CN104531730B - 产气荚膜梭菌α毒素人源化单链抗体8B - Google Patents
产气荚膜梭菌α毒素人源化单链抗体8B Download PDFInfo
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- CN104531730B CN104531730B CN201410771046.3A CN201410771046A CN104531730B CN 104531730 B CN104531730 B CN 104531730B CN 201410771046 A CN201410771046 A CN 201410771046A CN 104531730 B CN104531730 B CN 104531730B
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Abstract
本发明公开了产气荚膜梭菌α毒素人源化单链抗体8B，它是从噬菌体抗体库Source bioscience筛选出来的，是全人源抗产气荚膜梭菌α毒素抗体，既可以实现中和毒素的治疗作用，同时克服了异源性抗体的多种副作用，免除了异源性抗体进行人源化改造的繁琐步骤和高成本，由于单链抗体分子量小，体内穿透能力强，迅速到达受损组织和细胞发挥抗毒素作用，因此达到经济和高效的双重目的。α毒素与产气荚膜梭菌其他类型毒素具有一定的同源性，该抗体药物有可能对其他类型的毒素具有抑制和治疗效果，也可作为检测试剂检测产气荚膜梭菌α毒素。
Description
技术领域
本发明属于生物工程及疾病防治领域，具体地涉及产气荚膜梭菌α毒素人源化单链抗体8B及其在产气荚膜梭菌α毒素中毒诊断和治疗方法的应用。
背景技术
产气荚膜梭菌（Clostridium perfringens）亦称魏氏梭菌(C.welchii)，为革兰氏阳性菌，外形为两端钝圆的粗大杆状，专性厌氧，有荚膜无鞭毛，是引起人食物中毒、气性坏疽、抗生素相关性腹泻以及动物的肠毒血症和痢疾等疾病的主要病原菌。产气荚膜梭菌一般条件下很难形成芽孢，在无糖培养基中有利于形成芽孢，多数产气荚膜梭菌菌株可形成荚膜，该细菌DNA的G+C mol%为24-27。在基本培养基上能正常生长，适宜的生长温度在37-47℃，呈现出圆形、凸起、光滑、半透明、边缘整齐、无迁徙生长现象。产气荚膜梭菌是一种厌氧菌，分离培养需要特殊的设备和试剂，一般实验室难以开展该菌的研究，因此长久以来国内对厌氧菌及其在食物中毒中的作用也缺少认识，虽然国外有厌氧菌引起的食物中毒的报道，但国内较少见报道，该菌作为一种条件致病菌, 广泛存在于自然界的水源、土壤及人和动物肠道之中。当食入每克含菌量达105以上的污染食品时，即可引起食物中毒，临床表现为恶心呕吐，腹部绞痛，多次腹泻，不发热等现象。到目前为止，已发现的该菌外毒素有16种（α、β、γ、δ、ε、η、θ、ι、κ、λ、μ和ν等），但仅有几种毒素，即α(CPA)、β(CPB)、ε(ETX)、ι(ITX)毒素以及产气荚膜梭菌溶素O（PFO）、肠毒素（CPE）、β2(CPB2)毒素被认为是该菌的主要致病性毒素。根据产气荚膜梭菌产生四种致死性毒素（α、β、ε、ι毒素）的能力，将其分为五种血清类型，即A、B、C、D和E型，其中A型主要引起人类的食物中毒和抗生素相关性腹泻，也可以引起动物的气性坏疽，还可以引起牛、羔羊、驯鹿、仔猪和家兔的肠毒血症；B型菌主要引起羔羊痢疾，还可以引起狗、牛和羊等肠毒血症或坏死性肠炎；C型菌主要是绵羊猝狙的病原菌，也能引起羔羊、牛、仔猪和绵羊的肠毒血症、坏死性肠炎以及人的坏死性肠炎；D型菌引起羊、牛、仔猪以及灰鼠的肠毒血症；E型菌可致犊牛、羔羊肠毒血症，但是很少发生，其中各型均能产生α毒素，可见α毒素是产气荚膜梭菌的主要毒素和致病因子。
产气荚膜梭菌α毒素（Clostridium perfringens alpha-toxin，CPA）是引起人畜的创伤性气性坏疽和人类食物中毒的主要致病因子。α毒素是一种依赖于锌离子的多功能金属酶，具有膜磷脂C(PLC)和鞘磷脂酶（SMase）两种酶活性，能够同时水解细胞膜的磷脂酰胆碱和鞘磷脂，破坏细胞膜的完整性，导致细胞裂解，具有细胞毒性、溶血活性、皮肤坏死性、血小板聚集和增加血管渗透性等特性。产气荚膜梭菌α毒素是一种不畏氧的细菌毒素，可以水解卵磷脂形成磷脂胆碱和不溶性的甘油二脂，使红细胞发生溶血和分解卵黄磷脂。