CN1961002A - 能中和狂犬病病毒的结合分子及其应用 - Google Patents
能中和狂犬病病毒的结合分子及其应用 Download PDFInfo
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- CN1961002A CN1961002A CNA2005800172331A CN200580017233A CN1961002A CN 1961002 A CN1961002 A CN 1961002A CN A2005800172331 A CNA2005800172331 A CN A2005800172331A CN 200580017233 A CN200580017233 A CN 200580017233A CN 1961002 A CN1961002 A CN 1961002A
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Abstract
本发明提供了特异性结合狂犬病病毒并且能中和该病毒的结合分子。本发明进一步提供了编码该结合分子的核酸分子、包含该结合分子的组合物及鉴别或者产生该结合分子的方法。所述结合分子可用于得自狂犬病病毒的疾病的诊断、预防和/或治疗。优选地,其可用于狂犬病的暴露后预防。
Description
发明领域
本发明涉及医药学领域。本发明特别涉及中和狂犬病病毒的结合分子。所述结合分子可用于狂犬病的暴露后预防中。
发明背景
狂犬病是一种几乎在全世界分布的病毒感染,其主要影响野生动物和家畜,但也包括人,导致破坏性的、几乎不可改变的致命脑炎。估计每年有超过70000人丧命,其它数百万人需要暴露后治疗。
狂犬病病毒是一种子弹形状的、有包膜的、单链RNA病毒,分类为弹状病毒科和狂犬病毒属。狂犬病病毒的基因组编码5种病毒蛋白质:RNA-依赖性RNA聚合酶(L)、核蛋白(N)、磷酸化蛋白质(P)、位于病毒蛋白包膜内侧的基质蛋白(M)、及外表面糖蛋白(G)。
G蛋白(62-67kDa)是由505个氨基酸组成的一种I型糖蛋白,具有2-4个潜在N糖基化位点,其中仅一或两个是依赖于病毒株而糖基化的。G蛋白形成覆盖病毒粒包膜外表面的突起,已知其诱导病毒中和抗体。
狂犬病可以通过被动和主动免疫两种方式治疗或者预防。狂犬病暴露后预防包括迅速将局部伤口进行处理并给予被动(抗狂犬病免疫球蛋白)和主动免疫(疫苗)措施。
目前,抗狂犬病免疫球蛋白(RIG)是从狂犬病病毒免疫的人(HRIG)或者狂犬病病毒免疫的马(ERIG)的血清样品中制备的。ERIG以及HRIG的缺点是不能获得足够的量,在HRIG情况中太昂贵。另外,使用ERIG可导致不利反应,如过敏性休克。污染已知或未知病原体的可能性是与HRIG相关的另外的关注。为了克服这些缺点,提议在暴露后预防中使用能中和狂犬病病毒的单克隆抗体。本领域已知中和狂犬病病毒的鼠单克隆抗体(见Schumacher et al.,1989)。然而,由于与给予人体鼠抗体相关的问题导致鼠抗体在体内的应用受到限制,所述问题如血清半衰期短,不能触发某些人效应器功能,及在人体中激发对鼠抗体的非所需的明显免疫应答(人抗小鼠抗体(HAMA)反应)。
最近描述了中和人狂犬病病毒单克隆抗体(见Dietzschold et al.,1990,Champion et al.,2000,和Hanlon et al.,2001)。对于在暴露后预防中与HRIG同样有效的人抗狂犬病单克隆抗体而言,应使用单克隆抗体混合物。在这种混合物中,每种抗体应结合病毒上的不同表位或位点,以预防病毒抗性变体的逃避。
目前仍非常需要新的具有改良的暴露后预防潜力的人狂犬病病毒中和单克隆抗体,特别是具有不同表位识别特异性的抗体。本发明提供了这种人单克隆抗体,其可用于进行多种狂犬病病毒及其中和抗性变体的暴露后预防的混合物中。
附图描述
图1示出狂犬病病毒株CVS-11与E57逃逸病毒(escape virus)的氨基酸序列对比。在感染后2天收获病毒感染的细胞并分离总RNA。产生cDNA并用于DNA测序。图中示出了含有突变的区域,以黑体字表示突变。图1A示出核苷酸序列对比。氨基酸上面的数字表示来自包括信号肽的狂犬病病毒糖蛋白的氨基酸编号。图1B示出氨基酸序列对比。狂犬病病毒糖蛋白的示意图示于上方。黑框表示信号肽,灰色框表示跨膜结构域。图1中的序列也由SEQ ID No:130-141表示。
图2示出狂犬病病毒株CVS-11与EJB逃逸病毒的氨基酸序列对比。在感染后2天收获病毒感染的细胞并分离总RNA。产生cDNA并用于DNA测序。图中示出含有突变的区域,突变以黑体字表示。图2A示出核苷酸序列对比。氨基酸上面的数字表示来自包括信号肽的狂犬病病毒糖蛋白的氨基酸编号。图2B示出氨基酸序列对比。狂犬病病毒糖蛋白的示意图示于上方。黑框表示信号肽,灰色框表示跨膜结构域。图2中的序列也由SEQ ID No:142-151表示。
图3示出载体PDV-C06。
图4示出抗狂犬病病毒scFv与称作CR-57的生物素化的抗狂犬病病毒抗体的竞争ELISA。将用纯化的狂犬病病毒G蛋白包被的ELISA平板在加入CR-57bio(0.5μg/ml)之前与各自的scFv保温。随后,在有和无scFv的条件下监测CR-57bio结合。
图5示出抗狂犬病病毒scFv与称作CR-57的抗狂犬病病毒抗体的竞争ELISA。将用纯化的狂犬病病毒G蛋白包被的ELISA平板在加入过量的scFv之前与CR-57(1μg/ml)保温。随后,在有和无CR-57的条件下监测scFv结合。
图6示出抗狂犬病病毒G蛋白IgG与称作CR-57的抗狂犬病病毒抗体的竞争ELISA。将G蛋白(ERA毒株)与未标记的IgG(在X轴上示出)保温。加入生物素化的CR57(CR57bio),使之与G蛋白结合,然后利用链霉亲和素-HRP显色。ELISA信号以单独的CR57bio结合百分比示出。
图7示出抗狂犬病病毒G蛋白IgG与称作CR-57的抗狂犬病病毒抗体的竞争FACS分析。将表达G蛋白(ERA毒株)的PER.C6细胞与未标记的IgG(在X-轴上示出)保温。加入生物素化的CR57(CR57bio),使之与G蛋白表达细胞结合,然后利用链霉亲和素-PE显色。FACS信号以单独的CR57bio结合百分比示出。
图8示出CVS-11与E98逃逸病毒的氨基酸序列对比。在感染后2天收获病毒感染的细胞并分离总RNA。产生cDNA并用于DNA测序。图中示出含有点突变的区域,突变以黑体字表示。图8A示出核苷酸序列对比。核苷酸上面的数字表示无信号肽序列的狂犬病病毒糖蛋白开放读框的突变的核苷酸(以黑体字表示)。图8B示出氨基酸序列对比。氨基酸上面的数字表示无信号肽序列的狂犬病病毒糖蛋白的突变的氨基酸(以黑体字表示)。
图9示出123个狂犬病街毒的系统树(123个狂犬病病毒G糖蛋白序列,邻接法(Neighbor joining),Kimura-2-参数方法,靴值(bootstrap)500)。黑体字表示在E98逃逸病毒中观察到的具有N>D突变的病毒。
图10示出狂犬病糖蛋白上的中和表位。图中示出了狂犬病病毒糖蛋白的示意图,描述了包括新的CR57表位的抗原位点。信号肽(19个氨基酸)和跨膜结构域以黑框表示。图中示出了二硫键。氨基酸编号得自减去信号肽序列的成熟蛋白质。
发明描述
下文阐述了对本发明使用的术语进行的定义。
定义
结合分子
如本文所用,术语“结合分子”是指完整的免疫球蛋白,包括单克隆抗体,如嵌合的、人源化的或者人单克隆抗体,或者是指包含与完整免疫球蛋白竞争特异性结合免疫球蛋白的结合配偶体(如狂犬病病毒或其片段,例如G蛋白)的免疫球蛋白片段的抗原结合和/或可变结构域。无论结构如何,抗原结合片段均与完整免疫球蛋白所识别的相同抗原结合。抗原结合片段可包含一种肽或者多肽,所述肽或者多肽包含所述结合分子的氨基酸序列的至少2、5、10、15、20、25、30、35、40、50、60、70、80、90、100、125、150、175、200或者至少250个连续的氨基酸残基。
本文所用术语“结合分子”包括本领域已知的所有免疫球蛋白类和亚类。根据其重链恒定结构域的氨基酸序列,结合分子可以分为5个主要类别的完整抗体:IgA、IgD、IgE、IgG和IgM,这些类别有几个可进一步分为亚类(同种型),例如IgA1、IgA2、IgG1、IgG2、IgG3和IgG4。
抗原结合片段包括Fab、F(ab′)、F(ab′)2、Fv、dAb、Fd、互补决定区(CDR)片段、单链抗体(scFv)、二价单链抗体、单链噬菌体抗体、双链抗体(diabody)、三链抗体(triabody)、四链抗体(tetrabody)、(多)肽,其含有至少足以赋予所述(多)肽特异性抗原结合的免疫球蛋白片段,等等。上述片段可以合成产生或者通过酶或化学切割完整免疫球蛋白而产生或者通过重组DNA技术遗传工程化。生产方法为本领域所熟知,例如Antibodies:A Laboratory Manual,Edited by:E.Harlow and D,Lane(1988),Cold Spring Harbor Laboratory,Cold SpringHarbor,New York所述,所述文献在此并入作参考。结合分子或其抗原结合片段可具有一或多个结合位点。如果有一个以上的结合位点,则所述结合位点可以是相同或者不同的。
所述结合分子可以是裸露的或者未缀合的结合分子,但也可以是免疫缀合物的一部分。裸露的或者未缀合的结合分子是指与效应物(effector)部分或者标记如毒性物质、放射性物质、脂质体、酶未缀合的、可操纵地连接的或者另外物理或者功能结合的结合分子。应理解裸露的或者未缀合的结合分子不排除已经稳定化的、多聚体化的、人源化的或者以任何其它方式操纵的结合分子,除了与效应物部分或标记附着。因此,所有翻译后修饰的裸露和未缀合结合分子均包括在内,包括所述修饰是在产生天然结合分子的细胞环境中进行的,通过产生重组结合分子的细胞产生的及在最初制备结合分子后经人工导入的。当然,术语裸露的或者未缀合的结合分子不排除结合分子在给予机体后与效应细胞和/或分子形成功能性结合的能力,一些这种相互作用是发挥生物学作用必需的。因此,缺少相关的效应基团或者标记用于定义在体外而非在体内的裸露的或者未缀合的结合分子。
互补决定区(CDR)
本文所用术语“互补决定区”是指结合分子如免疫球蛋白的可变区内的序列,其通常在很大程度上提供在形态和电荷分布上与抗原识别的表位互补的抗原结合位点。CDR区域可以特异于线性表位、不连续表位、或者蛋白质或者蛋白质片段的构象表位,以其天然构象呈递在蛋白质上或者在一些情况中作为变性的蛋白质(例如在SDS中溶解)的构象呈递在蛋白质上。表位也可以由蛋白质的翻译后修饰组成。
功能变体
如本文所用术语“功能变体”是指这样的结合分子,其包含一种核苷酸和/或氨基酸序列,该序列与亲代结合分子的核苷酸和/或氨基酸序列相比有一或多个核苷酸和/或氨基酸发生改变,并仍能与亲代结合分子竞争结合结合配偶体,例如狂犬病病毒或其片段。换句话说,亲代结合分子的氨基酸和/或核苷酸序列中的修饰不显著影响或者改变由该核苷酸序列编码的或者包含该氨基酸序列的结合分子的结合特性,即所述结合分子仍能识别并结合其靶位。所述功能变体可具有保守序列修饰,包括核苷酸和氨基酸取代、添加和缺失。这些修饰可以通过本领域已知的标准技术导入,如定点诱变和随机PCR介导的诱变,并且可以包含天然以及非天然的核苷酸和氨基酸。
保守氨基酸取代包括其中氨基酸残基由具有相似结构或者化学性质的氨基酸残基置换的取代。本领域已经定义了具有相似侧链的氨基酸残基家族。这些家族包括具有碱性侧链的氨基酸(例如赖氨酸、精氨酸、组氨酸),具有酸性侧链的氨基酸(例如天冬氨酸、谷氨酸),具有无电荷的极性侧链氨基酸(例如天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸),具有非极性侧链氨基酸(例如甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸),具有β-分支侧链氨基酸(例如苏氨酸、缬氨酸、异亮氨酸)和具有芳族侧链氨基酸(例如酪氨酸、苯丙氨酸、色氨酸)。本领域技术人员明了也可以应用除了上述所用氨基酸分类之外的氨基酸残基家族的其它分类。此外,变体可以具有非保守的氨基酸取代,例如用具有不同结构或者化学性质的氨基酸残基置换氨基酸。相似的次要变化也可以包括氨基酸缺失或者插入或者这两者。确定哪个氨基酸残基可以被取代、插入或者缺失而不消除免疫学活性的指导可以使用本领域熟知的计算机程序发现。
核苷酸序列中的突变可以是在一个基因座的单一改变(点突变),如转换或者颠换突变,或者在一个基因座插入、缺失或者改变多个核苷酸。另外,可以在核苷酸序列内的许多基因座进行一或多个改变。所述突变可以通过本领域已知的任何合适方法进行。
宿主
