
MAB378LC可变结构域的核苷酸序列(SEQ ID NO:73)
GATATCCAGATGACCCAGTCTCCATCCTTCTTGTCTGCATCTGTAGGAGACAGAGTCACCATGACCTGCCGGGCCAGTCAGGGCATTAGCAGTTATTTAGCCTGGTATCAGCAAAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCGACTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCCGAAGATTTTGCAATTTATTACTGTCAACAGGTTAATGGTTACCCTCGGACTTTCGGCCCTGGGACCAAAGTGGATATCAAAC
RGLFGAIAGFIENGW(SEQ ID NO:74).
MAB53重链(SEQ ID NO:75)
QVQLVQSGAEVRKPGSSVKVSCKVSGGIIRKYAINWVRQAPGQGLEWMGGIIAIFNTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTALYYCARGMNYYSDYFDYWGQGSLVTVSPASTKGPSVFPLVPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
MAB53轻链(SEQ ID NO:76)
EIVLTQSPGTLSLSPGERATLSCRASQSVRSNNLAWYQHKPGQAPRLLIFGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPALTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
GGIIRKYAIN(SEQ ID NO:77)
GGIIAIFNTANYAQKFQG(SEQ ID NO:78)
ARGMNYYSDYFDY(SEQ ID NO:79)
RASQSVRSNNLA(SEQ ID NO:80)
GASSRAT(SEQ ID NO:81)
QQYGSSPALT(SEQ ID NO:82)
IGHV1-69*01(SEQ ID NO:83)
QVQLVQSGAEVRKPGSSVKVSCKVSGGIIRKYAINWVRQAPGQG
LEWMGGIIAIFNTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTALYYCARGMNYYSDYFDYWGQGSLVTTVS
IGKV3-20*01(SEQ ID NO:84)
EIVLTQSPGTLSLSPGERATLSCRASQSVRSNNLAWYQHKPGQAPRLLIFGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPALTFGGGTKVEIK
Claims (10)
1.一单克隆抗体或其免疫反应性片段,其与包括至少一种来自A型流感的1组和2组的分化枝在内的流感病毒分化枝的HA0蛋白质茎部区域结合;以及其包括:
重链可变区,所述重链可变区包含序列GGIIRKYAIN(SEQ ID NO:77)的CDR1、序列GGIIAIFNTANYAQKFQG(SEQ ID NO:78)的CDR2和序列ARGMNYYSDYFDY(SEQ ID NO:79)的CDR3;和
轻链可变区,所述轻链可变区包含序列RASQSVRSNNLA(SEQ ID NO:80)的CDR1、序列GASSRAT(SEQ ID NO:81)的CDR2和序列QQYGSSPALT(SEQ ID NO:82)的CDR3。
2.根据权利要求1所述的单克隆抗体或片段,其包含重链可变区,所述重链可变区由以下序列组成:
QVQLVQSGAEVRKPGSSVKVSCKVSGGIIRKYAINWVRQAPGQGLEWMGGIIAIFNTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTALYYCARGMNYYSDYFDYWGQGSLVTVSP(SEQ ID NO:75的氨基酸1到120)。
3.根据权利要求2所述的单克隆抗体或片段,其包含轻链可变区,所述轻链可变区由以下序列组成:
EIVLTQSPGTLSLSPGERATLSCRASQSVRSNNLAWYQHKPGQAPRLLIFGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPALTFGGGTKVEIK(SEQ ID NO:76的氨基酸1到109)。
4.一种医药组合物,其包含根据权利要求1到3中任一权利要求所述的单克隆抗体或片段。
5.一种根据权利要求1到3中任一权利要求所述的单克隆抗体或片段或根据权利要求4所述的组合物在制备药物中的用途,所述药物用于治疗或预防个体流感感染。
6.一种重组表达系统,其包含可操作地连接到表达的控制序列的编码根据权利要求1到3中任一权利要求所述的单克隆抗体或片段的重链或轻链可变区的核苷酸序列。
7.一种重组宿主细胞,其经修饰以含有根据权利要求6所述的表达系统。
8.一种产生与流感病毒免疫反应的单克隆抗体或片段的方法,所述方法包含在表达所述核苷酸序列的条件下培养根据权利要求7所述的细胞。
9.一种被动免疫以对抗A型流感的1组和2组的疫苗,其包括预防上或治疗上有效量的权利要求1所述的抗体或片段。