纯化浓缩的产气荚膜梭菌α毒素作为生物武器可以制成气溶胶形式释放，也可以释放在水和食物中，该生物战剂可引起人多系统多器官的严重反应，如缺乏食欲、恶心呕吐、胃部痉挛疼痛、脓血样腹泻；呼吸困难、喘息咳嗽、口腔咽喉疼痛、痰中带血；皮肤灼痛、红肿、瘙痒、皮疹或水泡，更严重的可以引起死亡。α毒素是第一个被发现既有酶活性又有毒素特性的细菌蛋白，具有冷热溶血效应，即α毒素在37℃与红细胞作用时，红细胞并不发生裂解，只有当红细胞变冷至4℃时，才会发生裂解，这种冷热溶血效应，发现在小鼠红细胞、家兔红细胞、绵羊红细胞和马红细胞上。α毒素对胰酶敏感，2.5%的胰酶与α毒素在37℃作用1 h，即可使其完全失活。另外，把α毒素加热至60℃-70℃时，就可以使其失活，当进一步加热至100℃时，有的可以恢复部分活性。α毒素结构基因大小为1194 bp，编码产物由398个氨基酸组成，其中有28个氨基酸是信号肽，其余的370个氨基酸构成成熟蛋白，相对分子量为43000Da，等电点pI为5.1。α毒素分为两个结构域，即α螺旋结构的N端结构域以及参与膜蛋白结合的C端结构域，经大量实验证明，α毒素的N端与C端具有不同的活性，N端具有磷脂酶C活性，C端具有鞘磷脂酶活性，只有两者协同，才能具有溶血活性与致死活性。α毒素是产气荚膜梭菌最重要的致病因子，至今尚无有效的治疗方法。关于抗α毒素人源化抗体的研究，在国内基本属于空白，研究抗产气荚膜梭菌α毒素治疗性抗体有广阔的应用前景。
20世纪90年代，组合化学技术与基因工程抗体技术相互结合产生了抗体库技术，抗体库技术就是用基因克隆技术克隆全套抗体重链和轻链可变区基因，然后重组到特定的原核表达载体中，再转化大肠杆菌表达有功能的抗体分子片段，并通过亲和筛选获得特异性抗体可变区基因的技术。根据使用的筛选技术不同，抗体库经历了组合抗体库、噬菌体抗体库、核糖体展示库三个阶段，其中噬菌体抗体库是迄今为止，发展最成熟、应用最广泛的抗体技术，噬菌体抗体库是指在丝状噬菌体表面表达Fab抗体或者scFv抗体，这称为噬菌体抗体，然后再利用基因工程手段克隆B细胞全套可变区基因，插入到表达载体，并在噬菌体表面表达，形成大量的噬菌体抗体，构成噬菌体抗体库，如由MRC HGMP资源中心创建的Human Single Fold scFv Libraries I+J( Tomlinson I + J)，该文库包含至少有108个不同的重组单链抗体基因片段，利用其能够淘选出抗α毒素单链抗体基因片段。为研制α毒素中毒的特效药物奠定了基础，提供新的依据。目前，人源单链抗体的制备，大部分都是利用噬菌体展示技术构建一个依托于噬菌体载体或者噬菌粒载体的噬菌体展示文库，通过目的抗原与抗体特异性结合，经过几轮淘选和富集过程，筛选到所需要的阳性克隆或者目的抗体，利用ELISA和PCR等技术对其进行定性定量分析。
发明内容
本发明的目的是为克服异源性抗体的多种副作用，免除异源性抗体进行人源化改造的繁琐步骤和高成本，而提供一种体分子量小，体内穿透能力强，迅速到达受损组织和细胞发挥抗毒素作用的，产气荚膜梭菌α毒素人源化单链抗体8B 。
产气荚膜梭菌α毒素人源化单链抗体8B，它的碱基序列如SEQ ID NO.2所示。
产气荚膜梭菌α毒素人源化单链抗体8B，它的氨基酸序列如SEQ ID NO.5所示。
产气荚膜梭菌α毒素人源化单链抗体8B在制备治疗和预防产气荚膜梭菌α毒素中毒的药物的应用。
一种检测产气荚膜梭菌α毒素的检测试剂，它包括氨基酸序列如SEQ ID NO.5所示的产气荚膜梭菌α毒素人源化单链抗体8B。
本发明提供了产气荚膜梭菌α毒素人源化单链抗体8B，它是从噬菌体抗体库Source bioscience筛选出来的，是全人源抗产气荚膜梭菌α毒素抗体，既可以实现中和毒素的治疗作用，同时克服了异源性抗体的多种副作用，免除了异源性抗体进行人源化改造的繁琐步骤和高成本，由于单链抗体分子量小，体内穿透能力强，迅速到达受损组织和细胞发挥抗毒素作用，因此达到经济和高效的双重目的。α毒素与产气荚膜梭菌其他类型毒素具有一定的同源性，该抗体药物有可能对其他类型的毒素具有抑制和治疗效果，也可作为检测试剂检测产气荚膜梭菌α毒素。
附图说明
图1为重组表达质粒pET-28a-CPA的双酶切鉴定；M：DL2000 DNA Marker；1：重组表达质粒pET-28a-CPA； 2：重组表达质粒pET-28a-CPA NdeⅠ和EcoRⅠ双酶切后；
图2为工程菌在诱导后的表达结果；M：蛋白质Marker；1：阴性对照；2-5：诱导菌体；
