CN112105637A - 可结合sftsv的纳米抗体及其应用 - Google Patents
可结合sftsv的纳米抗体及其应用 Download PDFInfo
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- CN112105637A CN112105637A CN201980001738.0A CN201980001738A CN112105637A CN 112105637 A CN112105637 A CN 112105637A CN 201980001738 A CN201980001738 A CN 201980001738A CN 112105637 A CN112105637 A CN 112105637A
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Abstract
本发明涉及一种可结合SFTSV的多肽,包括3个互补决定区CDR1‑3,CDR1序列为或包括SEQ ID NO:1‑74所示序列之一,CDR2序列为或包括SEQ ID NO:75‑151所示序列之一,CDR3序列为或包括SEQ ID NO:152‑232所示序列之一。本发明针对高致死率但缺乏有效疫苗和特异性抗病毒药物的SFTS进行纳米抗体药物开发和诊断试剂盒研发,通过制备GN蛋白、免疫双峰骆驼、利用噬菌体库展示纳米单抗的平台技术等,筛选到特异性结合GN的纳米抗体VHH,鉴定了其CDR序列,并构建了人源化抗体SNB;同时利用人源化小鼠模型体内评估SNB在治疗SFTSV感染的疗效。本发明为SFTS的临床治疗提供潜在的纳米抗体新药,同时为SFTS的诊断提供相应的检测试剂盒。
Description
技术领域
本发明涉及生物医药领域。更特别地,涉及一种可结合SFTSV的多肽,所述的多肽在制备SFTSV检测剂或SFTSV治疗药物中的应用,以及一种SFTSV检测试剂盒。
背景技术
发热伴血小板减少综合征(Severe fever with thrombocytopenia syndrome,SFTS)是一种由新型布尼亚病毒(Severe fever with thrombocytopenia syndromevirus,SFTSV)引起的急性传染病,主要通过蜱虫叮咬或急性病人的血液、黏膜接触传播,临床主要表现为发热、血小板减少、白细胞减少以及包括胃肠道、肝脏、肾脏在内的多器官功能异常。自2009年首次在湖北和河南报道SFTS以来,我国已有16个省份发布了病例报告,截止2014年的确诊病例数已超过3500例,且近年来发病率不断升高;同时,在韩国、日本、阿拉伯和美国均有SFTS病例报道,提示该病的流行区域正在扩大。目前报道的SFTS死亡率在6.3%-30%之间;而韩国和日本在2016年公布的死亡率分别高达35.4%和50%。然而,临床至今缺乏针对SFTS的特异性治疗药物,只能进行广谱抗病毒治疗和对症下药,这为SFTS的预防及控制带来极大困难。
特异性中和抗体在抗病毒治疗方面有着很好的临床疗效,如呼吸道合胞病毒单抗Palivizumab和狂犬病毒抗血清等。已有研究指出,针对SFTSV表面糖蛋白(GlycoproteinN,GN)的中和抗体对病人生存率起着重要作用。而我们前期的研究结果也显示,血清含抗GN抗体的SFTS病人均康复良好,而血清中不含GN抗体的SFTS病人其死亡率高达66.7%。这些研究提示,靶向GN的中和抗体治疗将是对抗SFTSV行之有效的方法。
1993年,一种来源于骆驼科的新型天然抗体被发现。该抗体天然缺失轻链而只由重链组成,其重链包含两个恒定区(CH2和CH3)、一个铰链区和一个重链可变区(Variableheavy chain domain,VHH,即抗原结合位点),该重链可变区的相对分子质量约为13KDa,仅为常规抗体的1/10,且分子高度和直径均在纳米级别,是目前可获得的最小的功能性抗体片段,因此又被称为纳米单抗(Nanobody,Nb)。因纳米单抗稳定性高(90℃条件下仍不会降解)、亲和力高、与人源抗体同源性超过80%、毒性和免疫原性均较低等特点,最近纳米单抗被广泛用于免疫诊断试剂盒研发、影像学研发以及针对肿瘤、炎症、传染病和神经系统疾病等领域的抗体药物研发。
目前已知抗GN的SFTS中和抗体是2013年通过噬菌体展示SFTS病人抗体库筛选得到的Mab4-5,其IC50为2μg/ml-44.2μg/ml。中和抗体的IC50越低越好,能极大节约抗体的使用量从而节省生产成本,同时也能延长抗体在体内维持有效浓度的时间。我们前期对SFTS病人血清的抗体效价做了检测,发现针对GN蛋白的抗血清仅为100左右的稀释倍数,这提示我们,以低抗体滴度的SFTS病人血清构建抗体库可能限制了高效中和抗体的筛选。因此我们期望通过新的技术手段,获得更为高效稳定的、IC50更低的SFTSV特异性中和抗体。
发明内容
本发明通过用抗原免疫骆驼,获取骆驼源纳米单抗及其VHH,用于诊断和治疗急性感染的SFTS病人。基于这些研究,本发明提供了一种可结合SFTSV的多肽,包括3个互补决定区CDR1-3,CDR1序列为或包括SEQ ID NO:1-74所示序列之一,CDR2序列为或包括SEQ IDNO:75-151所示序列之一,CDR3序列为或包括SEQ ID NO:152-232所示序列之一。
在一个具体实施方案中,所述多肽还包括4个框架区FR1-4,所述FR1-4与所述CDR1-3交错排列。例如,可将FR1-4序列设计为如SEQ ID NO:235-237所示,但本发明的范围不限于此。抗体的特异性识别和结合能力主要由CDR区序列决定,FR序列影响不大,可根据物种来设计,这是本领域公知的。例如,可设计人源、鼠源或骆驼源的FR区序列来连接上述CDR,从而一个可结合SFTSV的多肽或结构域。
在一个优选实施方案中,所述多肽为单克隆抗体。
在一个优选实施方案中,所述多肽为VHH。
在一个优选实施方案中,所述多肽为骆驼源的VHH或人源化的VHH。
在一个具体实施方案中,所述多肽的CDR序列如下:
I)CDR3的序列为SEQ ID NO:176;并且
II)CDR1的序列为SEQ ID NO:54并且CDR2的序列为SEQ ID NO:132;或者
CDR1的序列为SEQ ID NO:22并且CDR2的序列为SEQ ID NO:100。
在另一个具体实施方案中,所述多肽的CDR序列如下:
I)CDR1的序列为XXXSTAYY(SEQ ID NO:233),其中X为任意氨基酸,例如CDR1的序列选自SEQ ID NO:4、25、26、62、73;并且
II)CDR2的序列选自SEQ ID NO:78、80、84、90、103;并且
III)CDR3的序列选自SEQ ID NO:155、157、161、169、172、179、180、181、210、218、229、230、231。
在一个具体实施方案中,所述多肽的CDR序列如下:
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:78,并且CDR3的序列为SEQID NO:155;或
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:78,并且CDR3的序列为SEQID NO:157;或
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:80,并且CDR3的序列为SEQID NO:157;或
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQID NO:157;或
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQID NO:169;或
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQID NO:172;或
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQID NO:180;或
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQID NO:181;或
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQID NO:210;或
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQID NO:229;或
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQID NO:230;或
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQID NO:231;或
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:90,并且CDR3的序列为SEQID NO:161;或
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:90,并且CDR3的序列为SEQID NO:179;或
CDR1的序列为SEQ ID NO:25,CDR2的序列为SEQ ID NO:103,并且CDR3的序列为SEQ ID NO:179;或
CDR1的序列为SEQ ID NO:26,CDR2的序列为SEQ ID NO:80,并且CDR3的序列为SEQID NO:87;或
CDR1的序列为SEQ ID NO:26,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQID NO:157;或
CDR1的序列为SEQ ID NO:62,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQID NO:218;或
CDR1的序列为SEQ ID NO:73,CDR2的序列为SEQ ID NO:80,并且CDR3的序列为SEQID NO:157。
在另一个具体实施方案中,所述多肽的CDR序列如下:
I)CDR1的序列为SEQ ID NO:5;并且
II)CDR2的序列为SEQ ID NO:79,并且CDR3的序列为SEQ ID NO:156;或者
CDR2的序列为SEQ ID NO:79,并且CDR3的序列为SEQ ID NO:157。
在另一个具体实施方案中,所述多肽的CDR序列如下:
I)CDR1的序列为SEQ ID NO:6,CDR2的序列为SEQ ID NO:81;并且
II)CDR3的序列为SEQ ID NO:158、213或228。
在另一个具体实施方案中,所述多肽的CDR序列如下:
I)CDR1的序列为SEQ ID NO:24,CDR2的序列为SEQ ID NO:102;并且
II)CDR3的序列为SEQ ID NO:178、189或225。
在另一个具体实施方案中,所述多肽的CDR序列如下:
I)CDR3的序列为SEQ ID NO:170;并且
II)CDR1的序列为SEQ ID NO:66,并且CDR2的序列为SEQ ID NO:93;或者
CDR1的序列为SEQ ID NO:65,并且CDR2的序列为SEQ ID NO:143;或者
CDR1的序列为SEQ ID NO:16,并且CDR2的序列为SEQ ID NO:93;或者
CDR1的序列为SEQ ID NO:68,并且CDR2的序列为SEQ ID NO:93。
在另一个具体实施方案中,所述多肽的CDR序列如下:
CDR1的序列为SEQ ID NO:21,CDR2的序列为SEQ ID NO:98,并且CDR3的序列为SEQID NO:166;或
CDR1的序列为SEQ ID NO:13,CDR2的序列为SEQ ID NO:89,并且CDR3的序列为SEQID NO:166;或
CDR1的序列为SEQ ID NO:13,CDR2的序列为SEQ ID NO:99,并且CDR3的序列为SEQID NO:166;或
CDR1的序列为SEQ ID NO:13,CDR2的序列为SEQ ID NO:106,并且CDR3的序列为SEQ ID NO:166;或
CDR1的序列为SEQ ID NO:27,CDR2的序列为SEQ ID NO:104,并且CDR3的序列为SEQ ID NO:166;或
CDR1的序列为SEQ ID NO:18,CDR2的序列为SEQ ID NO:95,并且CDR3的序列为SEQID NO:173。
在另一个具体实施方案中,所述多肽的CDR序列如下:
CDR1的序列为SEQ ID NO:47,CDR2的序列为SEQ ID NO:125,并且CDR3的序列为SEQ ID NO:202;或
CDR1的序列为SEQ ID NO:60,CDR2的序列为SEQ ID NO:142,并且CDR3的序列为SEQ ID NO:202;或