如本文所用术语“宿主”是指其中已经导入载体如克隆载体或者表达载体的生物体或者细胞。所述生物体或者细胞可以是原核或者真核生物或者细胞。应理解该术语不仅是指特定生物体或细胞,也是指这种生物体或细胞的子代。因为某些修饰由于突变或者环境影响而可以在随后的世代中出现,这种子代事实上与亲代生物体或者细胞也许不同,但是仍包括在本文所用术语“宿主”范围内。
人
术语“人”当用于本文所述结合分子时,是指直接衍生自人的分子或者基于人序列的分子。当结合分子衍生自或者基于人序列并随后被修饰时,在本说明书中仍认为是人。换句话说,术语人当用于结合分子时是包括具有衍生自人种系免疫球蛋白序列的可变区和恒定区的结合分子,其基于在人或人淋巴细胞中出现或不出现的或者是以修饰的形式出现或者不出现的可变区或者恒定区。因此,人结合分子可包括不是由人种系免疫球蛋白序列编码的氨基酸残基,包含取代和/或缺失(例如通过体外随机或者位点特异性诱变或者体内体细胞突变而导入的突变)。本文所用术语“基于”是指核酸序列可以精确地从模板拷贝或者具有较少突变,例如通过易错PCR方法或者与模板精确匹配或者具有较少修饰而合成产生。基于人序列的半合成分子在本文中也认为是人。
单克隆抗体
如本文所用术语“单克隆抗体”是指单一分子组分即一级结构即具有单一氨基酸序列的抗体分子制品。单克隆抗体展示对于特定表位的单一结合特异性和亲和性。因此,术语“人单克隆抗体”是指展示单一结合特异性的抗体,其具有衍生自或者基于人种系免疫球蛋白序列或者衍生自完全合成的序列的可变区和恒定区。制备单克隆抗体的方法与本发明不相关。
核酸分子
如本文所用术语“核酸分子”是指多聚体形式的核苷酸,包括RNA、cDNA、基因组DNA的有义和反义链,及上述分子的合成形式与混合的聚合物。核苷酸是指核糖核苷酸、脱氧核苷酸或者任一类型核苷酸的修饰形式。该术语也包括DNA的单链和双链形式。另外,多核苷酸可包括天然发生的核苷酸或者通过天然发生的和/或非天然发生的核苷酸键连接在一起的修饰的核苷酸或者这两者。所述核酸分子可以经化学或者生物化学修饰或者可以含有非天然的或者衍生的核苷酸碱基,这易于由本领域技术人员所意识到。这种修饰包括例如标记、甲基化、用类似物取代一或多个天然发生的核苷酸、核苷酸间修饰(internucleotide modification)如无电荷的键(例如甲基膦酸酯、磷酸三酯、氨基磷酸酯、氨基甲酸等)、带电荷的键(例如硫代磷酸酯、二硫代磷酸酯等)、悬垂部分(pendent moiety)(例如多肽)、嵌入剂(例如吖啶、补骨脂素等)、螯合剂、烷化剂及修饰的键(例如α端基异构核酸等)。该术语还包括任何拓扑构象,包括单链、双链、部分双链、三链、发夹、环形和扣锁构象。该术语还包括合成的分子,其模拟多核苷酸通过氢键及其它化学相互作用结合指定序列的能力。本领域已知这种分子,并包括例如其中肽键代替分子主链中的磷酸键的分子。除非特别指出,则提及核酸序列时涵盖其互补体。因此,提及具有特定序列的核酸分子时应理解涵盖其互补链及其互补序列。互补链也可用于例如反义治疗、杂交探针和PCR引物中。
药物可接受的赋形剂
“药物可接受的赋形剂”是指与活性分子如药物、制剂或者结合分子组合以制备合适或者方便剂型的任何惰性物质。“药物可接受的赋形剂”是以应用的剂量和浓度应用时对于受者(recipient)是无毒的、或者至少其毒性对于其指定用途是可接受的赋形剂,并且与包含药物、制剂或者结合分子的制剂的其它成分相容。
暴露后预防
“暴露后预防(PEP)”是针对可能暴露于狂犬病动物的人而言。可能的暴露包括咬伤暴露(即通过牙齿对皮肤的任何穿透),包括动物咬伤及非咬伤暴露。非咬伤暴露包括在实验室或者洞穴中暴露于大量雾状散开的狂犬病病毒及移植了死于狂犬病的患者角膜的手术受者。开放性创伤、擦伤、粘膜的污染,或者理论上被狂犬病动物唾液或者其它潜在感染性物质(如神经组织)擦伤也构成了非咬伤暴露。其它自身接触,如抚摸狂犬病动物及与狂犬病动物的血液、尿液或者粪便接触不构成暴露,不是预防的指征。PEP应在暴露后立即进行。如果未暴露则无需进行暴露后预防。在所有暴露后预防方案中,除了先前已经免疫接种的人之外,均应同时进行主动和被动免疫。
特异性结合
如本文所用术语“特异性结合”在描述结合分子例如抗体与其结合配偶体例如抗原的相互作用时,是指该相互作用依赖于结合配偶体上特殊结构的存在,例如抗原决定簇或者表位。换句话说,抗体优先结合或者识别结合配偶体,甚至当结合配偶体存在于其它分子或者生物体的混合物时也如此。这种结合是通过共价或者非共价相互作用或者这两者而介导的。再换句话说,术语“特异性结合”是指免疫特异性结合一种抗原或其片段而非免疫特异性结合其它抗原。免疫特异性结合抗原的结合分子可以较低的亲和性结合其它肽或者多肽,例如通过放射性免疫分析(RIA)、酶联免疫吸附分析(ELISA)、BIACORE或者本领域已知的其它方法确定。免疫特异性结合抗原的结合分子或其片段可以与相关抗原交叉反应。优选地,免疫特异性结合抗原的结合分子或其片段与其它抗原不交叉反应。
治疗有效量
术语“治疗有效量”是指有效进行狂犬病暴露后预防的本文结合分子的量。
载体
术语“载体”是指其中可以插入第二种核酸分子以导入宿主中的核酸分子,在所述宿主中其将被复制,在一些情况中被表达。换句话说,载体能转运与其连接的核酸分子。克隆载体以及表达载体涵盖在如本文所用术语“载体”中。载体包括但非限于质粒、粘粒、细菌人工染色体(BAC)和酵母人工染色体(YAC)及衍生自噬菌体或者植物或者动物(包括人)病毒的载体。载体包含由指定宿主识别的复制起点,在表达载体情况中包含启动子及由宿主识别的其它调节区域。含有第二种核酸分子的载体例如通过转化、转染或者通过利用细菌或者病毒进入机制而导入细胞中。本领域已知将核酸导入细胞中的其它方式,例如对于植物细胞通常使用电穿孔或者粒子轰击方式等。将核酸导入细胞中的方法依赖于细胞类型等因素。这对于本发明无关紧要。某些载体在其被导入的宿主中能自发复制(例如具有细菌复制起点的载体可以在细菌中复制)。其它载体基于导入宿主而可以整合进宿主基因组中,从而随着宿主基因组而复制。
发明概述
本发明提供了能特异性结合并中和狂犬病病毒的结合分子。此外,本发明涉及至少编码这些结合分子的结合区域的核酸分子。本发明进一步提供了本发明的结合分子对处于发生得自狂犬病病毒的疾病危险中的对象进行暴露后预防中的应用。
发明详述
本发明第一方面包括能特异性结合狂犬病病毒的结合分子。优选地,本发明的结合分子还具有狂犬病病毒中和活性。优选地,本发明的结合分子是人结合分子。或者,它们也可以是其它动物的结合分子。狂犬病病毒是狂犬病毒属的一部分。狂犬病毒属共包括11个基因型:狂犬病病毒(基因型1)、Lagos蝙幅病毒(基因型2)、Mokola病毒(基因型3)、Duvenhage病毒(基因型4)、欧洲蝙幅狂犬病毒1(基因型5)、欧洲蝙幅狂犬病毒2(基因型6)、澳大利亚蝙幅狂犬病毒(基因型7)、Aravan病毒(基因型8)、Khujand病毒(基因型9)、Irkut病毒(基因型10)和West Caucasian病毒(基因型11)。除了结合狂犬病病毒,本发明的结合分子还能结合狂犬病毒属的其它基因型。优选地,所述结合分子还能中和狂犬病毒属的其它基因型。此外,本发明的结合分子甚至能结合和/或中和弹状病毒科除了狂犬病毒属之外的病毒。这个科包括细胞弹状病毒属(cytorhabdovirus)、ephemerovirus属、狂犬病毒属、核弹状病毒属(nucleorhabdovirus)、弹状病毒属(rhabdovirus)和vesiculovirus属。
所述结合分子能特异性结合天然形式或者灭活/减毒形式的狂犬病病毒。狂犬病病毒的灭活可以通过用如下方式处理而进行:β-丙内酯(BPL)处理(White and Chappel,1982)、在56℃加热30分钟以上、γ射线照射、用乙酰乙撑亚胺或者乙撑亚胺处理或者用抗坏血酸和硫酸铜处理72小时(Madhusudana et al.,2004)。也可以使用本领域已知的普通病毒灭活方法,例如巴氏消毒法(湿热)、干热处理、蒸汽热处理、低pH处理、有机溶剂/去污剂处理、纳米过滤;也可以使用UV光照射。优选地,通过用β-丙内酯(BPL)处理进行灭活。测试狂犬病病毒是否仍具有感染性或者部分或全部灭活的方法为本领域技术人员所熟知,可见于Laboratory techniques in rabies,Edited by:F.-X Meslin,M.M.Kaplan and H.Koprowski(1996),4th edition,Chapter 36,WorldHealth Organization,Geneva所述。
所述结合分子也能特异性结合狂犬病病毒的一或多个片段,如衍生自狂犬病病毒或者用狂犬病病毒蛋白和/或(多)肽转染的细胞的一或多种蛋白质和/或(多)肽制品。对于治疗和/或预防方法如狂犬病病毒的暴露后预防方法而言,所述结合分子优选能特异性结合狂犬病病毒的表面易接近的蛋白如M蛋白(见Ameyama et al.2003)或者G蛋白。对于诊断目的,人结合分子还能特异性结合不在狂犬病病毒表面上呈递的蛋白质。多种已知狂犬病病毒株的表面可接近的和内部蛋白质的氨基酸序列可见于EMBL数据库和/或其它数据库。
优选地,所述片段至少包含本发明的人结合分子识别的抗原决定簇。本文所用术语“抗原决定簇”是能以足够高亲和性结合本发明的人结合分子以形成可检测的抗原结合分子复合物的一个部分,如狂犬病病毒(多)肽、(糖)蛋白、或其类似物或片段。
本发明的结合分子可以是完整的免疫球蛋白分子,如多克隆或单克隆抗体,特别是人单克隆抗体,或者所述结合分子可以是抗原结合片段,包括但非限于Fab、F(ab′)、F(ab′)2、Fv、dAb、Fd、互补决定区(CDR)片段、单链抗体(scFv)、二价单链抗体、单链噬菌体抗体、双链抗体、三链抗体、四链抗体及含有至少免疫球蛋白的一个片段的(多)肽,该片段足以赋予对狂犬病病毒或其片段的特异性抗原结合。本发明的结合分子可以非分离的形式或者以分离的形式应用。此外,本发明的结合分子可以单独应用或者于包含至少一种人结合分子(或者其变体或片段)的混合物中应用。换句话说,所述结合分子可以组合应用,例如作为包含两或多种结合分子、其变体或者片段的药物组合物。例如,具有狂犬病病毒中和活性的结合分子可以在单一治疗中组合以达到所需的预防、治疗或者诊断作用。
RNA病毒如狂犬病病毒在病毒复制期间利用其自身的RNA聚合酶。这些RNA聚合酶趋于易错。这样在病毒感染期间导致所谓的“准种”形成。每个准种均具有独特地RNA基因组,可导致病毒蛋白质的氨基酸组成中的差异。如果这种突变发生在病毒结构蛋白中,则该病毒由于T或B细胞表位中的变化而从宿主免疫系统中逃避。当用两种结合分子如人单克隆抗体处理个体时发生这种情况的可能性高于用多克隆抗体混合物(HRIG)处理个体的情况。因此,用两种人单克隆抗体混合物治疗狂犬病的先决条件是这两种抗体识别其靶抗原即狂犬病病毒糖蛋白上的不重叠、不竞争的表位。从而使狂犬病逃逸病毒发生的机会降至最低。结果,本发明的结合分子优选能与狂犬病病毒的不同的、不重叠的、不竞争的表位反应,如狂犬病病毒G蛋白上的表位。结合分子的混合物可进一步包含至少一种其它的治疗剂,如适于狂犬病暴露后预防的药物。
典型地,本发明的结合分子可以结合其结合配偶体,即狂犬病病毒或其片段如狂犬病病毒蛋白,亲和性常数(Kd值)低于0.2×10-4M、1.0×10-5M、1.0×10-6M、1.0×10-7M,优选低于1.0×10-8M,更优选低于1.0×10-9M,更优选低于1.0×10-10M,更优选低于1.0×10-11M,特别优选低于1.0×10-12M。所述亲和性常数可以根据抗体同种型而变化。例如,对于IgM同种型的亲和性结合是指至少大约1.0×10-7M的结合亲和性。亲和性常数可例如使用表面等离子共振方法测定,即通过检测生物传感器基质内蛋白质浓度的变化分析实时生物特异性相互作用的光学现象,例如使用BIACORE系统(PharmaciaBiosensor AB,Uppsala,Sweden)。
本发明的结合分子可以结合纯化/分离形式的或者非纯化/非分离形式的狂犬病病毒。所述结合分子可以结合溶解形式的狂犬病病毒,例如样品中的狂犬病病毒,或者可以结合与载体或者底物例如微滴定平板、膜和珠等结合或附着于其的狂犬病病毒。载体或者底物可以由玻璃、塑料(例如聚苯乙烯)、多糖、尼龙、硝化纤维素或者特氟隆等制成。这种支持物的表面可以是实心的或者有孔的,并且可以是任何方便使用的形状。或者,所述结合分子还可以结合狂犬病病毒片段,如狂犬病病毒的蛋白质或者(多)肽。在一个实施方案中,所述结合分子能特异性结合狂犬病病毒G蛋白或其片段。所述狂犬病病毒蛋白或(多)肽可以是溶解形式或者是与上述载体或底物结合或者附着于其的狂犬病病毒。在另一个实施方案中,用G蛋白转染的细胞可以用作所述结合分子的结合配偶体。