图3为工程菌在不同培养基中的表达结果；M:蛋白质Marker；1:阴性对照；2:LB培养基中表达上清；3:LB培养基中表达沉淀；4:TB培养基中表达上清；5:TB培养基中表达沉淀；
图4为纯化后的α毒素蛋白；M:Marker;1:凝血酶酶切前样品;2: 凝血酶酶切后过金属螯合层析样品；
图5为10株scFv筛选阳性克隆菌株的PCR鉴定结果；
图6为纯化后的scFv；M:Marker;1:55%饱和度硫酸铵样品;2:蛋白A层析柱流穿3:蛋白A层析柱纯化后样品；
图7为抗产气荚膜梭菌α毒素scFv抗体活性鉴定结果。
具体实施方式
实施例1：重组表达质粒pET-28a-CPA的构建
根据Genbank中公布的产气荚膜梭菌α毒素（CPA）的全序列（Genbank登录号L43548.1），设计并合成产气荚膜梭菌α毒素的全基因序列，同时在基因的分别两端插入NdeⅠ和EcoRⅠ酶切位点，并克隆入pMD19-T载体中，构建质粒pMD19-T-CPA，然后转入E.coliJM109中，制成穿刺菌种保存。
将酶切后纯化回收的载体质粒pET-28a大片段和酶切后纯化回收的CPA酶切产物用T4 DNA连接酶连接，得到重组质粒pET-28a-CPA，转化大肠杆菌JM109感受态细胞，含kan抗性的琼脂平板进行初步筛选。挑选单菌落于LB液体培养基中培养；用质粒回收试剂盒提取质粒，双酶切鉴定，产物经1%琼脂糖凝胶电泳分析，获得1125 bp左右的条带，大小与插入的目的基因相符，并进行序列的测定，证明CPA目的片段正确插入载体中，成功构建了重组质粒pET-28a-CPA（见图1）。
实施例2：CPA的表达、纯化及蛋白性质研究
将重组质粒pET-28a-CPA转化表达菌-大肠杆菌BL21（DE3），IPTG诱导表达后，SDS-PAGE结果显示：重组蛋白CPA在43KD左右处有一明显表达带，大小与理论值相符，CPA的表达量占菌体总蛋白的15.6%（见图2）。
将重组蛋白表达菌裂解液上清和沉淀同时做SDS-PAGE电泳，结果显示，目的蛋白绝大多数在上清中，沉淀中相应位置也存在少量目的蛋白，通过诱导条件的优化，在适宜的诱导环境下能够以可溶形式表达（见图3）。
重组蛋白CPA的纯化，重组蛋白表达菌体经超声裂解，先后经过饱和硫酸铵沉淀、疏水层析、金属螯合层析、离子交换层析和凝血酶酶切后的金属螯合层析，获得纯度在95%以上的纯品α毒素。热原质检测<20EU/mg，满足蛋白性质研究的需要（见图4）。
实施例3：全人源抗产气荚膜梭菌α毒素中和性scFv抗体的筛选
将纯化的CPA重组蛋白作为抗原包被于96孔酶标板上，4℃过夜。次日弃上清，用2%的Milk-PBS 37℃封闭2h，加入制备的噬菌体抗体库Source bioscience（英国），购于北京西美科技有限公司（中国经销商），滴度为1.0×1013，室温下剧烈晃动孵育60min，静置60min。后弃去液体，用含0.1%Tween-20的PBS洗涤10次，洗涤后将每孔中残留的液体轻轻拍干，每孔加入50µL洗脱液（5mg/mL的胰酶-PBS），室温下剧烈晃动10min，洗脱噬菌体，收集4℃保存。
用洗脱的噬菌体侵染E.coli TG1，并涂布于TYE平板上（含100µg/mL Amp和1%的葡萄糖）37℃过夜培养。利用辅助噬菌体KM13扩增噬菌体库，通过PEG/NaCl回收噬菌体。重复以上过程3次，共4轮筛选。
筛选后的噬菌体侵染E.Coli HB2151，诱导表达后，利用ELISA鉴定，置酶标仪测定OD值（波长为490nm），每个样品做双孔测定，取OD平均值。阳性克隆菌株确定标准为：OD值为阴性对照的3倍以上。共获得300株阳性克隆菌株，经过活性检测比较，获得10株强阳性克隆菌株。
按照Tomlinson I+J试剂盒上的pIT-2载体的基因序列，合成上下游特异性PCR引物扩增scFv全基因片段。
P1 LMB3: 5’—CAG GAA ACA GCT ATG AC—3’
P2 pHEN: 5’—CTA TGC GGC CCC ATT CA—3’
确定目的片段为900bp左右的基因工程抗体片段(图5)。
实施例4：抗CPA-scFv表达以及纯化
强阳性scFv抗体克隆菌株在37℃培养，至OD600到0.9，加入诱导剂30℃培养过夜（16h），过夜培养物于4℃，3500×g离心30min，上清含有表达的scFv。诱导上清先后经过55%饱和度硫酸铵沉淀和rProtein-A亲和层析后，得到纯度在90%以上的样品（图6）
实施例5：抗CPA-scFv活性检测以及抗体亲和常数KD值测定