CDR1的序列为SEQ ID NO:60,CDR2的序列为SEQ ID NO:138,并且CDR3的序列为SEQ ID NO:216。
本发明还提供了上述多肽在制备SFTSV检测剂或SFTSV治疗药物中的应用。
本发明还提供了上述多肽的核酸编码序列。
在一个实施方案中,所述核酸编码序列为DNA编码序列或RNA编码序列。
在一个具体实施方案中,所述核酸编码序列存在于基因表达框中。
本发明还提供了包含上述核酸编码序列的表达框的表达载体。
在一个优选实施方案中,所述表达载体为病毒载体。
在一个优选实施方案中,所述表达载体为腺相关病毒表达载体(AAV载体)。
本发明还提供了上述核酸编码序列和表达载体在SFTSV治疗药物中的应用。
本发明还提供了一种SFTSV检测试剂盒,包括检测抗体、固体基质以及包被于所述固体基质上的包被抗体,所述检测抗体和所述包被抗体分别为上述多肽中的一种。
在一个具体实施方案中,所述检测抗体的CDR序列如下:
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQID NO:181;或
CDR1的序列为SEQ ID NO:54,CDR2的序列为SEQ ID NO:132,并且CDR3的序列为SEQ ID NO:176;或
CDR1的序列为SEQ ID NO:13,CDR2的序列为SEQ ID NO:99,并且CDR3的序列为SEQID NO:166。
在一个具体实施方案中,所述包被抗体的CDR序列如下:
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQID NO:181;或
CDR1的序列为SEQ ID NO:54,CDR2的序列为SEQ ID NO:132,并且CDR3的序列为SEQ ID NO:176;或
CDR1的序列为SEQ ID NO:6,CDR2的序列为SEQ ID NO:81,并且CDR3的序列为SEQID NO:158;或
CDR1的序列为SEQ ID NO:13,CDR2的序列为SEQ ID NO:99,并且CDR3的序列为SEQID NO:166。
在一个优选实施方案中,
I)所述检测抗体的CDR序列如下:CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQID NO:84,并且CDR3的序列为SEQ ID NO:181;或CDR1的序列为SEQ ID NO:13,CDR2的序列为SEQ ID NO:99,并且CDR3的序列为SEQ ID NO:166;
并且,
II)所述包被抗体的CDR序列如下:CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQID NO:84,并且CDR3的序列为SEQ ID NO:181;或CDR1的序列为SEQ ID NO:54,CDR2的序列为SEQ ID NO:132,并且CDR3的序列为SEQ ID NO:176;或CDR1的序列为SEQ ID NO:6,CDR2的序列为SEQ ID NO:81,并且CDR3的序列为SEQ ID NO:158;或CDR1的序列为SEQ ID NO:13,CDR2的序列为SEQ ID NO:99,并且CDR3的序列为SEQ ID NO:166。
在一个优选实施方案中,
I)所述检测抗体CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQ ID NO:181;并且
II)所述包被抗体的CDR序列如下:CDR1的序列为SEQ ID NO:54,CDR2的序列为SEQID NO:132,并且CDR3的序列为SEQ ID NO:176;或CDR1的序列为SEQ ID NO:13,CDR2的序列为SEQ ID NO:99,并且CDR3的序列为SEQ ID NO:166。
在另一个优选实施方案中,
I)所述检测抗体CDR1的序列为SEQ ID NO:13,CDR2的序列为SEQ ID NO:99,并且CDR3的序列为SEQ ID NO:166;并且
所述包被抗体的CDR序列如下:
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQID NO:181;或CDR1的序列为SEQ ID NO:54,CDR2的序列为SEQ ID NO:132,并且CDR3的序列为SEQ ID NO:176;或CDR1的序列为SEQ ID NO:6,CDR2的序列为SEQ ID NO:81,并且CDR3的序列为SEQ ID NO:158;或CDR1的序列为SEQ ID NO:13,CDR2的序列为SEQ ID NO:99,并且CDR3的序列为SEQ ID NO:166。
本发明针对高致死率但缺乏有效疫苗和特异性抗病毒药物的SFTS进行纳米抗体药物开发和诊断试剂盒研发,通过制备GN蛋白、免疫双峰骆驼、利用噬菌体库展示纳米单抗的平台技术等,筛选到特异性结合GN的纳米抗体VHH,鉴定了其CDR序列,并构建了人源化的VHH-huFc1(SNB);同时利用人源化小鼠模型体内评估SNB在治疗SFTSV感染的疗效。本发明为SFTS的临床治疗提供潜在的纳米抗体新药,同时为SFTS的诊断提供相应的检测试剂盒。
附图说明
图1为sGN第3和4次免疫骆驼一周后的抗血清效价检测曲线;
图2为不同稀释度的第4次免疫骆驼一周后的抗血清抑制SFTSV病毒体外感染Vero细胞的曲线,以免疫前的血清为对照;
图3为sGN-VHH噬菌体抗体文库为模板扩增的PCR产物的电泳图;
图4为sGN-VHH噬菌体抗体文库的淘选鉴定,其中,A为噬菌体文库针对sGN蛋白淘选后ELISA检测统计图;B为从第二轮(2nd)和第三轮(3rd)淘选后的噬菌体抗体文库各挑选96个克隆进行噬菌体ELISA检测统计图;
图5为原核表达的VHH抗体的ELISA检测统计图,每个点代表一个克隆,纵坐标为针对sGN的OD450/空白对照的OD450,比值大于5.0定义为阳性;
图6为阳性VHH抗体中和SFTSV病毒感染实验统计图,一个点代表一个克隆,Y轴为针对不同病毒的相对抑制率;
图7为ELISA检测不同纯化浓度的SNB与sGN蛋白的结合,不同的颜色代表不同的克隆号。
图8为在不同浓度的抗体存在的环境下进行病毒感染得到的荧光染色照片,荧光点代表SFTSV病毒,无病毒感染的细胞作为无感染对照(No infection control),不加抗体的病毒感染细胞为感染对照(infection control);
图9为根据图7统计的荧光点得到的抗体对SFTSV病毒抑制率图;
图10为不同小鼠攻毒后的相对抑制率统计图,相对抑制率为1-第9天病毒载量/第6天病毒载量,以人免疫球蛋白为对照(Hu-IgG);
图10为SNB双抗夹心ELISA检测sGN蛋白统计图,其中,分别用SNB01(A)、SNB02(B)和SNB37(C)为检测抗体;D为包被抗体SNB01,检测抗体SNB37的双抗体夹心ELISA检测不同浓度的sGN的OD450统计曲线。
图11为包被抗体SNB01,检测抗体SNB37的双抗体夹心ELISA检测不同浓度的SFTSV病毒的OD450统计曲线。
具体实施方式
1.免疫原的制备
我们依据NCBI网站上HB29 SFTSV的GN蛋白序列和基因序列信息,分析并设计了可有效诱导骆驼产生针对GN蛋白的特异性抗体的多肽sGN,在C端连接His-tag(sGN-his)或兔Fc(sGN-rFc)用于后续纯化及检测。
2.骆驼免疫与抗血清的获得
用250μg sGN-rFc蛋白与250μl弗氏完全佐剂的乳化混合物对双峰骆驼进行初免,在第14天、28天、42天用sGN-rFc蛋白与250μl弗氏不完全佐剂加强免疫3次,第2次和第3次免疫1周后,采血检测抗血清滴度;第4次免疫1周后,采血200ml用于噬菌体抗体库的构建。
抗血清效价通过ELISA检测,用浓度为0.5μg/ml的GN蛋白包被检测板,每孔加入梯度稀释的抗血清或者纯化的抗体100μl(对照为免疫前骆驼血清),37℃孵育1.5h,洗涤2次,每孔加入1:10000稀释的辣根过氧化物酶标记的Goat anti-Llamma IgG(H+L)二抗,37℃孵育1h,洗涤4-6次后,加100μl TMB底物,37℃孵育10min,50μl 0.2M的H2SO4中止反应,测定OD450nm。ELISA检测血清效价规定为在OD450是空白对照的2.1倍以上并且大于0.2的最高稀释倍数。
结果如图1所示,3免和4免的抗血清效价分别为2.19×106和4.61×106。由此可见,该抗原可诱导骆驼产生特异性针对GN蛋白的高滴度抗血清。
为了进一步验证该高滴度的骆驼抗血清是否能有效阻止SFTSV病毒感染,进行病毒感染的中和实验。将不同稀释浓度的抗血清和免疫前血清分别与SFTSV病毒共同孵育60min,随后转移到Vero细胞,48h后通过对sGN蛋白的细胞免疫荧光染色来判断SFTSV的感染。中和实验结果显示,sGN诱导的抗血清抑制90%SFTSV感染的ID90为540倍稀释度以上(图2)。综上所述,sGN诱导了高滴度抗血清,同时该抗血清具有高效抑制SFTSV病毒感染的能力。
3.VHH噬菌体库构建及淘选
收集200ml免疫后骆驼的外周血,利用淋巴细胞分离液(GE Ficoll-Paque Plus)分离获得骆驼的PBMC,根据TRIzol操作手册,提取RNA,并利用oligo(dT)反转为cDNA,通过引物扩增,以及分子克隆等技术,将骆驼的VHH基因克隆至phagemid质粒,转化TG1细菌,得到VHH噬菌体库。为了进一步鉴定sGN-VHH噬菌体库是否构建成功,通过PCR扩增免疫sGN骆驼的VHH目的基因,可以看出目的条带为500bp,大小符合预期(图3),说明该sGN-VHH噬菌体抗体文库里含有VHH基因。挑选50个克隆进行测序,测序结果显示,所测序列没有完全一致的重复序列;比对结果显示,差异序列大多在CDR结合区。经检测,该构建了一个sGN-VHH噬菌体抗体文库的库容为2.0×109,阳性率为100%,序列多样性(Diversity)为100%,有效插入率(In frame rate)大于95%。
在M13KO7辅助噬菌体的帮助下,用VHH-phagemid转化的细菌,进行噬菌体抗体库的复苏,并用PEG/NaCl进行沉淀。将包被有50μg/ml的sGN-His蛋白进行三次富集噬菌体抗体库。将富集的噬菌体,洗脱、转化、涂板、挑取单克隆进行噬菌体与sGN蛋白ELISA的结合鉴定,将结合读值>1.0的克隆进行测序,并克隆至表达载体pVAX1,转染293F细胞表达生产纳米单抗。
淘选后的文库与GN蛋白进行结合检测。噬菌体ELISA结果显示,没有富集前的sGN-VHH噬菌体文库与sGN蛋白的结合读值为0.57,经过一轮、二轮、三轮富集后的噬菌体文库读值分别为0.98、2.2、3.0(图4A)。为了进一步验证富集后的文库中结合sGN-VHH蛋白的阳性噬菌体率,从第2轮和第3轮富集后的文库里各挑选了96个克隆进行单个噬菌体ELISA检测。结果显示,第2轮文库里,24.5%的单个噬菌体克隆为阳性,第3轮文库里67%的噬菌体克隆克隆为阳性,而且结合的平均读值在3.0左右(图4B),通过sGN蛋白淘选成功的富集了高结合力的sGN-VHH噬菌体文库。
4.VHH原核表达文库的构建及VHH表达
对上述二轮和三轮淘选富集后的2nd-sGN-VHH和3rd-sGN-VHH噬菌体抗体文库进行PCR扩增;获取并纯化抗体库中所有VHH的基因片段,将VHH的基因片段克隆至原核表达载体,转化SS320菌株,构建VHH的原核表达抗体库;将原核表达抗体库涂布平板,过夜培养,次日随机挑选单克隆菌落1000个,使用IPTG诱导表达抗体上清,对抗体上清与sGN蛋白进行ELISA结合检测。
结果显示,有细菌上清与sGN蛋白结合,同时不与空白对照结合,sGN结合的读值/空白对照的读值大于5.0(图5和表1)。将这些序列进行测序比对,剔除重复序列,最终获得142个的VHH抗体序列(SEQ ID NO:1-142)。进一步的实验证实,这142个VHH抗体以及从VHH抗体得到的CDR均可特异性地结合SFTSV病毒。
表1 142个VHH抗体与sGN蛋白的结合值及其序列
为了进一步验证该序列是否能很好的抑制SFTSV病毒感染,将122个VHH抗体的细菌上清通过处理后与SFTSV病毒共孵,测试抗体是否能抑制SFTSV病毒感染。中和实验结果显示(图6),有23个抗体能达到50%以上的抑制效果。抗体编号分别为G77、G78、G79、G87、G95、G103、G109、G111、G112、G113、G114、G116、G117.1、G121、G124、G125、G126、G131、G133、G145、G170和G171。
5.VHH-huFc(SNB)真核表达
通过分子克隆技术,将上述23个纳米单抗VHH基因融合人的Fc基因并插入在pVAX1真核表达载体,构建形成Nb-huFc-pVAX1表达质粒。将构建好的Nb-huFc-pVAX1,转染293F细胞,表达生产Nb-huFc(SNB),并利用Protein G纯化。收集纯化的VHH-huFc1(SNB)抗体进行ELISA测定,部分抗体有很好的结合能力(图7)。构建的人源化抗体相应的序列号如表2所示。