在本发明的一个优选实施方案中,本发明的结合分子中和狂犬病病毒的感染性。这可以通过阻止狂犬病病毒与其宿主细胞上的受体附着而实现,所述受体如鼠p75神经营养蛋白受体、神经细胞粘附分子(CD56)和乙酰胆碱受体,或者通过抑制RNA释放进入细胞质中或者阻止RNA转录或者翻译而实现。在一个特殊实施方案中,与不存在所述结合分子的条件下狂犬病病毒感染宿主细胞相比,本发明的结合分子阻止狂犬病病毒感染宿主细胞至少99%、95%、90%、85%、80%、75%、70%、60%、50%、45%、40%、45%、35%、30%、25%、20%,或者至少10%。中和可例如Laboratory techniques in rabies,Edited by:F.-X Meslin,M.M.Kaplan and H.Koprowski(1996),4th edition,Chapters 15-17,World Health Organization,Geneva所述进行测定。此外,本发明的人结合分子可以是能有助于包膜的狂犬病病毒裂解的补体固定结合分子(complement fixing binding molecule)。本发明的人结合分子也可以作为调理素和增大对狂犬病病毒的吞噬作用,通过促进其由Fc或C3b受体摄取或者通过凝集狂犬病病毒使其更易于被吞噬而实现。
在一个优选实施方案中,本发明的结合分子包含至少一个CDR3区域,其包含选自如下的氨基酸序列:SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ IDNO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23和SEQ ID NO:24。在一个实施方案中,所述CDR3区域是重链CDR3区域。
在另一个实施方案中,本发明的结合分子包含一条可变重链,其基本上包含选自如下的氨基酸序列:SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、SEQ ID NO:40、SEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48和SEQ ID NO:49。在一个优选的实施方案中,本发明的结合分子包含一条可变重链,其基本上包含SEQ ID NO:335的第1-119位氨基酸的氨基酸序列。
在另一个实施方案中,本发明的结合分子包含一条包含SEQ IDNO:26所示氨基酸序列的可变重链和包含SEQ ID NO:50所示氨基酸序列的一条可变轻链、包含SEQ ID NO:27所示氨基酸序列的一条可变重链及包含SEQ ID NO:51所示氨基酸序列的一条可变轻链、包含SEQ ID NO:28所示氨基酸序列的一条可变重链及包含SEQ IDNO:52所示氨基酸序列的一条可变轻链、包含SEQ ID NO:29所示氨基酸序列的一条可变重链及包含SEQ ID NO:53所示氨基酸序列的一条可变轻链、包含SEQ ID NO:30所示氨基酸序列的一条可变重链及包含SEQ ID NO:54所示氨基酸序列的一条可变轻链、包含SEQ IDNO:31所示氨基酸序列的一条可变重链及包含SEQ ID NO:55所示氨基酸序列的一条可变轻链、包含SEQ ID NO:32所示氨基酸序列的一条可变重链及包含SEQ ID NO:56所示氨基酸序列的一条可变轻链、包含SEQ ID NO:33所示氨基酸序列的一条可变重链及包含SEQID NO:57所示氨基酸序列的一条可变轻链、包含SEQ ID NO:34所示氨基酸序列的一条可变重链及包含SEQ ID NO:58所示氨基酸序列的一条可变轻链、包含SEQ ID NO:35所示氨基酸序列的一条可变重链及包含SEQ ID NO:59所示氨基酸序列的一条可变轻链、包含SEQ ID NO:36所示氨基酸序列的一条可变重链及包含SEQ ID NO:60所示氨基酸序列的一条可变轻链、包含SEQ ID NO:37所示氨基酸序列的一条可变重链及包含SEQ ID NO:61所示氨基酸序列的一条可变轻链、包含SEQ ID NO:38所示氨基酸序列的一条可变重链及包含SEQ ID NO:62所示氨基酸序列的一条可变轻链、包含SEQ ID NO:39所示氨基酸序列的一条可变重链及包含SEQ ID NO:63所示氨基酸序列的一条可变轻链、包含SEQ ID NO:40所示氨基酸序列的一条可变重链及包含SEQ ID NO:64所示氨基酸序列的一条可变轻链、包含SEQ ID NO:41所示氨基酸序列的一条可变重链及包含SEQ IDNO:65所示氨基酸序列的一条可变轻链、包含SEQ ID NO:42所示氨基酸序列的一条可变重链及包含SEQ ID NO:66所示氨基酸序列的一条可变轻链、包含SEQ ID NO:43所示氨基酸序列的一条可变重链及包含SEQ ID NO:67所示氨基酸序列的一条可变轻链、包含SEQ IDNO:44所示氨基酸序列的一条可变重链及包含SEQ ID NO:68所示氨基酸序列的一条可变轻链、包含SEQ ID NO:45所示氨基酸序列的一条可变重链及包含SEQ ID NO:69所示氨基酸序列的一条可变轻链、包含SEQ ID NO:46所示氨基酸序列的一条可变重链及包含SEQ IDNO:70所示氨基酸序列的一条可变轻链、包含SEQ ID NO:47所示氨基酸序列的一条可变重链及包含SEQ ID NO:71所示氨基酸序列的一条可变轻链、包含SEQ ID NO:48所示氨基酸序列的一条可变重链及包含SEQ ID NO:72所示氨基酸序列的一条可变轻链、包含SEQ IDNO:49所示氨基酸序列的一条可变重链及包含SEQ ID NO:73所示氨基酸序列的一条可变轻链。在一个优选的实施方案中,本发明的人结合分子包含包含SEQ ID NO:335的第1-119位氨基酸的氨基酸序列的一条可变重链及包含SEQ ID NO:337的第1-107位氨基酸的氨基酸序列的一条可变轻链。
在一个优选的实施方案中,本发明的具有狂犬病病毒中和活性的结合分子是以IgG形式给予的,优选IgG1形式。
本发明的另一方面包括所述结合分子的功能变体。如果变体分子能与亲代结合分子竞争特异性结合狂犬病病毒或其片段,则认为该分子是本发明的结合分子的功能变体。换句话说,所述功能变体仍能结合狂犬病病毒或其片段。所述功能变体也应仍具有狂犬病病毒中和活性。功能变体包括但非限于与一级结构序列基本上相似、但含有例如体外或者体内修饰的衍生物,所述修饰是在亲代结合分子中未发现的化学和/或生物化学修饰。这种修饰包括乙酰化、酰化、ADP-核糖基化、酰胺化、共价附着黄素、共价附着血红素部分、共价附着核苷酸或者核苷酸衍生物、共价附着脂质或者脂质衍生物、共价附着磷酯酰肌醇、交联、环化、二硫键形成、去甲基化、共价交联形成、胱氨酸形成、焦谷氨酸形成、甲酰化、γ羧化、糖基化、GPI-锚形成、羟化、碘化、甲基化、豆蔻酰化、氧化、PEG化、蛋白酶解加工、磷酸化、异戊二烯化、外消旋、硒酰化(selenoylation)、硫酸化、转移RNA介导的向蛋白质中加入氨基酸如精氨酰化、遍在蛋白化等。
或者,功能变体可以是本发明所述的结合分子,与亲代结合分子的氨基酸序列相比,其包含含有一或多个氨基酸的取代、插入、缺失或者其组合的氨基酸序列。此外,功能变体可包含在氨基端或者羧基端或者这两端氨基酸序列截短。本发明的功能变体与亲代结合分子相比可具有相同或不同的(较高或者较低)结合亲和性,但是仍能结合狂犬病病毒或其片段并仍能中和狂犬病病毒。例如,本发明的功能变体与亲代结合分子相比可具有增加或者降低的对狂犬病病毒或其片段的结合亲和性,或者具有较高或者较低的狂犬病病毒中和活性。优选地,修饰可变区的氨基酸序列,包括但非限于构架区、高变区、特别是CDR3区。通常,轻链和重链可变区包含三个高变区,包含三个CDR,及所谓构架区(FR)的更保守的区域。所述高变区包含CDR的氨基酸残基和高变环的氨基酸残基。在本发明范围内的功能变体与本文所述亲代结合分子具有至少大约50%-99%、优选至少大约60%-99%、更优选至少大约70%-99%、更优选至少大约80%-99%、最优选至少大约90%-99%、特别是至少大约95%-99%、特别是至少大约97%-99%的氨基酸序列同源性。可以使用本领域技术人员已知的计算机算法如Gap或者Bestfit最佳对比氨基酸序列并确定相似或者相同的氨基酸残基。
在另一个实施方案中,当亲代结合分子在其序列中包含一个糖基化位点导致结合分子基于在真核细胞中表达而糖基化,并因此可能消除与抗原的结合时,产生功能变体。产生的功能变体不再含有糖基化位点,但是仍能结合狂犬病病毒并且仍具有中和活性。
功能变体可以通过本领域已知的一般分子生物学方法改变亲代结合分子或其部分而获得,所述方法包括但非限于易错PCR、寡核苷酸指导的诱变和定点诱变。此外,功能变体可具有互补固定活性,能有助于包膜的狂犬病病毒的裂解和/或作为调理素及增大对狂犬病病毒的吞噬作用,通过促进Fc或C3b受体对其摄取或者通过凝集狂犬病病毒使其更易于被吞噬而实现。
另一方面,本发明包括免疫缀合物,即包含至少一种本文所述结合分子或其功能变体并且进一步包含至少一种标记如可检测的部分/制剂的分子。本发明还涵盖了本发明的免疫缀合物的混合物或者至少一种本发明的免疫缀合物与另一种分子如治疗剂或者另一种结合分子或免疫缀合物的混合物。在另一个实施方案中,本发明的免疫缀合物可包含一或多个标记。这些标记可以是彼此相同或者不同,并且可以与所述结合分子非共价地结合/缀合。所述标记也可以通过共价键与所述结合分子直接结合/缀合,所述共价键包括但非限于二硫键、氢键、静电键、重组融合和构象键合。或者,所述标记通过一或多种连接化合物与所述键合分子结合/缀合。将标记与结合分子缀合的技术为本领域技术人员所熟知。
本发明的免疫缀合物的标记可以是治疗剂,但优选是可检测的部分/制剂。包含可检测制剂的免疫缀合物可诊断性用于例如评定对象是否感染了狂犬病病毒,或者用于监测狂犬病病毒感染的发生或进展作为部分临床测试程序,以例如确定提供的治疗方案的效力。然而,它们也可用于其它检测和/或分析和/或诊断目的。可检测的部分/制剂包括但非限于酶、辅基、荧光物质、发光物质、生物发光物质、放射性物质、正电子发射金属及非放射性顺磁性金属离子。
用于标记结合分子以进行检测和/或分析和/或诊断的标记依赖于特异性检测/分析/诊断技术和/或使用的方法而定,所述方法如对(组织)样品进行的免疫组织化学染色、流式细胞计量术检测、扫描激光器细胞计数检测、荧光免疫分析、酶联免疫吸附分析(ELISA)、放射性免疫分析(RIA)、生物分析(例如中和化分析)、Western印迹等。对于组织样品的免疫组织化学染色,优选的标记是催化可检测产物产生和局部沉积的酶。与结合分子典型缀合以使其可以进行免疫组织化学显色的酶为本领域所熟知,包括但非限于乙酰胆碱酯酶、碱性磷酸酶、β-半乳糖苷酶、葡萄糖氧化酶、辣根过氧化物酶和脲酶。产生和沉积可目测的产物的典型底物也为本领域所熟知。随后,本发明的免疫缀合物可以使用胶体金标记,或者它们可以用放射性同位素标记,如33P、32P、35S、3H和125I。本发明的结合分子可以通过本领域熟知的方法通过螯合剂直接或者间接附着于放射性核素。
当本发明的结合分子用于流式细胞计量术检测、扫描激光器细胞计数检测或者荧光免疫分析时,其可以用荧光团标记。可用于荧光标记本发明的结合分子的众多荧光团为本领域技术人员所已知。当本发明的结合分子用于使用标记的抗生物素蛋白、链霉亲和素、captavidin或者neutravidin进行二级检测时,结合分子可以使用生物素标记以形成合适的辅基复合物。
当本发明的免疫缀合物用于体内诊断时,结合分子也可以通过与例如磁共振成像(MRI)造影剂如二亚乙基三胺五乙酸钆、超声造影剂或者X线造影剂缀合或者通过放射性同位素标记而可被检测到。
此外,本发明的结合分子、其功能变体或者免疫缀合物也可以附着于固体支持物,以特别用于体外免疫分析或者纯化狂犬病病毒或其片段。这种固体支持物可以是有孔或者无孔的、平面或者非平面的,包括但非限于玻璃、纤维素、聚丙烯酰胺、尼龙、聚苯乙烯、聚氯乙烯或者聚丙烯支持物。人结合分子也可例如与过滤介质缀合,如与NHS-活化的Sepharose或者CNBr-活化的Sepharose缀合以进行免疫亲和层析。它们也可以典型地通过生物素—链霉亲和素相互作用而附着于顺磁性微球。所述微球可用于从含有狂犬病病毒或其片段的样品中分离狂犬病病毒或其片段。另一个例子,本发明的人结合分子可附着于用于ELISA的微滴定平板表面。
本发明的结合分子或其功能变体可以与标记序列如促进纯化的肽融合。标记序列的例子包括但不限于六组氨酸标记、血凝素(HA)标记、myc标记或者flag标记。
或者,抗体可以与第二种抗体缀合形成抗体异源缀合物。另一方面,本发明的人结合分子可以与一或多种抗原缀合/附着。优选地,这些抗原是由给予了结合分子—抗原缀合物的对象的免疫系统识别的抗原。所述抗原彼此可以相同或不同。将抗原与结合分子附着的缀合方法为本领域所熟知,包括但非限于使用交联剂。人结合分子结合狂犬病病毒,附着于人结合分子的抗原将引发对于该缀合物的强力T细胞进攻,最后导致狂犬病病毒的破坏。