取50% Egg Yolk Emulsion（海清生物，货号HB8295）4℃ 10000×g离心20min，取上清，用生理盐水1:10倍稀释，在细胞培养板中，每孔加入100µL稀释的卵黄液，每孔加入5µg 纯化的CPA毒素以及5µg scFv，用生理盐水做阴性对照，仅加CPA毒素做阳性对照，每个样品做复孔测定，37℃放置2 h，读取OD620平均值。通过比较吸光值，能准确得出活性较高的菌株，吸光值越低的阳性菌株活性越好（图7）。获得的8B和7D株有很好的中和活性，通过测序分析表明该序列为典型的人源单链抗体序列。
实施例6：利用非竞争酶联免疫法测定抗体的亲和常数。
利用非竞争酶免疫法测定7D和8B单链抗体的亲和常数，分别以2.5 µg/mL、1.25µg/mL、0.625µg/mL和0.3125 µg/mL包被α毒素，将单链抗体浓度调整到10-6 mol/L，倍比稀释1:2~1:512，用1:5000倍稀释的Protein A-HRP抗体作为二抗，OPD显色，测定OD490nm吸光值，每个样品做双孔测定，取OD平均值。根据抗原抗体结合反应的S形曲线图，能够求解出在不同抗原浓度下半数吸光值的抗体浓度，带入到公式KA=（n-1）/2(nAb’-Ab)中计算亲和常数，其中Ab’和Ab表示当抗原为Ag’和Ag时，产生半数吸光值的抗体浓度（mol/L），n=Ag’/Ag，当n=2时可以得到3个KA值，n=4时可得2个KA值，n=8时得1个KA值，取六个KA值平均数值得出抗体的亲和常数。
结果见表1：其中7D单链抗体亲和常数为（2.01±0.78）×108L/mol； 8B单链抗体亲和常数为（3.45±0.58）×108L/mol。
表1 抗CPA单链抗体7D和8B亲和力测定曲线进行模拟后求得的KA值
实施例7：动物体内CPA毒素中和治疗实验
利用纯化的CPA毒素进行攻毒剂量研究，以96小时为攻毒全程时间，确定了CPA毒素对昆明系小鼠的腹腔攻毒LD50为30μg/Kg体重。取30只昆明系小鼠随机分为为5组，雌雄各半，设阳性和阴性对照组各一组，给药组分高、中、低三个剂量组，除阴性对照组外其余各组分别腹腔给予5倍LD50的CPA毒素，攻毒1小时后阳性对照组给予PBS缓冲液安慰剂治疗，高剂量救治组给予30μg/Kg体重纯化的scFv、中剂量组给予20μg/Kg体重纯化的scFv、低剂量组给予10μg/Kg体重纯化的scFv。阴性对照组攻毒誓给予PBS缓冲液，救治试验中给予30μg/Kg体重纯化的scFv。结果：阳性对照组动物死亡率100%，高剂量组全部存活，中剂量组1只死亡，低剂量组2只死亡，阴性对照组无异常。由此可见，高剂量组小鼠保护率达到100%，且呈剂量依赖关系。
通过系统的实验证明筛选获得的抗CPA单链抗体具有中和毒素和实验动物保护能力。预计在人体内可以实现中和毒素的治疗作用，同时又克服了异源性抗体的多种副作用，免除了异源性抗体进行人源化改造的繁琐步骤和高成本，再由于单链抗体分子量小，体内穿透能力强，迅速到达受损组织和细胞发挥抗毒素作用，达到经济和高效的双重目的。
<110> 中国人民解放军军事医学科学院军事兽医研究所
<120> 产气荚膜梭菌α毒素人源化单链抗体8B
<160> 6
<210> 1
<211> 1125
<212> DNA
<213> 人工
<400> 1
catatgtggg atggaaagat tgatggaaca ggaactcatg ctatgattgt aactcaaggg 60
gtttcaatct tagaaaatga tctgtctaaa aatgaaccag aaagtgtaag aaaaaactta 120
gagattttaa aagagaacat gcatgagctt caattaggtt ctacttatcc agattatgat 180
aagaacgcct atgatctata tcaagatcat ttctgggatc ctgatacaga taataatttc 240
tcaaaggata atagttggta tttagcttat tctatacctg acacagggga atcacaaata 300
agaaaatttt cagcattagc tagatatgaa tggcaaagag gaaactataa acaagctaca 360
ttctatcttg gagaggctat gcactatttt ggagatatag atactccata tcatcctgct 420
aatgttactg ccgttgatag cgcaggacat gttaagtttg agacttttgc agaggaaaga 480