10.一单克隆抗体或其免疫反应性片段,其与包括至少一种来自A型流感的1组和2组的分化枝在内的流感病毒分化枝的HA0蛋白质茎部区域结合;以及其包括:
重链可变区,所述重链可变区由以下序列组成:
QVQLVQSGAEVRKPGSSVKVSCKVSGGIIRKYAINWVRQAPGQGLEWMGGIIAIFNTANYAQKFQGRVTITADESTSTVYMELSSLRSEDTALYYCARGMNYYSDYFDYWGQGSLVTVSP(SEQ ID NO:75的氨基酸1到120);以及
轻链可变区,所述轻链可变区包含序列RASQSVRSNNLA(SEQ ID NO:80)的CDR1、序列GASSRAT(SEQ ID NO:81)的CDR2和序列QQYGSSPALT(SEQ ID NO:82)的CDR3。
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SG11201503734UA (en) | 2012-11-13 | 2015-06-29 | Genentech Inc | Anti-hemagglutinin antibodies and methods of use |
MX2015012397A (es) | 2013-03-14 | 2016-07-26 | Contrafect Corp | Composiciones y metodos basados en anticuerpos neutralizados suministrados intranasalmente para eficacia terapeutica aumentada. |
CN106795216B (zh) | 2014-02-04 | 2021-04-20 | 抗非特公司 | 可用于被动流感免疫的抗体及其组合物、组合和使用方法 |
US10639370B2 (en) | 2014-02-04 | 2020-05-05 | Contrafect Corporation | Antibodies useful in passive influenza immunization, and compositions, combinations and methods for use thereof |
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TWI701258B (zh) | 2014-12-19 | 2020-08-11 | 美商再生元醫藥公司 | 流行性感冒病毒血球凝集素之人類抗體 |
EP3374390A1 (en) | 2015-11-13 | 2018-09-19 | Visterra, Inc. | Compositions and methods for treating and preventing influenza |
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CN113924147A (zh) | 2019-03-25 | 2022-01-11 | 威特拉公司 | 用于治疗和预防流感的组合物和方法 |
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US10676520B2 (en) | 2020-06-09 |
CA2839421C (en) | 2019-12-03 |
KR101849738B1 (ko) | 2018-04-17 |
CN103209994A (zh) | 2013-07-17 |
EP2582721A1 (en) | 2013-04-24 |
JP6050747B2 (ja) | 2016-12-21 |
KR20130137584A (ko) | 2013-12-17 |
CA2839421A1 (en) | 2011-12-22 |
AU2011268072C1 (en) | 2017-10-19 |
AU2017203924B2 (en) | 2019-08-08 |
US20120020971A1 (en) | 2012-01-26 |
RU2013102073A (ru) | 2014-07-27 |
WO2011160083A1 (en) | 2011-12-22 |
EP2582721B1 (en) | 2018-08-22 |
EP2582721A4 (en) | 2013-11-20 |
AU2011268072A2 (en) | 2013-02-28 |
AU2011268072B2 (en) | 2017-03-09 |
BR112012032185A2 (pt) | 2016-10-11 |
DK2582721T3 (en) | 2018-10-01 |
CN106397584A (zh) | 2017-02-15 |
AU2017203924A1 (en) | 2017-07-06 |
ES2687706T3 (es) | 2018-10-26 |
JP2013531993A (ja) | 2013-08-15 |
RU2635999C2 (ru) | 2017-11-17 |
AU2011268072A1 (en) | 2013-01-31 |
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