除了直接或者间接通过例如接头通过缀合而化学产生免疫缀合物,免疫缀合物也可以作为包含本发明的人结合分子和合适标记的融合蛋白而产生。融合蛋白可以通过本领域已知的方法产生,例如通过框内构建包含编码人结合分子的核苷酸序列及编码合适标记的核苷酸序列的核酸分子、然后表达所述核酸分子而重组产生。
本发明的另一方面提供了编码至少一种本发明的结合分子或其功能变体的核酸分子。这种核酸分子可用作中间物进行克隆,例如在上述亲和性成熟过程中。在一个优选的实施方案中,所述核酸分子是分离的或者纯化的。
技术人员意识到这些核酸分子的功能变体也是本发明的一部分。功能变体是用标准遗传密码可以直接翻译的核酸序列,以提供与从亲代核酸分子中翻译的序列相同的氨基酸序列。
优选地,所述核酸分子编码包含CDR3区、优选重链CDR3区的结合分子,其包含选自如下的氨基酸序列:SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23和SEQ ID NO:24。
更优选地,所述核酸分子编码包含可变重链的人结合分子,所述可变重链包含选自如下的氨基酸序列:SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、SEQ ID NO:40、SEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48和SEQ ID NO:49。在特别优选的实施方案中,所述核酸分子编码包含可变重链的结合分子,所述可变重链基本上包含SEQID NO:335的第1-119位氨基酸的氨基酸序列。
在另一个实施方案中,所述核酸分子编码包含包含SEQ ID NO:26所示氨基酸序列的可变重链及包含SEQ ID NO:50所示氨基酸序列的可变轻链的结合分子,或者编码包含SEQ ID NO:27所示氨基酸序列的可变重链及包含SEQ ID NO:51所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:28所示氨基酸序列的可变重链及包含SEQ ID NO:52所示氨基酸序列的可变轻链,或者编码包含SEQ IDNO:29所示氨基酸序列的可变重链及包含SEQ ID NO:53所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:30所示氨基酸序列的可变重链及包含SEQ ID NO:54所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:31所示氨基酸序列的可变重链及包含SEQ IDNO:55所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:32所示氨基酸序列的可变重链及包含SEQ ID NO:56所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:33所示氨基酸序列的可变重链及包含SEQ ID NO:57所示氨基酸序列的可变轻链,或者编码包含SEQID NO:34所示氨基酸序列的可变重链及包含SEQ ID NO:58所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:35所示氨基酸序列的可变重链及包含SEQ ID NO:59所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:36所示氨基酸序列的可变重链及包含SEQ IDNO:60所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:37所示氨基酸序列的可变重链及包含SEQ ID NO:61所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:38所示氨基酸序列的可变重链及包含SEQ ID NO:62所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:39所示氨基酸序列的可变重链及包含SEQ ID NO:63所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:40所示氨基酸序列的可变重链及包含SEQ ID NO:64所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:41所示氨基酸序列的可变重链及包含SEQID NO:65所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:42所示氨基酸序列的可变重链及包含SEQ ID NO:66所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:43所示氨基酸序列的可变重链及包含SEQ ID NO:67所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:44所示氨基酸序列的可变重链及包含SEQ ID NO:68所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:45所示氨基酸序列的可变重链及包含SEQ ID NO:69所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:46所示氨基酸序列的可变重链及包含SEQID NO:70所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:47所示氨基酸序列的可变重链及包含SEQ ID NO:71所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:48所示氨基酸序列的可变重链及包含SEQ ID NO:72所示氨基酸序列的可变轻链,或者编码包含SEQ ID NO:49所示氨基酸序列的可变重链及包含SEQ ID NO:73所示氨基酸序列的可变轻链。在一个优选的实施方案中,所述核酸分子编码包含可变重链和可变轻链的人结合分子,所述可变重链包含一种氨基酸序列,该氨基酸序列包含SEQ ID NO:335的第1-119位氨基酸,所述可变轻链包含一种氨基酸序列,该氨基酸序列包含SEQ IDNO:337的第1-107位氨基酸。
在本发明的一个特定实施方案中,编码本发明结合分子可变重链的核酸分子基本上包含选自如下的核苷酸序列:SEQ ID NO:74、SEQID NO:75、SEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78、SEQ IDNO:79、SEQ ID NO:80、SEQ ID NO:81、SEQ ID NO:82、SEQ IDNO:83、SEQ ID NO:84、SEQ ID NO:85、SEQ ID NO:86、SEQ ID NO:87、SEQ ID NO:88、SEQ ID NO:89、SEQ ID NO:90、SEQ ID NO:91、SEQ ID NO:92、SEQ ID NO:93、SEQ ID NO:94、SEQ ID NO:95、SEQ ID NO:96和SEQ ID NO:97.优选地,编码本发明结合分子的可变重链的核酸分子基本上包含一种核苷酸序列,该序列包含SEQ IDNO:334的第1-357位核苷酸。
在本发明的另一个特定实施方案中,编码本发明结合分子的可变轻链的所述核酸分子基本上包含选自如下一组的核苷酸序列:SEQID NO:98、SEQ ID NO:99、SEQ ID NO:100、SEQ ID NO:101、SEQID NO:102、SEQ ID NO:103、SEQ ID NO:104、SEQ ID NO:105、SEQ ID NO:106、SEQ ID NO:107、SEQ ID NO:108、SEQ ID NO:109、SEQ ID NO:110、SEQ ID NO:111、SEQ ID NO:112、SEQ ID NO:113、SEQ ID NO:114、SEQ ID NO:115、SEQ ID NO:116、SEQ ID NO:117、SEQ ID NO:118、SEQ ID NO:119、SEQ ID NO:120和SEQ IDNO:121。优选地,编码本发明人结合分子的可变轻链的核酸分子基本上包含一种核苷酸序列,该核苷酸序列包含SEQ ID NO:336的第1-321位核苷酸。
本发明的另一方面提供了包含本发明的一或多种核酸分子的载体,即核酸构建体。载体可以衍生自质粒,如F、R1、RP1、Co1、pBR322、TOL、Ti等;粘粒;噬菌体,如λ噬菌体、λ类噬菌体、M13、Mu、P1、P22、Qβ、T-even、T-odd、T2、T4、T7等;植物病毒,如苜蓿花叶病毒、雀麦花叶病毒、毛状病毒组(capillovirus)、香石竹潜病毒组(carlavirus)、香石竹斑驳病毒组(carmovirus)、caulivirus、线形病毒组(clostervirus)、豇豆花叶病毒组(comovirus)、隐病毒(cryptovirus)、南瓜花叶病毒组(cucumovirus)、香石竹环斑病毒组(dianthovirus)、蚕豆萎蔫病毒组(fabavirus)、斐济病毒组(fijivirus)、真菌传棒状病毒组(furovirus)、双粒病毒组(geminivirus)、大麦病毒(hordeivirus)、等轴不稳定环斑病毒组(ilarvirus)、黄矮病毒组(luteovirus)、machlovirus、玉米雷亚多非纳病毒组(marafivirus)、坏死病毒组(necrovirus)、线虫传多面体病毒(nepovirus)、phytorepvirus、植物弹状病毒、马铃薯X病毒组(potexvirus)、马铃薯Y病毒组(potyvirus)、南方菜豆花叶病毒组(sobemovirus)、水稻条纹叶枯病毒组(tenuivirus)、烟草花叶病毒(tobamovirus)、烟草脆裂病毒组(tobravirus)、番茄斑萎病毒(tomato spotted wilt virus)、番茄丛矮病毒(tombusvirus)、芜菁黄花叶病毒组(tymovirus)等;或者动物病毒,如腺病毒、沙粒病毒科、杆状病毒科、双RNA病毒科、布尼安病毒科(bunyaviridae)、杯状病毒科(calciviridae)、心病毒属(cardioviruses)、冠形病毒科、被盖病毒科、囊状病毒科、Epstein-Barr病毒、肠道病毒、线状病毒科、黄病毒科、足口病病毒(Foot-and-Mouthdisease virus)、嗜肝DNA病毒科、肝炎病毒、疱疹病毒科、免疫缺陷病毒、流感病毒、丝状病毒科、虹彩病毒科、正粘病毒科、乳多空病毒、副粘病毒科、细小病毒科、小RNA病毒科、脊髓灰质炎病毒、多DNA病毒科、痘病毒科、呼肠孤病毒科、反转录病毒、弹状病毒科、鼻病毒、Semliki Forest病毒、四病毒科、披膜病毒科、toroviridae、痘苗病毒、疱疹性口腔炎病毒等。载体可用于克隆和/或表达本发明的人结合分子,甚至可以用于基因治疗。与一或多种表达调节核酸分子可操纵地连接的、包含本发明的一或多种核酸分子的载体也涵盖在本发明范围内。载体的选择依赖于重组方法及使用的宿主。将载体导入宿主细胞中可以通过磷酸钙转染、病毒感染、DEAE-葡聚糖介导的转染、lipofectamine转染或者电穿孔进行。载体可自主复制或者可以与其导入的染色体一起复制。优选地,所述载体含有一或多个选择标记。标记的选择可依赖于选择的宿主细胞,尽管这对于本发明无关紧要并且为本领域技术人员所熟知。所述标记包括但非限于卡那霉素、新霉素、嘌呤霉素、潮霉素、zeocin、来自单纯疱疹病毒的胸苷激酶基因(HSV-TK)、小鼠二氢叶酸还原酶基因(dhfr)。本发明还包括包含编码人结合分子的一或多种核酸分子的载体,其与编码可用于分离结合分子的蛋白质或肽的一或多个核酸分子可操纵地连接。这些蛋白质或肽包括但非限于谷胱苷肽-S-转移酶、麦芽糖结合蛋白、金属结合多组氨酸、绿色荧光蛋白、荧光素酶和β-半乳糖苷酶。