aaagaacagt ataaaataaa cacagcaggt tgcaaaacta atgaggattt ttatgctgat 540
atcttaaaaa acaaagattt taatgcatgg tcaaaagaat atgcaagagg ttttgctaaa 600
acaggaaaat caatatacta tagtcatgct agcatgagtc atagttggga tgattgggat 660
tatgcagcaa aggtaacttt agctaactct caaaaaggaa cagcaggata tatttataga 720
ttcttacacg atgtatcaga gggtaatgat ccatcagttg gaaagaatgt aaaagaacta 780
gtagcttaca tatcaactag tggtgagaaa gatgctggaa cagatgacta catgtatttt 840
ggaatcaaaa caaaggatgg aaaaactcaa gaatgggaaa tggacaaccc aggaaatgat 900
tttatgactg gaagtaaaga cacttatact ttcaaattaa aagatgaaaa tctaaaaatt 960
gatgatatac aaaatatgtg gattagaaaa agaaaatata cagcattccc agatgcttat 1020
aagccagaaa acataaagat aatagcaaat ggaaaagttg tagtggacaa agatataaat 1080
gagtggattt caggaaattc aacttataat ataaaataag aattc 1125
<210> 2
<211> 870
<212> DNA
<213> 人工
<400> 2
ataatgaaat acctattgcc tacggcagcc gctggattgt tattactcgc ggcccagccg 60
gccatggccg aggtgcagctgttggagtct gggggaggct tggtacagcc tggggggtcc 120
ctgagactct cctgtgcagc ctctggattc acctttagca gctatgccat gagctgggtc 180
cgccaggctc cagggaaggg gctggagtgg gtctcaggga ttccgaagca tggtgggcgt 240
acaagttacg cagactccgt gaagggccgg ttcaccatct ccagagacaa ttccaagaac 300
acgctgtatc tgcaaatgaa cagcctgaga gccgaggaca cggccgtata ttactgtgcg 360
aaaggtggga cgatgtttga ctactggggc cagggaaccc tggtcaccgt ctcgagcggt 420
ggaggcggtt caggcggagg tggcagcggc ggtggcgggt cgacggacat ccagatgacc 480
cagtctccat cctccctgtc tgcatctgta ggagacagag tcaccatcac ttgccgggca 560
agtcagagca ttagcagcta tttaaattgg tatcagcaga aaccagggaa agcccctaag 600
ctcctgatct atagggcatc ccgtttgcaa agtggggtcc aatcaaggtt cagtggcagt 660
ggatctggga cagatttcac tctcaccatc agcagtctgc aacctgaaga ttttgcaact 720
tactactgtc aacaggggtc ggcgcgtcct gcgacgttcg gccaagggac caaggtggaa 780
atcaaacggg cggccgcaca tcatcatcac catcacgggg ccgcagaaca aaaactcatc 840
tcagaagagg atctgaatgg ggccgcatag 870
<210> 3
<211> 870
<212> DNA
<213> 人工
<400> 3
ataatgaaat acctattgcc tacggcagcc gctggattgt tattactcgc ggcccagccg 60