表2人源化抗体SNB对应的原抗体编号及CDR序列
通过BIAcore x100仪器,根据氨基偶联试剂盒说明书,偶联4000RU的sGN蛋白至CM5芯片上;乙醇胺封闭偶联好的芯片。抗体梯度稀释为不同的浓度。Bioevaluationversion 4.0软件设置检测程序:抗体浓度从低浓度到高浓度检测,每个浓度做2个重复检测;结合时间设为180秒,流速为30μl/min;解离时间设为180秒,流速为30μl/min;pH2.510mM的甘氨酸将流速设为30μl/min,时间为30秒,活化、重生芯片表面;PBS平衡5秒,流速为30μl/min。分析实验数据,获得结合、解离和亲和常数。结果如表3所示,大部分的抗体的亲和力能达到10-9(Nano mole级),其中有两个抗体SNB02和SNB07能达到10-10(Pico mole级)。由此可见,我们获得了具有高亲和力的VHH-huFc1(SNB)抗体。
表3 SNB亲和力的总结。
Clone ID | ka(1/Ms) | kd(1/s) | KD(M) |
SNBO1 | 4.05E+04 | 6.91E-05 | 1.70589E-09 |
SNB02 | 1.88E+07 | 3.91E-03 | 2.08391E-10 |
SNB07 | 8.66E+04 | 3.86E-05 | 4.45398E-10 |
SNB28 | 1.05E+05 | 2.97E-04 | 2.8361E-09 |
SNB29 | 7.39E+03 | 5.56E-05 | 7.51393E-09 |
SNB37 | 3.74E+04 | 1.09E-04 | 2.92338E-09 |
注:ka为结合常数,kd为解离常数,KD为亲和力。
6.SNB中和SFTSV感染Vero细胞
选取VHH-huFc1中的SNB02和SNB16进行体外中和实验。将抗体梯度稀释为不同的浓度,与SFTSV病毒一起,于5%CO237℃下共孵育1个小时,添加1.5x 104个Vero细胞,5%CO237℃温箱培养48小时后,移除细胞上清,添加4%多聚甲醛固定15min后,经过洗涤封闭后,添加抗GN的兔多克隆血清(1∶1000稀释),4℃过夜,PBST洗涤后,添加50μl抗兔的二抗(Alexa Fluor 488Anti-Rabbit IgG(H+L),Code:111-545-144,Jackson ImmunoResearchLaboratories,1∶1000稀释)室温孵育40min,接着进行DAPI 10min染色,洗涤后,荧光显微镜拍照观察,统计绿色斑点和荧光强度计算中和抑制率与中和滴度,抑制率=[1-(样品组的荧光强度均值-细胞对照组CC的荧光强度均值)/(对照处理组的荧光强度均值-细胞对照组CC的荧光强度均值)]×100%。中和滴度(ID50或ND50)表述为50%抑制率时的稀释度的倍数。
结果如图8和9所示,SNB02具有很好的中和活性,当抗体浓度在9μg/ml时,抑制率能达到83.5%。利用人源化小鼠模型来评估SNB02的疗效。
7.SNB治疗SFTS体内感染
ImmunodeficientNOD.Cg-Prkdcscidll2rgtm1Wjl/SzJ(NCG)小鼠购自南京大学模式动物所,与NSG小鼠类似,该小鼠在SCID小鼠基础上缺失了IL2受体基因,导致体内没有小鼠T细胞,B细胞以及极少量的NK细胞。1.0-15x 107PBMC腹腔注射进4-6周的NCG小鼠体内;三周后,采血流式检测人T细胞,通过染色人的CD45+、CD3+、CD4+和CD8+。人CD45阳性细胞的比例到达5%以上,判定为小鼠人源化成功。接种2x 107TCID50的SFTSV病毒,感染后第3和6天,分别进行一次抗体治疗,即,腹腔注射400μg SNB02抗体/小鼠(抗体的量为大约20mg/kg小鼠)。每次抗体治疗前和第9天进行采血,检测小鼠血液中的病毒载量,从而判定小鼠是否成功的感染了SFTS病毒以及SNB抗体是否能控制SFTSV感染小鼠,以人IgG为对照。结果如图11所示,完成治疗三天后(第9天),检测小鼠体内的病毒载量,接受SNB02治疗的9只小鼠,7只小鼠体内的病毒载量均得到了很好的抑制,而接受Hu-IgG治疗的对照组小鼠,体内SFTS病毒在大量繁殖,两组病毒抑制率对比分析,SNB02有显著性的的控制SFTS病毒感染(图10)。
8.使用AAV病毒载体装载的SNB02进行体内实验
腺相关病毒载体(AAV)源于非致病的野生型腺相关病毒,由于其安全性好、宿主细胞范围广(分裂和非分裂细胞)、免疫源性低,在体内表达外源基因时间长等特点,被视为最有前途的基因转移载体之一,在世界范围内的基因治疗和疫苗研究中得到广泛应用。
AAV Helper-Free病毒包装系统购于Cell Biolabs,San Diego USA。将上述SNB02的DNA编码序列通过分子克隆技术插入到pAAV-MCS质粒;通过测序证明构建成功后,将构建好的质粒pAAV-Ab与pHelper和pAAV-DJ质粒按照质量比1:1:1的方式使用PEI转染试剂共转染AAV-293T细胞。转染后分别于48、72、96和120小时收集上清,并用5xPEG8000(sigma)进行浓缩,最后用1.37g/ml氯化铯进行纯化。纯化的AAV溶解于PBS里,进行鉴定和分装后保存于-80℃。
将上述人源化小鼠接种2x 107TCID50的SFTSV病毒,感染后第3天采血以及接受AAV-SNB02(1x1011 gc/100μl)肌肉注射,并在第6、9和12天采血,检测病毒载量,以AAV-GFP为对照组。结果显示,注射了AAV-SNB02的小鼠体内的SFTSV病毒载量均很低,而对照组小鼠体内的SFTSV病毒大量繁殖。
9.双抗夹心ELISA
用不同浓度的SNB抗体包被检测板,每孔100μl,37℃孵育2h,洗涤2-4次,10%牛血清封闭,每孔200μl,37℃孵育1h,洗涤2-4次,每孔加入梯度稀释的蛋白,病毒或者样品100μl,37℃孵育1.5h,洗涤2次,每孔加入1:200-1:10000稀释的辣根过氧化物酶标记的SNB抗体100μl,37℃孵育1h,洗涤4-6次后,加100μl TMB底物,37℃孵育10min,50μl 0.2M的H2SO4中止反应,测定OD450nm。ELISA检测的阳性样品规定为在OD450是空白对照(即不包被检测原,图中标记为Neg)的2.1倍以上并且其光密度值大于0.2的最高稀释倍数。
结果显示,当包被抗体为SNB02或SNB07,检测抗体为SNB01时,该组合能够识别sGN蛋白和阴性对照蛋白(图11A);当检测抗体为SNB02时,ELISA检测背景很高(图11B);当检测抗体为SNB37,包被抗体为SNB01、SNB02和SNB07时,ELISA能识别sGN蛋白和阴性对照蛋白(图11C)。SNB抗体可以应用于双抗体夹心ELISA检测sGN试剂盒的开发,其中SNB01与SNB37的双抗组合其检测灵敏度为3.9ng/ml(图11D)。测量该组合检测SFTSV真病毒的灵敏度为3.75x 106gc/ml(图12),说明该试剂盒不仅能检出SFTSV的真病毒,还能检出低至10^6拷贝数的SFTSV真病毒。由此可见,该纳米抗体双抗夹心检测试剂盒能应用在SFTSV病毒感染检测。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
序列表
<110> 源道隆(苏州)医学科技有限公司
<120> 可结合SFTSV的纳米抗体及其应用
<150> PCT/CN2019/097350
<151> 2019-07-23
<160> 237
<170> SIPOSequenceListing 1.0
<210> 1
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Gly Phe Thr Phe Asp Asp Ser Asn
1 5
<210> 2
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Gly His Thr Leu Ser Ser Asn Cys
1 5
<210> 3
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Gly Pro Phe Tyr Asn Thr His Cys
1 5
<210> 4
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Gly Asp Thr Ser Thr Ala Tyr Tyr
1 5
<210> 5
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Gly Asp Thr Tyr Ser Ser Ser Cys
1 5
<210> 6
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Gly Phe Thr Ser Cys
1 5
<210> 7
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Gly Val Thr Leu Asp Asp Phe Leu
1 5
<210> 8
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Gly Val Thr Leu Asp Asp Phe Leu
1 5
<210> 9
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Gly Tyr Thr Phe Ser Asn Thr Cys
1 5
<210> 10
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Gly Arg Thr Tyr Arg Thr Tyr Cys
1 5
<210> 11
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Glu Asp Ala His Ser Thr Thr Glu Tyr Ile Val Ser Thr Thr Cys
1 5 10 15
<210> 12
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Gly Val Thr Tyr Gly Ser Tyr Cys
1 5
<210> 13
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Gly Phe Thr Leu Ser Met Tyr Asp
1 5
<210> 14
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Glu Tyr Thr Gly Ser Arg Asn Cys
1 5
<210> 15
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Gly Tyr Thr Tyr Asn Asn Tyr Arg
1 5
<210> 16
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Gly Leu Tyr Tyr Pro Pro Leu Cys
1 5
<210> 17
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Arg Tyr Asp Tyr Ser Arg Thr Cys
1 5
<210> 18
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Gly Phe Thr Val Ser Arg Tyr Asp
1 5
<210> 19
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Gly Ser Ala Tyr Ser Thr Asn Cys
1 5
<210> 20
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Gly Tyr Thr Tyr Ser Ser Asn Cys
1 5
<210> 21
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Gly Phe Thr Phe Asn Ala Tyr Asp
1 5
<210> 22
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Val Tyr Thr Tyr Arg Gly Asn Asn
1 5
<210> 23