本发明另一方面涉及含有上述载体的一或多个拷贝的宿主。优选地,所述宿主是宿主细胞。宿主细胞包括但非限于哺乳动物、植物、昆虫、真菌或细菌来源的细胞。细菌细胞包括但非限于革兰氏阳性细菌,如芽孢杆菌属(Bacillus)、链霉菌属(Streptomyces)和葡萄球菌属(Staphylococcus)的一些菌种,或者革兰氏阴性细菌如埃希氏菌属(Escherichia)的一些菌种,如大肠杆菌(E.coli)及假单胞菌属(Pseudomonas)。在真菌细胞中优选使用酵母细胞。在酵母中的表达可以通过使用酵母株如巴斯德毕赤氏酵母(Pichia pastoris)、酿酒酵母(Saccharomyces cerevisiae)和多形汉逊氏酵母(Hansenulapolymorpha)进行。此外,昆虫细胞如果蝇细胞和Sf9细胞可以用作宿主细胞。除此之外,宿主细胞可以是植物细胞。通过已知方法产生的转化(转基因)的植物或者植物细胞,例如农杆菌介导的基因转移、叶盘转化、通过聚乙二醇诱导的DNA转移的原生质体转化、电穿孔、超声、显微注射或者bolistic基因转移。另外,合适的表达系统可以是杆状病毒系统。本发明优选使用哺乳动物细胞如中国仓鼠卵巢(CHO)细胞、COS细胞、BHK细胞或者Bowes黑素瘤细胞的表达系统。哺乳动物细胞提供的表达的蛋白质具有与哺乳动物天然分子最相似的翻译后修饰。由于本发明涉及给予人体的分子,因此特别优选完全的人表达系统。因此,更优选宿主细胞是人细胞。人细胞的例子是HeLa、911、AT1080、A549、293和HEK293T细胞。优选的哺乳动物细胞是人视网膜细胞如911细胞,或者是于1996年2月29日保藏在欧洲动物细胞保藏中心(ECACC;CAMR,Salisbury,Wiltshire SP4OJG,Great Britain)的细胞系,保藏号为96022940,以PER.C6_商标销售(PER.C6是Crucell Holland B.V.的注册商标)。在本申请中,“PER.C6”是指以保藏号96022940保藏的细胞,或者祖细胞、上游或者下游传代以及来自保藏的细胞祖先的后代,以及前述任何细胞的衍生物。
在优选的实施方案中,人生产细胞包含可表达形式的编码腺病毒E1区域的核酸序列的至少功能部分。在更优选的实施方案中,所述宿主细胞衍生自人视网膜,并且用包含腺病毒E1序列的核酸无限增殖化,如于1996年2月29日以保藏号96022940保藏在欧洲动物细胞保藏中心(ECACC;CAMR,Salisbury,Wiltshire SP4 OJG,GreatBritain)的细胞系,商标为PER.C6_。宿主细胞中重组蛋白质的产生可以根据本领域熟知的方法进行。以商标PER.C6_销售的细胞作为感兴趣蛋白质的生产平台的应用已经在WO 00/63403中描述,所述文献在此以其全文并入作参考。
产生本发明的结合分子或功能变体的方法是本发明的另一部分。所述方法包括如下步骤:a)在有益于结合分子或其功能变体表达的条件下培养本发明的宿主,及b)任选地,回收表达的结合分子或其功能变体。表达的结合分子或其功能变体可以从无细胞提取物中回收,但优选从培养基中回收。从无细胞提取物或者培养基中回收蛋白质如结合分子的方法为本领域技术人员所熟知。可通过上述方法获得的结合分子或者其功能变体也是本发明的一部分。
或者,在宿主如宿主细胞中表达之后,本发明的结合分子或其功能变体可以通过常规肽合成仪合成产生,或者使用衍生自本发明的DNA分子的RNA核酸在无细胞翻译系统中产生。可通过上述合成产生方法或者无细胞翻译系统获得的结合分子或其功能变体也是本发明的一部分。
在另一个实施方案中,本发明的结合分子或其功能变体可以通过转基因非人哺乳动物产生,例如表达人免疫球蛋白基因的转基因小鼠或者兔。优选地,所述转基因非人哺乳动物具有一个基因组,该基因组包含编码上述所有或部分人结合分子的人重链转基因和人轻链转基因。所述转基因非人哺乳动物可以用纯化的或者浓缩的狂犬病病毒或其片段制品免疫。免疫非人哺乳动物的方案为本领域所熟知。见Using Antibodies:A Laboratory Manual,Edited by:E.Harlow,D.Lane(1998),Cold Spring Harbor Laboratory,Cold Spring Harbor,New York及Current Protocols in Immunology,Edited by:J.E.Coligan,A.M.Kruisbeek,D.H.Margulies,E.M.Shevach,W.Strober(2001),JohnWiley & Sons Inc.,New York所描述,所述文献在此并入作参考。
另一方面,本发明提供了一种鉴别能特异性结合狂犬病病毒的结合分子如本发明人单克隆抗体或其片段或者本发明的核酸分子的方法,所述方法包括如下步骤:a)将可复制的遗传包装表面上的结合分子集合与狂犬病病毒或其片段在有益于结合的条件下接触,b)至少选择一次与狂犬病病毒或其片段结合的可复制遗传包装,及c)分离并回收与狂犬病病毒或其片段结合的可复制遗传包装。
所述选择步骤可以在存在狂犬病病毒的条件下进行。所述狂犬病病毒可以是分离的或者是非分离的,例如存在于感染个体的血清和/或血液中。在另一个实施方案中,所述狂犬病病毒是灭活的。或者,所述选择步骤可以在存在狂犬病病毒片段如狂犬病病毒胞外部分、衍生自狂犬病病毒的一或多种(多)肽如G蛋白、包含这些蛋白质或(多)肽的融合蛋白等的条件下进行。在另一个实施方案中,用狂犬病病毒G蛋白转染的细胞用于选择程序。
再一方面,本发明提供了一种获得本发明的结合分子或者核酸分子的方法,其中所述方法包括如下步骤:a)进行上述鉴别结合分子的方法,所述结合分子如本发明的人单克隆抗体或其片段或者本发明的核酸分子,及b)从回收的可复制遗传包装中分离所述结合分子和/或编码所述结合分子的核酸。一旦使用上述鉴别结合分子或者编码结合分子的核酸分子的方法确定或者鉴别了新的单克隆抗体,则编码scFv或Fab的DNA可以从细菌或者可复制遗传包装中分离,组合标准的分子生物学技术产生编码二价scFv或者具有所需特异性的全部人免疫球蛋白(例如IgG、IgA或者IgM)的构建体。这些构建体可以转染进合适的细胞系中,产生完全的人单克隆抗体(见Huls et al.,1999;Boel et al.,2000)。
本文所用可复制遗传包装(replicable genetic package)可以是原核或者真核生物,包括细胞、孢子、细菌、病毒、(细菌)噬菌体和多核糖体。优选的可复制遗传包装是噬菌体。人结合分子如单链Fv′s在可复制的遗传包装上展示,即它们附着于位于可复制遗传包装外表面的基团或者分子上。可复制遗传包装是一种包含被筛选的人结合分子的可筛选单位,其与编码结合分子的核酸分子连接。所述核酸分子应该是可在体内(例如载体)或者体外(例如通过PCR、转录和翻译)复制的。在体内复制可以是自发的(对于细胞),在宿主因子的帮助下(对于病毒)或者在宿主和辅助病毒二者的帮助下(对于噬菌粒)复制。展示人结合分子集合的可复制遗传包装是通过将被展示的编码外源结合分子的核酸分子导入可复制遗传包装的基因组中,与通常在可复制遗传包装外表面表达的内源蛋白形成融合蛋白而形成的。融合蛋白的表达、转运至外表面及装配导致外源结合分子在可复制遗传包装的外表面展示。本发明再一方面涉及能结合狂犬病病毒或其片段并且可通过上述鉴别方法获得的人结合分子。
本发明另一方面涉及一种鉴别潜在具有狂犬病病毒中和活性的结合分子的方法,所述方法包括如下步骤:(a)将可复制遗传包装表面上的结合分子集合与狂犬病病毒在有益于结合的条件下接触,(b)从未结合的结合分子中分离和回收与狂犬病病毒结合的结合分子,(c)分离至少一种回收的结合分子,(d)检验分离的结合分子是否具有狂犬病病毒中和活性,特征在于步骤a中所述狂犬病病毒被灭活。灭活的狂犬病病毒在被灭活之前可以纯化。可以利用本领域熟知的适于病毒的纯化方法进行纯化,例如通过甘油垫(glycerol cushion)离心。步骤a中灭活的狂犬病病毒在使用之前可以固定在合适的材料上。或者,步骤a中的狂犬病病毒仍可以是活性的。在另一个实施方案中,在步骤a中使用狂犬病病毒的片段,如一种狂犬病病毒的多肽如G蛋白。在另一个实施方案中,使用经狂犬病病毒G蛋白转染的细胞选择潜在具有狂犬病病毒中和活性的结合分子。如本文所示,当表达狂犬病病毒G蛋白的细胞包括在选择方法中时,选择的中和抗体的数目与其中仅使用纯化的狂犬病病毒G蛋白和/或灭活的狂犬病病毒的选择方法相比是比较高的。
在另一个实施方案中,上述鉴别潜在具有狂犬病病毒中和活性的结合分子的方法进一步包括分离和回收及任选分离含有可变重链3-30种系基因的人结合分子的步骤。本领域技术人员可以通过本领域已知的方法鉴别特异的种系基因,例如通过核苷酸测序。分离和回收含有可变重链3-30种系基因的结合分子的步骤可以在步骤c之前或者之后进行。如下文所示,本发明的大多数中和狂犬病病毒的人单克隆抗体包含这种特异性VH种系基因。
鉴别和获得(中和)结合分子例如抗体的噬菌体展示方法是本领域技术人员熟知的方法。例如在美国专利No.5,696,108;Burton andBarbas,1994;de Kruif et al.,1995b;及Phage Display:A LaboratoryManual.Edited by:CF Barbas,DR Burton,JK Scott and GJ Silverman(2001),Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NewYork中描述。这些文献在此均以其全文并入作参考。
为了构建噬菌体展示文库,例如以单链Fv(scFv)或者Fab形式将人单克隆抗体重链和轻链可变区基因集合在噬菌体、优选丝状噬菌体颗粒的表面上表达(见de Kruif et al.,1995b)。表达抗体片段的噬菌体大型文库典型含有1.0×109以上的抗体特异性,并且可以从在免疫的或未免疫的个体的B淋巴细胞中表达的免疫球蛋白V区中装配。在本发明的一个特定实施方案中,人结合分子的噬菌体文库、优选scFv噬菌体文库,是从分离自细胞的RNA中制备的,所述细胞得自已经针对狂犬病进行免疫接种或者暴露于狂犬病病毒的对象。RNA可以分离自骨髓或者外周血,优选分离自外周血淋巴细胞。所述对象可以是接种了或者暴露于狂犬病病毒的动物,但优选是已经接种或者已经暴露于狂犬病病毒的人。优选所述人对象已经进行了免疫接种。本发明的另一方面包括上述可复制遗传包装表面上的人结合分子集合,如scFv噬菌体文库。
或者,噬菌体展示文库可以从免疫球蛋白可变区中构建,其已经在体外部分装配以在文库(半合成文库)中导入额外的抗体多样性。例如,体外装配的可变区在对于抗体特异性重要的那些分子区域例如CDR区域中含有合成产生的、随机化的或者部分随机化的DNA序列。狂犬病病毒特异性噬菌体抗体可以选自文库,通过将靶抗原如来自狂犬病病毒的抗原固定在固相上,随后将靶抗原暴露于噬菌体文库以使得可以与表达特异于固相上结合的抗原的抗体片段的噬菌体结合。通过洗涤除去未结合的噬菌体,将结合的噬菌体从固相洗脱以感染大肠杆菌并随后进行增殖。通常需要多轮选择和增殖以足以富集特异性结合靶抗原的噬菌体。在将噬菌体文库暴露于靶抗原之前,如果需要,首先可通过将噬菌体文库暴露于与固相结合的非靶抗原而进行扣除。噬菌体也可以针对与复合抗原的结合而选择,所述复合抗原如狂犬病病毒蛋白或(多)肽的混合物、表达一或多种狂犬病病毒蛋白或(多)肽的宿主细胞或者(灭活的)狂犬病病毒自身。抗原特异性噬菌体抗体可以从文库中选择,通过将其上结合了灭活的狂犬病病毒制品的固相与噬菌体抗体文库保温,以使得例如噬菌体的scFv或者Fab部分与狂犬病病毒制品的蛋白/多肽结合而进行。在保温及几次洗涤以除去未结合的和松散附着的噬菌体之后,洗脱已经与该制品的scFv或Fab部分结合的噬菌体,并用于感染大肠杆菌以扩增新的特异性。通常,需要进行一或多轮选择以从大量未结合噬菌体中分离感兴趣的噬菌体。或者,可以将已知的狂犬病病毒蛋白或(多)肽在宿主细胞中表达,这些细胞可用于选择特异于所述蛋白质或(多)肽的噬菌体抗体。使用这些宿主细胞的噬菌体展示方法可以通过在筛选期间通过加入过量的不包含靶分子或者与靶分子相似但不相同的非靶分子的宿主细胞扣除不相关的结合物而扩展和改良,从而显著增加发现相关结合分子的机会(这种方法称作MAbstract_方法,MAbstract_是CrucellHolland B.V.的注册商标,也见并入本文作参考的美国专利No.6,265,150所述)。
另一方面,本发明提供了包含本发明的至少一种结合分子、至少一种其功能变体或片段、至少一种免疫缀合物或者其组合的组合物。所述组合物可进一步包含稳定分子,如白蛋白或者聚乙二醇,或者盐。优选地,使用的盐是保留人结合分子的所需生物学活性但无任何非所需的毒性作用的盐。如果需要,本发明的人结合分子可以包被在一种材料中或用一种材料包被,以保护其免于酸或者可以使结合分子灭活的其它天然或非天然条件的作用。
再一方面,本发明提供了包含本发明至少一种核酸分子的组合物。所述组合物可包含水溶液如含有盐(例如NaCl或者如上述盐)、去污剂(例如SDS)和/或其它合适成分的水溶液。
此外,本发明涉及药物组合物,其包含本发明的至少一种结合分子、至少一种其功能变体或片段、至少一种免疫缀合物、至少一种组合物或其组合。本发明的药物组合物进一步包含至少一种药物可接受的赋形剂。