gccatggccg aggtgcagct gttggagtct gggggaggct tggtacagcc tggggggtcc 120
ctgagactct cctgtgcagc ctctggattc acctttagca gctatgccat gagctgggtc 180
cgccaggctc cagggaaggg gctggagtgg gtctcacaga tttcgaatca tggtgggtat 240
acagcttacg cagactccgt gaagggccgg ttcaccatct ccagagacaa ttccaagaac 300
acgctgtatc tgcaaatgaa cagcctgaga gccgaggaca cggccgtata ttactgtgcg 360
aaagggtcgc agaggtttga ctactggggc cagggaaccc tggtcaccgt ctcgagcggt 420
ggaggcggtt caggcggagg tggcagcggc ggtggcgggt cgacggacat ccagatgacc 480
cagtctccat cctccctgtc tgcatctgta ggagacagag tcaccatcac ttgccgggca 540
agtcagagca ttagcagcta tttaaattgg tatcagcaga aaccagggaa agcccctaag 600
ctcctgatct atggtgcatc ccgtttgcaa agtggggtcc aatcaaggtt cagtggcagt 660
ggatctggga cagatttcac tctcaccatc agcagtctgc aacctgaaga ttttgcaact 720
tactactgtc aacaggctca gttgattcct gagacgttcg gccaagggac caaggtggaa 780
atcaaacggg cggccgcaca tcatcatcac catcacgggg ccgcagaaca aaaactcatc 840
tcagaagagg atctgaatgg ggccgcatag 870
<210> 4
<211> 372
<212> PRT
<213> 人工
<400> 4
His Met Trp Asp Gly Lys Ile Asp Gly Thr Gly Thr His Ala Met Ile
5 10 15
Val Thr Gln Gly Val Ser Ile Leu Glu Asn Asp Leu Ser Lys Asn Glu
20 25 30
Pro Glu Ser Val Arg Lys Asn Leu Glu Ile Leu Lys Glu Asn Met His
35 40 45
Glu Leu Gln Leu Gly Ser Thr Tyr Pro Asp Tyr Asp Lys Asn Ala Tyr
50 55 60
Asp Leu Tyr Gln Asp His Phe Trp Asp Pro Asp Thr Asp Asn Asn Phe
65 70 75 80
Ser Lys Asp Asn Ser Trp Tyr Leu Ala Tyr Ser Ile Pro Asp Thr Gly
85 90 95
Glu Ser Gln Ile Arg Lys Phe Ser Ala Leu Ala Arg Tyr Glu Trp Gln
100 105 110
Arg Gly Asn Tyr Lys Gln Ala Thr Phe Tyr Leu Gly Glu Ala Met His
115 120 125
Tyr Phe Gly Asp Ile Asp Thr Pro Tyr His Pro Ala Asn Val Thr Ala
130 135 140
Val Asp Ser Ala Gly His Val Lys Phe Glu Thr Phe Ala Glu Glu Arg
145 150 155 160
Lys Glu Gln Tyr Lys Ile Asn Thr Ala Gly Cys Lys Thr Asn Glu Asp
165 170 175
Phe Tyr Ala Asp Ile Leu Lys Asn Lys Asp Phe Asn Ala Trp Ser Lys
180 185 190