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Arg Tyr Thr Pro Thr Ile Thr Arg
1 5
<210> 24
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Val Tyr Thr Ser Ser Thr Met Trp
1 5
<210> 25
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Gly Tyr Thr Ser Thr Ala Tyr Tyr
1 5
<210> 26
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Gly Gly Thr Ser Thr Ala Tyr Tyr
1 5
<210> 27
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Gly Phe Thr Ser Ser Asn Tyr Asp
1 5
<210> 28
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Gly Phe Thr Ser Ser Ser Cys Gly
1 5
<210> 29
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Gly Tyr Thr Tyr Ser Ser Val Cys
1 5
<210> 30
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Gly Tyr Thr Tyr Asn Thr Ala Tyr
1 5
<210> 31
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
Gly Tyr Ala Tyr Ser Thr Tyr Cys
1 5
<210> 32
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Gly Tyr Thr Tyr Asn Glu Tyr Ser
1 5
<210> 33
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
Gly Tyr Asn Phe Asn Asn Val Cys
1 5
<210> 34
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Glu Tyr Thr Arg Ser Ser Arg Cys
1 5
<210> 35
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
Gly Ser Thr Asp Ser Arg Arg Cys
1 5
<210> 36
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 36
Gly Tyr Pro Tyr Ser Ser Lys Thr Tyr Thr Asn Asn Cys
1 5 10
<210> 37
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 37
Arg Tyr Ser Ser Ser Arg Arg Cys
1 5
<210> 38
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
Gly Tyr Ile Tyr Asn Asp Tyr Phe
1 5
<210> 39
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
Thr Tyr Asn Tyr Glu Ser Ser Gln
1 5
<210> 40
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 40
Thr Thr Thr Asn Tyr
1 5
<210> 41
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 41
Gly Tyr Thr Tyr Asn Tyr Tyr Cys
1 5
<210> 42
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 42
Gly Tyr Thr Tyr Tyr Asn Ser Asn Cys
1 5
<210> 43
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 43
Gly Gly Ser Val Thr Thr Gly Asn Tyr Tyr
1 5 10
<210> 44
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 44
Gly Tyr Thr Phe Asn Thr Arg Cys
1 5
<210> 45
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 45
Leu Tyr Thr Tyr Ser Tyr Asn Cys
1 5
<210> 46
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 46
Gly Phe Thr Ser Asn Ser Cys Gly
1 5
<210> 47
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 47
Gly Met Met Ser Asn Ala Cys
1 5
<210> 48
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 48
Gly Tyr Thr His Ser Ser Asp Ser
1 5
<210> 49
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 49
Arg Ser Val Asn Arg Asp Thr Cys
1 5
<210> 50
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 50
Ala Phe Ile Ser Asn Asn His Cys
1 5
<210> 51
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 51
Gly Phe Thr Phe Ser Ser Tyr Asp
1 5
<210> 52
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 52
Gly Phe Thr Phe Asp Asp Ser Asp
1 5
<210> 53
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 53
Gly Tyr Arg Cys
1
<210> 54
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 54
Ala Tyr Thr Tyr Arg Gly Asn Asn
1 5
<210> 55
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 55
Gly Ala Thr Tyr Asn Ile Asn Phe
1 5
<210> 56
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 56
Gly Tyr Thr Tyr Ser Asn Tyr
1 5
<210> 57
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 57
Gly Phe Thr Phe Ser Ser Tyr Tyr
1 5
<210> 58
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 58
Gly Ser Ile Tyr Ser Ser Asn Ala
1 5
<210> 59
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 59
Gly Tyr Thr Tyr Ser Ser Ala Cys
1 5
<210> 60
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 60
Gly Met Tyr Ser Asn Thr Cys
1 5
<210> 61
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 61
Gly Gly Ser Ile Thr Thr Asn Tyr Tyr Gly
1 5 10
<210> 62
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 62
Gly Asp Ser Ser Thr Ala Tyr Tyr
1 5
<210> 63
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 63
Gly Asn Thr Tyr Thr Ser Ser Cys
1 5
<210> 64
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 64
Gly Gly Ser Ile Thr Thr Ala Gly Tyr Gly
1 5 10
<210> 65
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 65
Gly Leu Tyr Tyr Leu Pro Leu Cys
1 5
<210> 66
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 66
Gly Leu Trp His Pro Pro Leu Cys
1 5
<210> 67
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 67
Gly Tyr Thr Tyr Gly Ser Tyr Cys
1 5
<210> 68
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 68
Gly Leu Tyr Tyr Ser Pro Leu Cys
1 5
<210> 69
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 69
Arg Tyr Thr Ser Ser
1 5
<210> 70
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 70
Gly Tyr Arg Tyr Asn Ala Cys Ser
1 5
<210> 71
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 71
Gly Asn Pro Ser Gly Arg Lys Phe
1 5
<210> 72
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 72
Gly Ser Ser Gly Leu Ile Phe Ser Gly Ser Ala
1 5 10
<210> 73
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 73
Glu Asp Thr Ser Thr Ala Tyr Tyr
1 5
<210> 74
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 74
Gly Tyr Thr Tyr Ser Ser His Cys
1 5
<210> 75
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 75
Ile Lys Ser Asp Gly Ser Thr Ser
1 5
<210> 76
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 76
Ile Tyr Thr Gly Gly Gly His Thr Tyr
1 5
<210> 77
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 77