在一个优选的实施方案中,本发明的药物组合物包含至少一种额外的结合分子,即所述药物组合物可以是结合分子的cocktail/混合物。所述药物组合物可以包含本发明的至少两种结合分子,或者包含至少一种本发明的结合分子和至少一种另外的抗狂犬病病毒结合分子。所述另外的结合分子优选包含CDR3区,该CRD3区包含SEQ ID NO:25所示氨基酸序列。包含包含SEQ ID NO:25所示氨基酸序列的CDR3区的结合分子可以是一种嵌合的或者人源化的单克隆抗体或其功能片段,但优选是人单克隆抗体或其功能片段。在一个实施方案中,所述结合分子包含重链可变区,该重链可变区包含SEQ ID NO:273所示氨基酸序列。在另一个实施方案中,所述结合分子包含轻链可变区,该轻链可变区包含SEQ ID NO:275所示氨基酸序列。在另一个实施方案中,所述结合分子包含分别包含SEQ ID NO:123和SEQ IDNO:125所示氨基酸序列的重链和轻链。药物组合物中的结合分子应该能与狂犬病病毒的不同的、非竞争的表位反应。所述表位可以存在于狂犬病病毒的G蛋白上,可以是不同的非重叠的表位。所述结合分子应该是高亲和性的,并且应该具有广泛的特异性。优选地,它们中和尽可能多的狂犬病病毒固定毒株和街毒。更优选地,它们还呈现对狂犬病毒属其它基因型或者甚至弹状病毒科其它病毒的中和活性,而与其它病毒或者正常的细胞蛋白无交叉反应性。优选地,所述结合分子能中和混合物中其它结合分子的逃逸变体。
本发明的另一方面涉及一种药物组合物,其包含至少两种中和狂犬病病毒的结合分子,优选本发明的人结合分子,特征在于所述结合分子能与狂犬病病毒的不同的、非竞争的表位反应。在一个实施方案中,所述药物组合物包含第一种中和狂犬病病毒的结合分子和第二种中和狂犬病病毒的结合分子,所述第一种结合分子能与位于狂犬病病毒G蛋白的抗原位点I的表位反应,所述第二种结合分子能与位于狂犬病病毒G蛋白的抗原位点III的表位反应。狂犬病病毒糖蛋白的抗原结构最初由Lafon et al.(1983)阐述。抗原位点是使用一组小鼠mAb及其各自的mAb抗性病毒变体鉴别的。此后,抗原位点已经通过鉴别mAb抗性变体的糖蛋白中氨基酸突变而作图(见Seif et al.,1985;Prehaud et al.,1988;和Benmansour et al.,1991)。大多数狂犬病中和mAb针对抗原位点II(见Benmansour et al.,1991),其是包含氨基酸34-42和氨基酸198-200的一个不连续的构象表位(见Prehaud et al.,1988)。抗原位点III是在氨基酸330-338的一个连续构象表位并且具有两个荷电残基K330和R333,影响病毒的致病性(见Seif et al.,1985;Coulon et al.,1998;和Dietzschold et al.,1983)。仅有一个mAb,509-6限定了构象抗原位点I,位于第231位氨基酸(见Benmansour et al.,1991;和Lafon et al.,1983)。已知抗原位点IV具有重叠线性表位(见Tordo,1996;Bunschoten et al.,1989;Luo et al.,1997;和Ni et al.,1995)。Benmansour et al.(1991)还描述了位于第342-343位的一个小位点的存在,尽管其与抗原位点III紧邻,但与其截然不同。CR-57表位与目前已知的狂犬病病毒糖蛋白上的线性和构象中和表位的序列对比(图10)表明CR-57表位位于与构象抗原位点I相同的区域中,由单一的mAb 509-6限定。基于CR04-098的逃逸病毒糖蛋白的核苷酸序列和氨基酸序列,由这种抗体识别的表位看起来位于与连续构象抗原位点III相同的区域中。
在一个优选的实施方案中,所述药物组合物包含第一种中和狂犬病病毒的结合分子和第二种中和狂犬病病毒的结合分子,所述第一种结合分子包含至少一个CDR3区、优选重链CDR3区,其包含SEQ IDNO:25所示氨基酸序列,第二种结合分子包含至少一个CDR3区、优选重链CDR3区,其包含选自如下的氨基酸序列:SEQ ID NO:4、SEQ ID NO:10、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16和SEQ ID NO:22。更优选地,第二种中和狂犬病病毒的结合分子包含至少一个CDR3区、优选重链CDR3区,其包含SEQ ID NO:14所示氨基酸序列。优选地,第一种中和狂犬病病毒的结合分子包含分别包含SEQ ID NO:123和SEQ ID NO:125所示氨基酸序列的重链和轻链,第二种中和狂犬病病毒的结合分子包含分别包含SEQ ID NO:335和SEQ ID NO:337所示氨基酸序列的重链和轻链。优选地,第一种中和狂犬病病毒的结合分子的重链和轻链分别由SEQ ID NO:122和SEQID NO:124编码,第二种中和狂犬病病毒的结合分子的重链和轻链分别由SEQ ID NO:334和SEQ ID NO:336编码。
包含两种结合分子的药物组合物(其中结合分子的pI不同)当选择使这两种结合分子均最佳稳定的合适缓冲液时有困难。当调节所述组合物的缓冲液的pH以增加一种结合分子的稳定性时,这将降低另一种结合分子的稳定性。结合分子的稳定性降低甚至不稳定可导致其沉淀或者聚集,或者导致其自发降解,引起结合分子的功能性丧失。因此,本发明的另一方面提供了包含至少两种结合分子、优选人结合分子的药物组合物,特征在于所述结合分子的等电点(pI)彼此不同,小于大约1.5、1.4、1.3、1.2、1.1、1.0、0.9、0.8、0.7、0.6、0.5、0.4、0.3,优选小于(包括)0.25pI单位。pI可以通过实验测定,例如利用等电聚焦,或者基于结合分子的氨基酸序列计算。在一个实施方案中,所述结合分子是本发明的结合分子,所述药物组合物是本发明的药物组合物。优选地,所述结合分子是单克隆抗体,例如人单克隆抗体如IgG1抗体。优选地,所述结合分子能结合和/或中和一种感染因子,例如病毒、细菌、酵母、真菌或者寄生虫。在一个实施方案中,所述结合分子能结合和/或中和狂犬病毒属病毒,例如狂犬病病毒。在一个特定实施方案中,两种结合分子的计算出的pI均在8.0-9.5、优选8.1-9.2、更优选在8.2-8.5之间。优选地,所述结合分子分别具有SEQ ID NO:14和SEQ ID NO:25所示的重链CDR3区。
在另一个实施方案中,本发明提供了两或多种人或其它动物结合分子包括但非限于抗体的混合物,其中至少一种结合分子衍生自抗体噬菌体或者其它可复制包装展示技术,至少一种结合分子可通过杂交瘤技术获得。当使用不同的技术时,选择具有相容pI的结合分子对于获得组合物是非常有益的,其中每种结合分子均是足够稳定的以便于贮存、处理和随后的应用。
在另一个实施方案中,本发明的药物组合物中存在的结合分子彼此增强了中和活性,即当将它们组合时协同起作用。换句话说,所述药物组合物可呈现狂犬病病毒及甚至狂犬病毒属病毒的协同中和活性。如本文所用术语“协同”是指结合分子当组合应用时的组合作用高于其单独应用时作用的加和。本发明的药物组合物成分的范围和比率应基于其各自的效力确定,并且在体外中和分析或者动物模型如仓鼠中测试。
此外,本发明的药物组合物可包含至少一种其它的治疗、预防和/或诊断剂。所述另外的治疗和/或预防剂可以是抗病毒制剂如病毒唑或者α-干扰素。
本发明的结合分子或药物组合物在用于人体之前可以在合适的动物模型系统中测试。这种动物模型系统包括但非限于小鼠、大鼠、仓鼠、猴等。
典型地,药物组合物必需是无菌的及在生产和贮存条件下是稳定的。本发明的人结合分子、其变体或片段、免疫缀合物、核酸分子或者组合物可以是粉末形式,在给予之前或在给予时在合适的药物可接受的赋形剂中重建(reconstitution)。在制备无菌可注射溶液的无菌粉末情况中,优选的制备方法是真空干燥和冷冻干燥(冻干),这样产生活性成分加上来自预先过滤灭菌溶液的任何其它所需成分的粉末。
或者,本发明的结合分子、其变体或片段、免疫缀合物、核酸分子或者组合物可以于溶液中,在给予之前或者给予时可以加入和/或混合合适的药物可接受的赋形剂以提供单位剂量的可注射形式。优选地,本发明中使用的药物可接受的赋形剂适合高药物浓度,可以保持适当的流动性,如果需要的话可以延缓吸收。
给予所述药物组合物的最佳途径的选择受到许多因素的影响,包括组合物中活性分子的物理—化学性质、临床状况的紧急程度及活性分子的血浆浓度与所需治疗作用之间的关系。例如,如果需要,本发明的人结合分子可以与载体一起制备,这样将保护其免于迅速释放,如控制释放制剂,包括植入体、经皮贴片及微囊化输送系统。可以使用可生物可降解的、生物相容的聚合物,如乙烯醋酸乙烯酯、聚酐类、聚乙醇酸、胶原、聚原酸酯和聚乳酸。此外,可以用防止人结合分子灭活的材料或混合物包被人结合分子或者与其共同给予。例如,人结合分子可以在合适的载体例如脂质体或者稀释剂中给予对象。
给予途径通常可分为两种主要方式,口服和胃肠外给予。本发明的人结合分子和药物组合物的优选给予方式是给予伤口内和周围及臀肌区肌内注射。人结合分子和药物组合物的配制依赖于给予途径。
另一方面,本发明的结合分子、功能变体、免疫缀合物、组合物或者药物组合物可以用作药物。因此,本发明另一方面提供了一种使用本发明的人结合分子、功能变体、免疫缀合物、组合物或者药物组合物的治疗和/或预防狂犬病毒属病毒感染的方法。所述狂犬病毒属病毒可以是任何已知基因型的病毒,但优选是狂犬病病毒。上述分子或组合物可以用于狂犬病的暴露后预防中。
上述分子或组合物可与可用于诊断、预防和/或治疗狂犬病病毒的其它分子联合应用。它们可以在体外、离体或在体内应用。例如,本发明的人结合分子、功能变体、免疫缀合物或者药物组合物可以与狂犬病疫苗共同给予。或者,所述疫苗也可以在给予本发明的分子或组合物之前或者之后给予。给予本发明的分子或组合物及疫苗适于暴露后预防。狂犬病疫苗包括但非限于纯化的鸡胚细胞(PCEC)疫苗(RabAvert)、人二倍体细胞疫苗(HDCV;Imovax vaccine)或者吸附的狂犬病疫苗(RVA)。
本发明的组合物和药物组合物中的分子是以治疗或者诊断有效量典型配制的。可以调节剂量方案以提供最佳的所需应答(例如治疗应答)。合适的剂量范围可例如是0.1-100IU/kg体重,优选1.0-50IU/kg体重,更优选10-30IU/kg体重,如20IU/kg体重。
优选地,给予单一推注(bolus)本发明的结合分子或者药物组合物。本发明的分子和药物组合物优选是无菌的。本领域熟知使得这些分子和组合物无菌的方法。暴露后预防的给药方案是在先前未接种狂犬病病毒疫苗的个体在暴露后第0、3、7、14和28天肌内给予5剂狂犬病疫苗。本发明的人结合分子或者药物组合物应该在第0天给予伤口中和伤口周围,或者在暴露后尽快给予,在远离接种的部位肌内给予剩余的体积。未接种的个体给予抗狂犬病病毒人结合分子,但技术人员清楚需要这种治疗的接种个体也可以给予抗狂犬病病毒人结合分子。
另一方面,本发明涉及本发明的结合分子或其功能变体、免疫缀合物、核酸分子、组合物或者药物组合物在制备诊断、预防、治疗或组合用于得自狂犬病毒属病毒感染的疾病的药物中的应用。所述狂犬病毒属病毒可以是任何已知基因型的病毒,但优选是狂犬病病毒。优选上述分子用于制备狂犬病暴露后预防的药物中。
本发明还提供了试剂盒,所述试剂盒包含本发明的至少一种结合分子、至少一种其功能变体、至少一种免疫缀合物、至少一种核酸分子、至少一种组合物、至少一种药物组合物、至少一种载体、至少一种宿主,或者其组合。任选地,本发明的试剂盒的上述组分包装在合适的容器中,并标记了诊断、预防和/或治疗的指定疾病。上述组分可以贮存在单位剂量或者多剂量容器中,例如密封的安瓿、小瓶、瓶子、注射器和试管中,是水相优选无菌溶液或者是用于重建的冻干的优选无菌的制剂。所述容器可以由多种材料制成,如玻璃或者塑料,可以具有一个无菌的进入口(例如该容器可以是具有可用皮下注射针刺穿的塞子的静脉内注射溶液袋或者小瓶)。所述试剂盒另外包含包含药物可接受的缓冲液如磷酸盐缓冲盐水、Ringer′s溶液和葡萄糖溶液的多个容器。所述试剂盒可进一步包括商业上和使用者需要的其它材料,包括用于一或多种合适宿主的其它缓冲剂、稀释剂、过滤器、针头、注射器、培养基。所述试剂盒中通常在治疗、预防或诊断产品的商业包装中附带使用说明书,说明书中含有关于例如这种治疗、预防或诊断产品的适应症、使用、剂量、生产、给予、禁忌症和/或使用注意事项的信息。