Glu Tyr Ala Arg Gly Phe Ala Lys Thr Gly Lys Ser Ile Tyr Tyr Ser
195 200 205
His Ala Ser Met Ser His Ser Trp Asp Asp Trp Asp Tyr Ala Ala Lys
210 215 220
Val Thr Leu Ala Asn Ser Gln Lys Gly Thr Ala Gly Tyr Ile Tyr Arg
225 230 235 240
Phe Leu His Asp Val Ser Glu Gly Asn Asp Pro Ser Val Gly Lys Asn
245 250 255
Val Lys Glu Leu Val Ala Tyr Ile Ser Thr Ser Gly Glu Lys Asp Ala
260 265 270
Gly Thr Asp Asp Tyr Met Tyr Phe Gly Ile Lys Thr Lys Asp Gly Lys
275 280 285
Thr Gln Glu Trp Glu Met Asp Asn Pro Gly Asn Asp Phe Met Thr Gly
290 295 300
Ser Lys Asp Thr Tyr Thr Phe Lys Leu Lys Asp Glu Asn Leu Lys Ile
305 310 315 320
Asp Asp Ile Gln Asn Met Trp Ile Arg Lys Arg Lys Tyr Thr Ala Phe
325 330 335
Pro Asp Ala Tyr Lys Pro Glu Asn Ile Lys Ile Ile Ala Asn Gly Lys
340 345 350
Val Val Val Asp Lys Asp Ile Asn Glu Trp Ile Ser Gly Asn Ser Thr
355 360 365
Tyr Asn Ile Lys
370
<210> 5
<211> 289
<212> PRT
<213> 人工
<400> 5
Iie Met Lys Tyr Leu Leu Pro Thr Ala Ala Ala Gly Leu Leu Leu Leu
5 10 15
Ala Ala Gln Pro Ala Met Ala Glu Val Gln Leu Leu Glu Ser Gly Gly
20 25 30
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
35 40 45
Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro
50 55 60
Gly Trp Gly Leu Glu Trp Val Ser Gly Ile Pro Trp His Gly Gly Arg
65 70 75 80
Thr Ser Tyr Ala Asp Ser Val Trp Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asn Ser Trp Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Trp Gly Gly Thr Met Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Asp Ile Gln Met Thr
145 150 155 160
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
165 170 175
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln
180 185 190
Gln Trp Pro Gly Trp Ala Pro Trp Leu Leu Ile Tyr Arg Ala Ser Arg
195 200 205
Leu Gln Ser Gly Val Gln Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
210 215 220
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
225 230 235 240
Tyr Tyr Cys Gln Gln Gly Ser Ala Arg Pro Ala Thr Phe Gly Gln Gly