Val Tyr Pro His Leu Thr Tyr
1 5
<210> 78
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 78
Ile Tyr Arg Gly Gly Arg Ala Thr Val
1 5
<210> 79
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 79
Ile Cys Ser Asp Gly Ser Ala Ala
1 5
<210> 80
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 80
Ile Tyr Arg Gly Gly His Ser Thr Val
1 5
<210> 81
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 81
Ile Tyr Thr Arg Asp Gly Arg Pro Tyr
1 5
<210> 82
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 82
Ile Asp Ser Glu Gly Arg Ile Asp
1 5
<210> 83
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 83
Ile Asp Ser Gly Gly Ser Ser Ser
1 5
<210> 84
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 84
Ile Tyr Arg Gly Gly Arg Ser Thr Val
1 5
<210> 85
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 85
Ile Asp Arg Ser Gly Ser Ala Ser
1 5
<210> 86
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 86
Ile Thr Ala Leu Ser Ala Thr Ser
1 5
<210> 87
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 87
Thr Tyr Arg His Gly Gly Thr Thr Val
1 5
<210> 88
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 88
Leu Glu Ser Asp Gly Ser Thr Ser
1 5
<210> 89
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 89
Ile Tyr Thr Ser Gly Arg Arg Pro Trp
1 5
<210> 90
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 90
Ile Phe Arg Gly Gly Arg Ser Thr Val
1 5
<210> 91
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 91
Ile Ser Ile Leu Tyr Ser Gly Ile Thr Val Ser Tyr
1 5 10
<210> 92
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 92
Ile Ser Ala Gly Gly Asp His Thr Tyr
1 5
<210> 93
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 93
Ile Asp Arg Asp Gly Ser Thr Ser
1 5
<210> 94
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 94
Ile Cys Ser Asp Gly Ser Thr Ser
1 5
<210> 95
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 95
Ile Phe Val Ser Gly Arg Ser Pro Trp
1 5
<210> 96
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 96
Ile Tyr Arg Asp Asp Gly Thr Thr Tyr
1 5
<210> 97
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 97
Ile Tyr Thr Gly Gly Gly Ser Thr Tyr
1 5
<210> 98
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 98
Ile Phe Arg Ser Gly Arg Thr Ser Trp
1 5
<210> 99
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 99
Ile Phe Thr Ser Gly Arg Arg Pro Trp
1 5
<210> 100
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 100
Ile Thr Ser Thr Gly Thr Arg Gln Tyr
1 5
<210> 101
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 101
Ile Tyr Thr Arg Gly Asp Arg Thr Phe
1 5
<210> 102
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 102
Ile Tyr Arg Gly Asn Gly Ala Thr Gly
1 5
<210> 103
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 103
Ile Trp Arg Gly Gly His Ser Thr Leu
1 5
<210> 104
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 104
Ile Phe Ser Ser Gly Arg Arg Pro Trp
1 5
<210> 105
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 105
Leu His Thr Asp Gly Leu Thr Ser
1 5
<210> 106
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 106
Ile Phe Thr Ser Gly Arg Arg Ser Trp
1 5
<210> 107
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 107
Ile Tyr Thr Ala Thr Gly Arg Thr Tyr
1 5
<210> 108
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 108
Ile Asp Ser Asp Gly Ser Thr Ser
1 5
<210> 109
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 109
Ile Asp Ser Asp Gly Val Thr Asp
1 5
<210> 110
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 110
Ile Asn Ser Val Gly Arg Thr Arg
1 5
<210> 111
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 111
Ile Tyr Thr Ser Ile Gly Arg Thr Tyr
1 5
<210> 112
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 112
Ile Glu His Asp Gly Lys Ile Ile
1 5
<210> 113
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 113
Ile Tyr Arg Gly Ser Gly Thr Thr His
1 5
<210> 114
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 114
Ile Tyr Leu Ala Asn Gly Ala Thr Tyr
1 5
<210> 115
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 115
Ile Tyr His Gly Asp Gly Thr Thr Tyr
1 5
<210> 116
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 116
Ile Gly Ser Asp Gly Thr Thr Lys
1 5
<210> 117
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 117
Val Ser Pro Arg Gly Glu Ser Ile Tyr
1 5
<210> 118
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 118
Ile Phe Ser Ser Arg Asp Tyr Thr Asp
1 5
<210> 119
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 119
Ile Asp Thr Gly Gly Ser Thr Tyr
1 5
<210> 120
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 120
Ile Tyr Thr Arg Asp Ser Arg Thr Tyr
1 5
<210> 121
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 121
Ile Thr Ala Ser Gly Ser Thr Tyr
1 5
<210> 122
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 122
Ile Ser Ala Gly Gly Ile Ser Ile Asp
1 5
<210> 123
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 123
Trp Gly Ser Val Gly Ser Ser Thr Thr Tyr
1 5 10
<210> 124
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 124
Ile Phe Ser Asp Gly Glu Thr Ala
1 5
<210> 125
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 125
Ile Tyr Thr Gly Ile Gly Thr Thr Tyr
1 5
<210> 126
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 126
Ile Tyr Thr Gly Asp Gly Ser Thr His
1 5
<210> 127
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 127
Ile Ser Ala Gln Gly Val Ile Pro Gly
1 5
<210> 128
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 128
Ile Asp Ser Ala Gly Ser Thr Arg
1 5
<210> 129
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 129