目前,HRIG产品用于狂犬病暴露后预防。1500IU的成人剂量HRIG仅在10ml体积中提供(75kg个体,20IU/kg)。更浓缩的HRIG产品是不可能的,因为目前可获得的10ml剂量含有1-1.5g的总IgG。鉴于目前HRIG产品具有两个缺点。首先,其通常在解剖学上不适合在咬伤伤口中和其周围给予推荐的完全剂量,其次,目前给予的HRIG的体积与明显的疼痛相关。本发明提供了解决这些缺点的方法,本发明提供了一种药物组合物,其包含大约2ml或更少体积(如果需要)的全部成人剂量。这种药物组合物可包含例如能中和狂犬病病毒的两种结合分子,优选CR57和CR04-098。所述药物组合物进一步包含一种药物可接受的赋形剂,体积为大约2ml。可以有更大的体积,但是考虑到与注射更大体积相关的疼痛因此不希望更大的体积。低于2ml也是可能的。所述药物组合物包含成功进行暴露后预防需要的全部成人剂量(IU)。在一个实施方案中,所述药物组合物贮存在10ml小瓶中,例如10ml的具有塞子的ready-to-use小瓶(I型玻璃)中。通过提供10ml小瓶,在个体存在较大创伤表面积的情况中可以选择将药物组合物稀释为更大体积。本发明还提供了一种试剂盒,其包含至少一个包含药物组合物的容器(例如小瓶)。所述试剂盒可进一步包含具有适于将药物组合物稀释为更大体积的稀释剂的第二种容器。合适的稀释剂包括但非限于药物组合物的药物可接受的赋形剂和盐水溶液。此外,所述试剂盒可包含稀释该药物组合物的说明书和/或给予稀释或未稀释的该药物组合物的说明书。
本发明进一步涉及一种检测样品中狂犬病病毒的方法,所述方法包括如下步骤:a)将样品与诊断有效量的本发明的结合分子、功能变体或免疫缀合物接触,及b)确定所述结合分子、功能变体或者免疫缀合物是否特异性结合样品的分子。所述样品可以是生物学样品,包括但非限于(潜在)感染对象的血液、血清、组织或者其它生物学材料。所述(潜在)感染的对象可以是人,但是对怀疑是狂犬病病毒携带者的动物也可以使用本发明的人结合分子、功能变体或者免疫缀合物测试狂犬病病毒的存在与否。首先对样品进行操纵,使其更适合检测方法。操纵意味着对怀疑含有和/或含有狂犬病病毒的样品进行处理,由此狂犬病病毒分解为抗原成分如蛋白质、(多)肽或者其它抗原片段。优选地,将本发明的结合分子、功能变体或者免疫缀合物与该样品在使得人结合分子与样品中可能存在的狂犬病病毒或者其抗原成分之间形成免疫复合物的条件下接触。如果免疫复合物形成则表明该样品中存在狂犬病病毒,然后通过合适方式检测并测定。这种方法包括均质(homogeneous)和异质(heterogeneous)结合免疫分析,如放射性免疫分析(RIA)、ELISA、免疫荧光、免疫组织化学、FACS、BIACORE和Western印迹分析。
此外,本发明的结合分子可用于鉴别狂犬病病毒蛋白如G蛋白的表位。所述表位可以是线性的,但也可以是结构和/或构象的。在一个实施方案中,本发明的结合分子与狂犬病病毒蛋白如狂犬病病毒G蛋白的一系列重叠肽如15-mer肽的结合可以利用PEPSCAN分析(见WO 84/03564、WO 93/09872、Slootstra et al.1996)。人结合分子与每种肽的结合可以在基于PEPSCAN的酶联免疫吸附测定(ELISA)中检测。在另一个实施方案中,可以对包含狂犬病病毒蛋白的肽的随机肽文库筛选能与本发明的人结合分子结合的肽。在上述分析中,中和狂犬病病毒的人结合分子的应用可以鉴别一或多个中和表位。发现的肽/表位可以用作疫苗或者用于狂犬病的诊断。
另一方面,本发明提供了一种筛选与本发明的结合分子或功能变体所结合的表位不同的、优选非重叠的狂犬病病毒表位特异性结合的结合分子或结合分子功能变体的方法,所述方法包括如下步骤:a)将被筛选的结合分子或功能变体、本发明的结合分子或功能变体与狂犬病病毒或其片段(例如狂犬病病毒G蛋白)接触,b)测定被筛选的结合分子或功能片段是否能与本发明的结合分子或功能变体竞争特异性结合狂犬病病毒或其片段。如果未检测到竞争,则被筛选的结合分子或功能变体结合不同的表位。在上述筛选方法的一个特定实施方案中,可以对人结合分子或其功能变体进行筛选,以鉴别能结合与包含CDR3区(该CDR3区包含SEQ ID NO:25氨基酸序列)的结合分子识别的表位不同的表位的人结合分子或其功能变体。优选地,所述表位是非重叠或者非竞争性的。技术人员已知上述筛选方法也可用于鉴别能结合相同表位的结合分子或其功能变体。在进一步的步骤中,可以确定不能竞争性特异性结合狂犬病病毒或其片段的经筛选的结合分子是否具有中和活性。也可以确定能竞争性特异性结合狂犬病病毒或其片段的经筛选的结合分子是否具有中和活性。在筛选方法中发现的中和抗狂犬病病毒的结合分子或其功能变体也是本发明的另一部分。在筛选方法中,“与相同表位特异性结合”包括特异性结合与本发明的人结合分子结合的表位基本上或者实质上相同的表位。阻断或者与本发明的人结合分子竞争结合狂犬病病毒的能力典型表明筛选的结合分子与狂犬病病毒上的表位或者结合位点结合,所述表位或者结合位点与本发明的结合分子免疫特异性识别的狂犬病病毒上的结合位点在结构上重叠。或者,这可以表明筛选的结合分子与本发明的结合分子免疫特异性识别的结合位点十分邻近的表位或者结合位点结合,以空间排阻或者抑制本发明的结合分子与狂犬病病毒或其片段的结合。
通常,竞争性抑制是通过一种分析测定的,其中将抗原组合物,即包含狂犬病病毒或其片段(如G蛋白)的组合物与参考结合分子及筛选的结合分子混合。在一个实施方案中,所述参考结合分子可以是本发明的人结合分子之一,筛选的结合分子可以是本发明的另一种人结合分子。在另一个实施方案中,参考结合分子可以是包含CDR3区的结合分子,该CDR3区包含SEQ ID NO:25的氨基酸序列,筛选的结合分子可以是本发明的人结合分子之一。在另一个实施方案中,参考结合分子可以是本发明的人结合分子之一,筛选的结合分子可以是包含CDR3区的结合分子,该CDR3区包含SEQ ID NO:25的氨基酸序列。通常,筛选的结合分子过量存在。基于ELISA的方案适合用于这种简便的竞争性研究中。在某些实施方案中,可以预先将参考结合分子与不同量的筛选结合分子混合(例如1∶10、1∶20、1∶30、1∶40、1∶50、1∶60、1∶70、1∶80、1∶90或者1∶100)一段时间,之后用于抗原组合物。在其它实施方案中,参考结合分子与不同量的筛选的结合分子可以在暴露于抗原组合物期间简便地混合。在任何情况中,通过使用物种或者同种型二级抗体,技术人员均可以仅检测结合的参考结合分子,其结合可以由于识别基本相同的表位的筛选的结合分子的存在而降低。在进行参考结合分子与任何筛选的结合分子之间的结合分子竞争性研究中(不论物种或者同种型),技术人员可首先用可检测的标记对参考结合分子进行标记,所述标记例如是生物素、酶、放射性标记或者在随后可以鉴别的其它标记。在这些情况中,将标记的参考结合分子与筛选的结合分子以不同比率预先混合或者保温(例如1∶10、1∶20、1∶30、1∶40、1∶50、1∶60、1∶70、1∶80、1∶90或者1∶100),及(任选在合适的时间之后)分析标记的参考结合分子的反应性,将其与无潜在竞争性结合分子保温的情况中获得的对照值进行对比。所述分析再可以是基于抗体杂交的任何免疫学分析,参考结合分子通过检测其标记而可以被检测,例如在生物素化的参考结合分子的情况中使用链霉亲和素或者通过使用生色底物连同酶标记(如3,3′5,5′-四甲基联苯胺(TMB)底物与过氧化物酶)检测,或者通过简便检测放射性标记检测。结合与参考结合分子相同的表位的筛选的结合分子能有效地竞争结合,并因此显著降低参考结合分子的结合,通过结合标记的减少而表明。结合不同的非竞争表位的结合分子示出标记未减少。(标记的)参考结合分子在不存在与竞争性不相关的结合分子的情况中的反应性是对照高值。对照低值是通过将标记的参考结合分子与实际上相同类型的未标记的参考结合分子一起保温,当竞争发生并降低标记的参考结合分子的结合时获得的数值。在测试分析中,在存在筛选的结合分子的情况中,标记的参考结合分子反应性显著降低表明存在识别相同表位的结合分子,即与标记的参考结合分子“交叉反应”的结合分子。如果其反应性不降低,则所述结合分子结合不同的非竞争表位。
通过这些竞争分析鉴别的结合分子(竞争性结合分子)包括但非限于与参考结合分子结合的表位或者结合位点结合的抗体、抗体片段及其它结合剂,以及与参考结合分子结合的表位十分邻近的表位或者结合位点结合的抗体、抗体片段及其它结合剂,以在筛选的结合分子与参考结合分子之间发生竞争性结合。优选地,本发明的竞争性结合分子当过量存在时抑制参考结合分子与选择的靶位的特异性结合至少10%,优选至少25%、50%,最优选至少75%-90%或者甚至更高。与本发明的结合分子的大约相同、基本上相同、实质上相同、或者相同的表位结合的一或多种竞争性结合分子的鉴别是一个简单的技术操作。因为竞争性结合分子是通过与参考结合分子相对比而鉴别,所以应理解鉴别与参考结合分子结合相同或者基本上相同表位的竞争性结合分子不是在任何情况下均必须实际确定参考结合分子和竞争性结合分子所结合的表位。或者,通过这些竞争分析鉴别的结合不同的非竞争性表位的结合分子包括但非限于抗体、抗体片段及其它结合剂。
本发明另一方面提供了鉴别结合分子或者编码这种结合分子的核酸分子的方法,所述结合分子潜在地具有中和导致活体疾病的感染因子的活性,其中所述方法包括如下步骤:a)将可复制遗传包装表面上的结合分子集合与至少一种在其表面上表达导致活体发生疾病的感染因子的蛋白质的细胞在有益于结合的条件下相接触,b)从与所述细胞未结合的结合分子中分离并回收与在其表面上表达导致活体发生疾病的感染因子蛋白质的细胞结合的结合分子,c)分离至少一种回收的结合分子,d)检验分离的结合分子是否具有中和导致活体发生疾病的感染因子的活性。在其表面上表达导致活体发生疾病的感染因子的蛋白质的细胞可以是用所述蛋白质转染的细胞。本领域技术人员已知除了蛋白质之外的感染因子抗原也可成功用于该方法中。在一个特定实施方案中,所述细胞是PER.C6_细胞。然而,其它(E1-无限增殖化的)细胞系也可以用于表达蛋白质,如BHK、CHO、NS0、HEK293或者911细胞。在一个实施方案中,所述结合分子是人结合分子。所述感染因子可以是病毒、细菌、酵母、真菌或者寄生虫。在一个实施方案中,所述蛋白质是在感染因子表面上正常表达的蛋白质,或者包含可在表面接近的蛋白质的至少一部分。在一个特定实施方案中,可复制遗传包装表面上的结合分子集合用用于表达感染因子蛋白质的细胞扣除/反选择(subtracted/counterselected),即该细胞与步骤a中使用的细胞相同,条件是它们在其表面上不表达感染因子蛋白质。被扣除/反选择的细胞可以是未转染的细胞。或者,细胞可以用一种蛋白质或其(胞外)部分转染,所述蛋白质在序列或者结构方面与感染因子的蛋白质相似和/或高度同源,和/或其衍生自相同科或者甚至相同属的感染因子。
本发明另一方面涉及具有狂犬病病毒中和活性的结合分子,特征在于所述人结合分子包含至少一个重链CDR3区,该CDR3区包含SEQ ID NO:25的氨基酸序列,进一步特征在于所述人结合分子具有至少2500IU/mg蛋白质的狂犬病病毒中和活性。更优选地,所述人结合分子具有至少2800IU/mg蛋白质、3000IU/mg蛋白质、3200IU/mg蛋白质、3400IU/mg蛋白质、3600IU/mg蛋白质、3800IU/mg蛋白质、4000IU/mg蛋白质、4200IU/mg蛋白质、4400IU/mg蛋白质、4600IU/mg蛋白质、4800IU/mg蛋白质、5000IU/mg蛋白质、5200IU/mg蛋白质、5400IU/mg蛋白质的狂犬病病毒中和活性。结合分子的中和活性通过体外中和分析测定(修改的RFFIT(快速荧光灶抑制试验,rapid fluorescent focus inhibition test))。这个分析在实施例章节中详细描述。
在一个实施方案中,所述结合分子包含一条可变重链,该可变重链包含SEQ ID NO:273所示氨基酸序列。在另一个实施方案中,所述结合分子包含一条重链,该重链包含SEQ ID NO:123所示氨基酸序列。所述结合分子的可变轻链可包含SEQ ID NO:275所示的氨基酸序列。所述结合分子的轻链可包含SEQ ID NO:125所示的氨基酸序列。
编码上述结合分子的核酸分子也是本发明的一部分。优选地,所述核酸分子包含SEQ ID NO:122所示核苷酸序列。另外,所述核酸分子还可包含SEQ ID NO:124所示核苷酸序列。本发明还提供了包含所述核酸分子的载体及包含这种载体的宿主细胞。优选地,宿主细胞是哺乳动物细胞如人细胞。适于产生人结合分子的细胞的例子是HeLa、911、AT1080、A549、293和HEK293T细胞。优选的哺乳动物细胞是人视网膜细胞如911细胞或者于1996年2月29日保藏在欧洲动物细胞保藏中心(ECACC;CAMR,Salisbury,Wiltshire SP4OJG,Great Britain)的保藏号为96022940的细胞系,其商标为PER.C6_(PER.C6是Crucell Holland B.V.的注册商标)。在本申请中,“PER.C6”是指以保藏号96022940保藏的细胞或其祖先、上游或下游传代以及来自保藏细胞的祖先的后代以及任何前述细胞的衍生物。