245 250 255
Thr Trp Val Glu Ile Trp Arg Ala Ala Ala His His His His His His
260 265 270
Gly Ala Ala Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Asn Gly Ala
275 280 285
Ala
289
<210> 6
<211> 289
<212> PRT
<213> 人工
<400> 6
Iie Met Lys Tyr Leu Leu Pro Thr Ala Ala Ala Gly Leu Leu Leu Leu
5 10 15
Ala Ala Gln Pro Ala Met Ala Glu Val Gln Leu Leu Glu Ser Gly Gly
20 25 30
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
35 40 45
Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro
50 55 60
Gly Lys Gly Leu Glu Trp Val Ser Gln Ile Ser Asn His Gly Gly Tyr
65 70 75 80
Thr Ala Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Lys Gly Ser Gln Arg Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Asp Ile Gln Met Thr
145 150 155 160
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
165 170 175
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln
180 185 190
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Gly Ala Ser Arg
195 200 205
Leu Gln Ser Gly Val Gln Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
210 215 220
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
225 230 235 240
Tyr Tyr Cys Gln Gln Ala Gln Leu Ile Pro Glu Thr Phe Gly Gln Gly
245 250 255
Thr Lys Val Glu Ile Lys Arg Ala Ala Ala His His His His His His
260 265 270
Gly Ala Ala Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Asn Gly Ala
275 280 285
Ala
289
Claims (4)
1.产气荚膜梭菌α毒素人源化单链抗体8B，它的碱基序列如SEQ ID NO.2所示。
2.产气荚膜梭菌α毒素人源化单链抗体8B，它的氨基酸序列如SEQ ID NO.5所示。
3.产气荚膜梭菌α毒素人源化单链抗体8B在制备治疗和预防产气荚膜梭菌α毒素中毒的药物中 的应用。
4.一种检测产气荚膜梭菌α毒素的检测试剂，它包括氨基酸序列如SEQ ID NO.5所示的产气荚膜梭菌α毒素人源化单链抗体8B。
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| CN101198352A (zh) * | 2005-04-18 | 2008-06-11 | 谢尔英·普劳有限公司 | 产气荚膜梭菌α类毒素疫苗 |
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| 产气荚膜梭菌α毒素的原核表达及纯化;于佳 等;《中国生物制品学杂志》;20141031;第27卷(第10期);摘要，第1.4节 * |
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