Ile Arg Ser Gly Gly Gly Asn Thr Tyr
1 5
<210> 130
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 130
Ile Ser Arg Ile Asp Asn Ser Thr Tyr
1 5
<210> 131
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 131
Phe Val Thr Gly Ala Gly Ser Thr Tyr
1 5
<210> 132
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 132
Ile Thr Val Thr Gly Thr Arg Gln Tyr
1 5
<210> 133
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 133
Ile Asp Asn Asn Gly Trp Ser Thr
1 5
<210> 134
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 134
Ile Asp Thr Asn Gly Ser Thr Ser
1 5
<210> 135
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 135
Ile Tyr Arg Asp Gly Ser Ala Pro Tyr
1 5
<210> 136
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 136
Ile Tyr Thr Gly Gly Ser Ala Thr Ser
1 5
<210> 137
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 137
Ile Cys Ser Asp Gly Ser Ser Ala
1 5
<210> 138
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 138
Ile Tyr Thr Gly Ile Gly Ser Thr Tyr
1 5
<210> 139
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 139
Ile Gly Tyr Ser Gly Ser Thr Tyr
1 5
<210> 140
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 140
Ile Cys Ser Asp Gly Ser Thr Ala
1 5
<210> 141
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 141
Ile Thr Phe Thr Gly Arg Thr Leu
1 5
<210> 142
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 142
Ile Tyr Thr Asn Val Gly Thr Thr Tyr
1 5
<210> 143
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 143
Ile Asp Arg Asp Gly Arg Thr Ser
1 5
<210> 144
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 144
Ile His Thr Asp Gly Ser Thr Ser
1 5
<210> 145
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 145
Ser Asn Thr Asn Gly Gly Ser Thr Tyr
1 5
<210> 146
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 146
Thr Asn Arg Asp Gly Met Ser Tyr
1 5
<210> 147
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 147
Val Tyr Asn Asp Gly Gly His Thr Tyr
1 5
<210> 148
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 148
Ile Phe Thr Arg Gly Thr Thr Lys
1 5
<210> 149
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 149
Leu Tyr Leu Gly Gly Ser Ile Thr Tyr
1 5
<210> 150
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 150
Ile Asp Thr Ile Gly Glu Ile Asp
1 5
<210> 151
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 151
Leu Asp Gly Asp Gly Arg Val Arg
1 5
<210> 152
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 152
Ala Ala Ala Trp Arg Pro Pro Cys Val Pro
1 5 10
<210> 153
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 153
Ala Ala Asp Leu Ser Pro Tyr Asp Cys Tyr Thr Gly Ser Leu Asp Met
1 5 10 15
Ala Ser Arg Phe Thr
20
<210> 154
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 154
Ala Ala Val Leu Cys Thr Asp Asp Tyr Lys Met Ala Pro Ala Asn Tyr
1 5 10 15
<210> 155
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 155
Ala Ala Gly Leu Ala Gly Gly Ser Gly Tyr Leu Pro Leu Asn Trp Ala
1 5 10 15
Gly Phe Arg Tyr
20
<210> 156
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 156
Ala Ala Arg Arg Thr Trp His Ala Gly Phe Pro Tyr
1 5 10
<210> 157
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 157
Ala Ala Gly Leu Asp Gly Gly Ser Gly Tyr Leu Pro Leu Asn Trp Ala
1 5 10 15
Gly Phe Arg Tyr
20
<210> 158
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 158
Ala Ala Asn Arg Arg Ala Tyr Pro Tyr Gly Gly Asp Cys Arg Leu Arg
1 5 10 15
His Ala Glu Phe Asp Tyr
20
<210> 159
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 159
Ala Ala Asp Val Pro Gly Arg Arg Glu Val Arg Gly Leu Gly Pro Cys
1 5 10 15
Asp Arg Met Tyr Asp Tyr
20
<210> 160
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 160
Ala Ala Lys Val Pro Phe Gly Arg Gly Ser Cys Ala Tyr Ser Thr Ala
1 5 10 15
His Trp Phe Pro Tyr
20
<210> 161
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 161
Ala Ala Gly Leu Asp Gly Gly Ser Gly Tyr Leu Pro Leu Asn Trp Asp
1 5 10 15
Gly Phe Arg Tyr
20
<210> 162
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 162
Val Ala Asp Leu Ser Ala Trp Cys Arg Ala Val Arg Pro Gly Val Ile
1 5 10 15
Thr Tyr Asn Tyr
20
<210> 163
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 163
Ala Ala Asp Pro Arg Asp Pro Asn Gly Ser Arg Thr Asp Cys Thr Val
1 5 10 15
Leu Thr Ser Lys Asp Leu Tyr Asn Ser
20 25
<210> 164
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 164
Ala Ala Gly Pro Gly Cys Ser Trp Ser Ser Phe Ala Tyr
1 5 10
<210> 165
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 165
Val Ala Met Thr Trp Asp Gly Thr Cys His Ile Thr Ser Glu Phe Tyr
1 5 10 15
<210> 166
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 166
Ala Ala Val Ile Gly Val Asp Ile Arg
1 5
<210> 167
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 167
Ala Ile Arg Trp Gly Asp Cys Asp Ser Ala Ser Trp Ser Arg Arg Thr
1 5 10 15
Trp Tyr Ala Val
20
<210> 168
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 168
Ala Arg Ser Arg Ala Ser Leu Trp Ser Gly Asn Trp Tyr Arg Ser Leu
1 5 10 15
Ser Glu Asp Glu Tyr Asn Ser
20
<210> 169
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 169
Ala Ala Gly His Asp Gly Gly Ser Gly Tyr Leu Pro Leu Asn Trp Asp
1 5 10 15
Gly Phe Arg Tyr
20
<210> 170
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 170
Ala Ala Ala Asp Ala Gln Arg Gly Arg Thr Cys Phe Phe Gly Ala
1 5 10 15
<210> 171
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 171
Ala Val Arg Trp Tyr Trp Asp Ala Gly Phe Lys Tyr
1 5 10
<210> 172
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 172
Ala Ala Gly His Asp Gly Arg Ser Gly Tyr Leu Pro Leu Asn Trp Ala
1 5 10 15
<210> 173
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 173
Ala Ala Val Ile Gly Tyr Asp Ile Arg
1 5
<210> 174
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 174
Ala Ala Asp Ser Arg Thr Pro Ser Asp Cys Tyr Ser Gly Ser Trp Leu
1 5 10 15
Glu Lys Tyr Pro Ser Glu Tyr Ser Tyr
20 25
<210> 175
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 175
Ala Ala Asp Val Val Ser Tyr Tyr Ser Asp Tyr Val Cys Thr Asp Ala
1 5 10 15
Ala Asp Phe Gly Tyr
20
<210> 176
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 176
Ala Ala Gly Thr Thr Arg Leu Gly Ser Leu Leu Ala Pro Thr Tyr Arg
1 5 10 15
Tyr
<210> 177
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 177
Ala Ala Gly Phe Met Tyr Gly Glu Thr Arg Ser Pro Asn Trp Val Asn
1 5 10 15
Tyr
<210> 178
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 178
Ala Lys Lys Arg Thr Tyr Asp Cys Tyr Ser Gly Thr Cys Ser
1 5 10
<210> 179
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 179
Ala Ala Gly Leu Tyr Gly Gly Ser Pro Tyr Phe Pro Leu Asn Trp Thr
1 5 10 15
Gly Phe Arg Tyr
20
<210> 180
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 180
Ala Ala Gly Leu Arg Gly Gly Ser Gly Tyr Leu Pro Leu Asn Trp Ala
1 5 10 15
Gly Phe Arg Tyr
20
<210> 181
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 181
Ala Ala Gly His Asp Gly Gly Ser Gly Tyr Leu Pro Leu Asn Trp Ala
1 5 10 15
Gly Phe Arg Tyr
20
<210> 182
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 182
Lys Thr Val Lys Asp Pro Thr Ser Pro Pro Gly Cys Ser Arg Gly Tyr
1 5 10 15
<210> 183
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 183
Ala Ala Asp Leu Leu Ile Gly Ala Cys Ser Gln Met Arg Arg Thr Asn
1 5 10 15
Phe Asp Tyr
<210> 184
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 184
Ala Ala Asn Pro Tyr Ser Pro Gly Ala Gly Arg Glu Leu Leu Ser Tyr
1 5 10 15
Pro Tyr Thr Asp
20
<210> 185
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 185
Ala Ala Asn Gln Gly Ser Gly Asp Tyr Cys Tyr Met Ala Met Leu Ile
1 5 10 15
Tyr Gly Met Phe Tyr
20
<210> 186
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 186
Ala Ala Arg Asp Gly Ser Trp Phe Leu Ser Leu Val Pro Ala Thr Tyr
1 5 10 15
Gly Tyr
<210> 187
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 187
Ala Ala Asp Leu Gln Ile Gly Ser Cys Ser Gln Met Arg Arg Tyr Asn
1 5 10 15
Tyr Ala Tyr
<210> 188
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 188
Gly Ala Asp Pro Gly Glu Gly Ser Tyr Cys Ala Tyr Glu Ala Pro Glu
1 5 10 15
Val Gly Ala Leu Asp Ile
20
<210> 189
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 189
Ala Ala Gly Arg Thr Tyr Asp Cys Tyr Pro Gly Thr Cys Ser
1 5 10
<210> 190
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 190
Ala Ala Ser Leu Arg Ala Arg Trp Val Gln Arg Gly Ala Pro Leu Leu
1 5 10 15
Pro Ser Phe Tyr Gly Tyr
20
<210> 191
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 191
Ala Ala Gly Pro Trp Val Ala Thr Pro Glu Ile Ala Asn Glu Tyr Asn
1 5 10 15
Tyr
<210> 192
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 192
Val Ala Gly Ile Trp Thr Cys Gly Arg Ser Ala Leu Thr Asp Pro Asn
1 5 10 15
Asn Tyr
<210> 193
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 193
Ala Ala Thr Phe Gly Leu Phe Trp Glu Ser Trp Glu Trp Tyr Lys Asn
1 5 10 15
Trp His Tyr
<210> 194
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 194
Ala Ala Asp Pro Gly Val Leu Cys Gly Arg Ser Trp Val Gly Arg Phe
1 5 10 15
Pro Tyr
<210> 195
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 195
Ala Ala His Gly Ala Phe Ala Ala Arg Asn Asp Pro Arg Gln Trp Arg
1 5 10 15
Tyr
<210> 196
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 196
Ala Ala Gln Tyr Gly Thr Cys Gln Gly Leu Leu Ser Arg Tyr Phe Ala
1 5 10 15
Tyr
<210> 197
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 197
Ala Ala Ala His Glu Pro Gly Ser Trp Thr Asp Ile Glu Ala Arg Gly
1 5 10 15
Lys Ile Ser Asp Asp Pro Phe Gly Tyr
20 25
<210> 198
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 198
Ala Arg Ala Ser Phe Arg Gly Ser Trp Phe Phe Glu Gly
1 5 10
<210> 199
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 199
Ala Ala Ala Arg Arg Trp Tyr Tyr Glu Asn Ser Cys Leu Lys Val Leu
1 5 10 15
Arg Ser Pro Gly Asp Tyr
20
<210> 200
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 200
Ala Ala Gly Pro Pro Ser Gly Pro Leu Arg Ala Cys His Glu Ser Val
1 5 10 15
Phe Gly Tyr
<210> 201
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 201
Lys Thr Val Arg Asp Pro Ala Ser Pro Pro Ser Cys Ser Gly Gly Tyr
1 5 10 15
<210> 202
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 202
Ala Ala Asp Arg Val Leu Gly Arg Cys Ser Arg Arg Leu Leu Ser Asp
1 5 10 15
Phe Gly Tyr
<210> 203
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 203
Ala Ala Gly Thr Tyr Tyr Ser Asp Tyr Asp Pro Pro Arg Tyr Glu Tyr
1 5 10 15
Lys Tyr
<210> 204
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 204
Ala Ala Lys Glu Arg Pro Leu Cys Gly Ser Phe Trp Glu Arg Gly Asp
1 5 10 15
Glu Tyr Ala Ser
20
<210> 205
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 205
Ala Ala Val Ser Trp Ala Cys Trp Arg Leu Ser Gly Thr Gly Phe Asn
1 5 10 15
Tyr
<210> 206
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 206
Ala Ala Asp Leu Gly Val Asp Asp Tyr Ser Asp Tyr Leu Asp His Pro
1 5 10 15
Phe Gly Tyr
<210> 207
<211> 29
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 207
Ala Ala Asp Ile Gly Gly Ser Trp Pro Arg Lys Pro His Pro Asp Pro
1 5 10 15
Asn Phe Gly Gly Glu Cys Gly Gly Tyr Gly Met Ala Phe
20 25
<210> 208
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 208
Ala Ala Asp Ser Ser Ser Leu Pro Cys Tyr Pro Arg Ala Ala Gln Phe
1 5 10 15
Pro Arg Leu Arg Tyr
20
<210> 209
<211> 26
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 209
Ala Ala Arg Pro Ala Pro Val Ser Gly Ile Thr Arg Phe Arg Leu Asn
1 5 10 15
Arg Ser Leu Leu Pro Asn Glu Tyr Asn Ser
20 25
<210> 210
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 210
Ala Ala Gly Leu Asp Gly Gly Ser Gly Tyr Leu Pro Leu Asn Trp Ala
1 5 10 15
Asn Phe Arg Tyr
20
<210> 211
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 211
Ala Ala Glu Gly Gly Trp Arg Asp Tyr Val Arg Ser Trp Gly Arg Asn
1 5 10 15
Phe Gly Tyr
<210> 212
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 212
Ala Ala Asp Leu Trp Arg Gly Pro Pro Phe Gly Gly Tyr Trp Ser Pro
1 5 10 15
Thr Lys Ser Glu Phe Ala Tyr
20
<210> 213
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 213
Ala Ala Asn Arg Arg Ala Tyr Pro Tyr Gly Gly Asp Cys Arg Val Arg
1 5 10 15
His Ala Glu Phe Asp Tyr
20
<210> 214
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 214
Ala Ala Arg Phe Arg Ala His Asp Gly Tyr Trp Asn Trp Gln Asn Ala
1 5 10 15
Gly Asn Tyr Asn Tyr
20
<210> 215
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 215
Ala Ala Arg His Tyr Trp Ser Ala Gly Phe Pro Tyr
1 5 10
<210> 216
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 216
Ala Ala Asp Arg Val Leu Gly Arg Cys Ser Arg Arg Ile Leu Ser Asp
1 5 10 15
Phe Gly Tyr
<210> 217
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 217
Ala Arg Ser Ser Pro Arg Thr Val Val Ala Gly Phe Gly Asp
1 5 10
<210> 218
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 218
Ala Ala Gly Leu Asp Gly Gly Asn Gly Tyr Leu Pro Leu Asn Trp Ala
1 5 10 15
Gly Phe Arg Tyr
20
<210> 219
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 219
Ala Arg Gly Pro Phe Gly Cys Tyr Ser Val Ser Gly Cys Tyr Arg Lys
1 5 10 15
Gly Gly Val Asp Asn Tyr
20
<210> 220
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 220
Lys Thr Val Arg Asp Pro Thr Ser Pro Arg Ser Cys Ser Gly Gly Tyr
1 5 10 15
<210> 221
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 221
Ala Ala Tyr His Ser Gly Ser Trp Cys Tyr Leu Pro His Leu Gly Ser
1 5 10 15
Tyr Gly Tyr
<210> 222
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 222
Ala Ala Gly Trp Arg Leu Ser Leu Arg Val Ser Asp Phe Asn Tyr
1 5 10 15
<210> 223
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 223
Ala Ala Ser Phe Arg Pro Thr Trp Phe Cys Arg Gly Leu Ala Pro Tyr
1 5 10 15
Lys Tyr Asn Leu
20
<210> 224
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 224
Thr Ser Ala Ser Leu Thr Trp Asp Gly Gly Asn Trp Tyr Cys Pro Thr
1 5 10 15
His Gly Tyr
<210> 225
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 225
Ala Ala Gly Arg Thr Tyr Asp Cys Tyr Ser Gly Thr Cys Ser
1 5 10
<210> 226
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 226
Ala Ala Gly Ala Tyr Arg Ala Ser Phe Thr Tyr
1 5 10
<210> 227
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 227
Asn Thr Met Trp Gly Ala Arg Gln Asn Lys Asp
1 5 10
<210> 228
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 228
Ala Ala Asn Arg Arg Pro Tyr Pro Tyr Gly Gly Asp Cys Arg Leu Arg
1 5 10 15
His Ala Glu Phe Asp Tyr
20
<210> 229
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 229
Ala Ala Gly Leu Asp Gly Gly Ser Gly Tyr Leu Pro Leu Ala Trp Ala
1 5 10 15
Gly Phe Arg Tyr
20
<210> 230
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 230
Ala Ala Gly Leu Asp Gly Gly Ser Gly Tyr Leu Pro Leu Asn Trp Ala
1 5 10 15
Arg Phe Arg Tyr
20
<210> 231
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 231
Ala Ala Gly Val Ala Gly Gly Ser Gly Tyr Leu Pro Leu Asn Trp Ala
1 5 10 15
Gly Phe Arg Tyr
20
<210> 232
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 232
Ala Ala Gly Phe Ala Gly Cys Tyr Gly Ser Ser Trp Tyr Gly Ser Ala
1 5 10 15
Asp Phe Gly Tyr
20
<210> 233
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 233
Xaa Xaa Xaa Ser Thr Ala Tyr Tyr
1 5
<210> 234
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 234
Gln Val Arg Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Glu
1 5 10 15
Thr Leu Arg Leu Ser Cys Thr Ala Ser
20 25
<210> 235
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 235
Met Gly Trp Tyr Arg Gln Gly Pro Gly Asn Glu Cys Glu Met Val Ala
1 5 10 15
Tyr
<210> 236
<211> 36
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 236
Ala Asp Ser Thr Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys
1 5 10 15
His Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly
20 25 30
Val Tyr Tyr Cys
35
<210> 237
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 237
Gly Gln Gly Thr Arg Val Thr Val Ser Ser
1 5 10
Claims (10)
1.一种可结合SFTSV的多肽,其特征在于,包括3个互补决定区CDR1-3,CDR1序列为或包括SEQ ID NO:1-74所示序列之一,CDR2序列为或包括SEQ ID NO:75-151所示序列之一,CDR3序列为或包括SEQ ID NO:152-232所示序列之一。
2.根据权利要求1所述的多肽,其特征在于,所述多肽还包括4个框架区FR1-4,所述FR1-4与所述CDR1-3按顺序交错排列。
3.根据权利要求2所述的多肽,其特征在于,所述多肽为单克隆抗体。
4.根据权利要求2所述的多肽,其特征在于,所述多肽为VHH。
5.根据权利要求4所述的多肽,其特征在于,所述多肽为骆驼源的VHH或人源化的VHH。
6.权利要求1-5中任一项所述的多肽在制备SFTSV检测剂或SFTSV治疗药物中的应用。
7.一种核酸编码序列,其特征在于,编码权利要求1-5中任一项所述的多肽。
8.权利要求7所述的核酸编码序列在制备SFTSV治疗药物中的应用。
9.一种SFTSV检测试剂盒,其特征在于,包括检测抗体、固体基质以及包被于所述固体基质上的包被抗体,所述检测抗体和所述包被抗体分别为权利要求1-5中任一项所述的多肽中的一种。
10.根据权利要求9所述的试剂盒,其特征在于,所述检测抗体的CDR序列如下:
CDR1的序列为SEQ ID NO:4,CDR2的序列为SEQ ID NO:84,并且CDR3的序列为SEQ IDNO:181;或CDR1的序列为SEQ ID NO:54,CDR2的序列为SEQ ID NO:132,并且CDR3的序列为SEQ ID NO:176;或CDR1的序列为SEQ ID NO:13,CDR2的序列为SEQ ID NO:99,并且CDR3的序列为SEQ ID NO:166。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN110713536A (zh) * | 2019-07-23 | 2020-01-21 | 源道隆(苏州)医学科技有限公司 | 可结合sftsv的多肽、其核酸编码序列及应用 |
CN112724248A (zh) * | 2021-01-28 | 2021-04-30 | 南京拓峰生物科技有限公司 | 可结合SARS-CoV-2的纳米抗体及其应用 |
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