实施例
为了例证本发明,提供了如下实施例。所述实施例非以任何方式限制本发明的范围。
实施例1
人抗狂犬病病毒抗体CR-57和CR-JB的表位识别
为了确定称作CR-57和CR-JB的人单克隆抗体是否识别非重叠的、非竞争的表位,产生称作CR-57和CR-JB的人单克隆抗体的逃逸病毒。通过将相应抗体基因的可变重链和轻链编码区导入称作pcDNA3002(Neo)的人IgG1表达载体中,CR-57和CR-JB基本如(见Jones et al.,2003)所述产生。所得载体pgSO57C11和pgSOJBC11用于在细胞中瞬时表达,所述细胞来自于1996年2月29日以保藏号96022940保藏在欧洲动物细胞保藏中心(ECACC;CAMR,Salisbury,Wiltshire SP4 OJG,Great Britain)的商标为PER.C6_的细胞系。这些抗体的重链和轻链的核苷酸和氨基酸序列分别示于SEQ ID NO:122-129。将狂犬病病毒株CVS-11的系列稀释液(0.5ml)(稀释范围10-1-10-8)与恒定量(~4IU/ml)的抗体CR-57或CR-JB(0.5ml)在37℃/5%CO2条件下保温1小时,之后加入含有小鼠成神经细胞瘤细胞(MNA细胞)或者BSR细胞(幼仓鼠肾样细胞系)的孔中。在存在人单克隆抗体CR-57或CR-JB的条件下选择3天后,收获含有潜在逃逸病毒的培养基(1ml),在4℃贮存直至进一步应用。随后,将细胞用丙酮在4℃固定20分钟,在37℃/5%CO2条件下用抗狂犬病病毒N-FITC抗体缀合物(Centocor)染色过夜。通过免疫荧光记录每个孔中转化灶(foci)的数目,选择含有1-6个转化灶的孔中的培养基进行病毒扩增。所有的E57逃逸病毒均从一个转化灶中产生,E57B1除外(3个转化灶)。EJB逃逸病毒分别分离自1个转化灶(EJB3F)、3个转化灶(EJB2B)、4个转化灶(EJB2C)、5个转化灶(EJB2E、2F)或者6个转化灶(EJB2D)。每个逃逸病毒均首先在BSR或MNA细胞上根据其生长特性小规模扩增。然后将这些小批量的病毒用于在MNA或BSR细胞上进一步大规模扩增。然后将扩增的病毒在MNA细胞上滴定,以确定每个逃逸病毒批次物的效价以及逃逸病毒的最佳稀释度(在24小时后产生80-100%感染),以在病毒中和分析中使用。
进行修改的RFFIT(快速荧光灶抑制试验)分析,以检测E57(CR-57的逃逸病毒)和EJB(CR-JB的逃逸病毒)分别与CR-JB和CR-57的交叉保护作用。因此,从1∶5稀释开始对CR-57或CR-JB进行系列3倍稀释。向每个稀释液中加入一定浓度的狂犬病病毒(CVS-11毒株),使得产生80-100%感染。将病毒/IgG混合物在37℃/5%CO2条件下保温1小时,之后加入MNA细胞中。在感染后24小时(在34℃/5%CO2条件下),将细胞在4℃用丙酮固定20分钟,用抗狂犬病病毒N-FITC抗体缀合物(Centocor)进行最少3小时染色。然后在荧光显微镜下分析孔的狂犬病病毒感染情况,以确定50%终点稀释度。这是在这个分析中病毒感染被阻断50%的稀释度。为了计算效力,在每个修改的RFFIT中均包括国际标准(Rabies ImmuneGlobulin Lot R3,来自Standards and Testing DMPQ/CBER/FDA实验室的参考材料)。这个标准的50%终点稀释度相应于效力为2IU/ml。对单独的人单克隆抗体CR-57和CR-JB以及这些抗体的组合的中和效力进行测试。
EJB病毒不再由CR-JB或者CR-57中和(见表1所示),提示这两种抗体结合狂犬病病毒糖蛋白的相似区域并诱导其中氨基酸改变。E57病毒不再由CR-57中和,而6个E57病毒中有4个病毒仍由CR-JB中和,但效力较低(见表1所示)。抗体CR-57和CR-JB的混合物(1∶1IU/mg比率)提供与单一抗体相似的结果(数据未示出)。
为了鉴别狂犬病病毒糖蛋白中可能的突变,确定每个EJB和E57逃逸病毒的糖蛋白开放读框(ORF)的核苷酸序列。每个逃逸病毒和CVS-11的病毒RNA均分离自病毒感染的MNA细胞,通过标准RT-PCR转变为cDNA。随后,使用cDNA对狂犬病病毒糖蛋白ORF进行核苷酸测序以鉴别突变。
E57和EJB逃逸病毒均示出在糖蛋白的相同区域中的突变(分别见图1和2所示;见图1和2描述的全部序列SEQ ID NO:130-151)。这表明这两种抗体识别重叠表位。由上文可以推断混合物中CR-57和CR-JB的组合不阻止中和抗性变体的逃逸,并因此不是狂犬病暴露后预防的理想的免疫球蛋白制品。
实施例2
用狂犬病接种的供体的外周血淋巴细胞构建scFv噬菌体展示文库
在最后一次加强免疫后一周从4个狂犬病接种的人个体的静脉中取50ml血。用Ficoll细胞密度分级分离从这些血样中分离外周血淋巴细胞(PBL)。血清冷冻保存在-20℃。在狂犬病病毒糖蛋白转染的293T细胞上用FACS染色测得血清中抗狂犬病抗体的存在呈阳性。用有机相分离(TRIZOLTM)和随后的乙醇沉淀从PBL中制备总RNA。将获得的RNA溶解在DEPC处理的超纯水中,通过OD 260nm测量确定浓度。之后,将RNA稀释至100ng/μl的浓度。接着,如下将1μg RNA转化成cDNA:向10μl总RNA中加入13μl DEPC处理的超纯水和1μl随机六聚体(500ng/μl),将获得的混合物在65℃加热5分钟并在湿冰上迅速冷却。然后,向混合物中加入8μl 5X第一链缓冲液、2μl dNTP(各10mM)、2μl DTT(0.1M)、2μl Rnase抑制剂(40U/μl)和2μl SuperscriptionTM III MMLV逆转录酶(200U/μl),在室温保温5分钟,并在50℃保温1小时。通过热失活终止反应,即将混合物在75℃保温15分钟。
用DEPC处理的超纯水将获得的cDNA产物稀释至终体积为200μl。获得的cDNA产物的稀释液的50倍稀释溶液(于10mM Tris缓冲液中)的OD260nm的值为0.1。
对于每一供体,5-10μl稀释的cDNA产物用作模板,用特异性寡核苷酸引物(见表2-7)PCR扩增免疫球蛋白γ重链家族和κ或λ轻链序列。在终体积50μl的20mM Tris-HCl(pH8.4)、50mM KCl、2.5mMMgCl2、250μM dNTP和1.25单位Taq聚合酶中,PCR反应混合物除了含有稀释的cDNA产物之外还含有25pmol有义引物和25pmol反义引物。在温度为96℃的加热盖热循环仪中,获得的混合物快速解链2分钟,随后30个循环的96℃30秒、60℃30秒和72℃60秒。
在第一轮扩增中,17种轻链可变区有义引物(针对λ轻链有11种(见表2),针对κ轻链有6种)的每一种与识别C-κ的称为HuCk5′-ACACTCTCCCCTGTTGAAGCTCTT-3′(见SEQ ID NO:152)或识别C-λ恒定区的称为HuCλ2 5′-TGAACATTCTGTAGGGGCCACTG-3′(见SEQ ID NO:153)和HuCλ75′-AGAGCATTCTGCAGGGGCCACTG-3′(见SEQ ID NO:154)的反义引物(HuCλ2和HuCλ7反义引物在使用前等摩尔混和)组合,产生4倍的约600碱基对的17种产物。这些产物在2%琼脂糖凝胶上纯化并用Qiagen凝胶提取柱从凝胶中分离。在一使用相同的17种有义引物的如上所述相同的PCR反应中使用1/10每种分离的产物,其中每种λ轻链有义引物与3种Jλ-区特异性反义引物的一种组合,每种κ轻链有义引物与5种Jκ-区特异性反义引物的一种组合。用于第二个扩增中的引物用限制位点延伸(见表4)以使得直接克隆在噬菌体展示载体PDV-C06中(见图3和SEQIDNO:155)。这产生4倍约350碱基对的63种产物,这些产物混和(pooled)成总共10个级分。选择这一数量的级分以保持不同轻链家族在文库内的天然分布而不会过度代表某些家族或某些家族代表不足。用家族内的等位基因数量确定文库内呈现的百分比(见表5)。在下一步,将2.5μg混和的级分和100μg PDV-C06载体用SalI和NotI消化并从凝胶中纯化。之后,在16℃如下连接过夜:在含有50mM Tris-HCl(pH7.5)、10mM MgCl2、10mM DTT、1mM ATP、25μg/ml BSA和2.5μl T4DNA连接酶(400U/μl)的总体积为50μl的连接混合物中向500ng PDV-C06载体中加入70ng混和的级分。每种混和的级分均进行这一程序。用本领域技术人员熟知的方法经苯酚/氯仿、氯仿提取和乙醇沉淀而纯化连接混合物。将获得的DNA溶解在50μl超纯水中,根据厂商方案(Stratagene)每种连接混合物2倍2.5μl等份被电穿孔进40μl TG1感受态大肠杆菌细菌中。转化子在含有补加50μg/ml氨苄青霉素和4.5%葡萄糖的2TY琼脂的30个培养皿上于37℃过夜生长(每种混和的级分3个培养皿,培养皿尺寸240mm×240mm)。通过从琼脂平板上刮下转化子获得轻链可变区的(亚)文库。这一(亚)文库被直接用于用QiagenTM QIAFilterMAXI prep试剂盒进行质粒DNA制备。
对于每种供体,以如上针对轻链区所述的类似的两轮PCR程序和相同反应参数从相同cDNA制备物中扩增重链免疫球蛋白序列,条件是使用表6和表7的引物。用一组9个有义方向引物(见表6;覆盖全部重链可变区家族)进行第一次扩增,每种引物与称为HuCIgG5′-GTC CAC CTT GGT GTT GCT GGG CTT-3′(SEQ ID NO:156)的IgG特异性恒定区反义引物组合,产生4倍约650碱基对的9种产物。这些产物在2%琼脂糖凝胶上纯化并用Qiagen凝胶提取柱从凝胶中分离。在如上所述的使用相同9种有义引物的相同PCR反应中使用1/10每种分离的产物,其中每种重链有义引物与4种JH区特异性反义引物中的一种组合。第二轮中使用的引物用限制位点延伸(见表7)以使得在轻链(亚)文库载体中定向克隆。这导致每个供体产生为约350碱基对的36种产物。这些产物根据每种使用的(VH)有义引物每种供体混和成9种级分。获得的产物用Qiagen PCR纯化柱纯化。接着,将级分用SfiI和XhoI消化并使用上述针对轻链(亚)文库所述的相同连接程序和体积连接进轻链(亚)文库载体中,该轻链(亚)文库载体已用相同限制酶切割。或者,所述级分用NcoI和XhoI消化并使用上述针对轻链(亚)文库所述的相同连接程序和体积连接进轻链载体中,该轻链载体已用相同限制酶切割。还根据以上针对轻链(亚)文库所述那样进行连接纯化和所得确定文库的后续转化,在此时根据每VH库组合每个供体的连接混合物。转化子在含有补加了50μg/ml氨苄青霉素和4.5%葡萄糖的2TY琼脂的27个培养皿中生长(每个混和的级分3个培养皿;培养皿尺寸:240mm×240mm)。所有细菌收集在含有50μg/ml氨苄青霉素和4.5%葡萄糖的2TY培养基中,与甘油混和至15%(v/v)并以1.5ml等份冷冻在-80℃。每一文库的拯救和选择如下所述进行。
实施例3
携带特异性识别狂犬病病毒糖蛋白的单链Fv片段的噬菌体的选择
基本上如美国专利6,265,150和WO 98/15833(两者均引入本文作参考)所述,用抗体噬菌体展示文库、通用噬菌体展示技术和Mabstract_技术选择抗体片段。所用抗体噬菌体文库是两种不同的半合成scFv噬菌体文库(JK1994和WT2000)以及实施例2中制备的免疫scFv噬菌体文库(RAB-03-G01和RAB-04-G01)。第1种半合成scFv噬菌体文库(JK1994)在de Kruifet al.(1995b)中描述,第2种(WT2000)基本上如de Kruif et al.(1995b)所述构建。简单地说,文库具有半合成形式,其中用将变异掺入CDR区域内的简并寡核苷酸将变异掺入重链和轻链V基因中。仅仅VH3重链基因被使用,其与κ和λ轻链基因组合。重链的CDR1和CDR3以及轻链的CDR3在与deKruif et al.(1995b)所述类似的基于PCR的途径中合成构建。由此构建的V区基因以scFv形式依次克隆在噬菌粒载体中并被扩增以产生如前所述的噬菌体文库。另外WO 02/103012(引入本文作参考)所述的方法和辅助噬菌体用于本发明中。为了鉴别识别狂犬病病毒糖蛋白的噬菌体抗体,用通过β-丙内酯处理而灭活的完全狂犬病病毒(狂犬病病毒Pitman-Moore毒株)、纯化的狂犬病病毒糖蛋白(狂犬病病毒ERA毒株)和/或表达狂犬病病毒G蛋白(狂犬病病毒ERA毒株)的转染细胞进行噬菌体选择实验。
如下从狂犬病病毒ERA毒株纯化G蛋白。向病毒溶液中加入1/10体积的10%辛基-β-吡喃葡糖苷并温和混合。在4℃保温30分钟,在SW51转子中离心病毒样品(36000rpm,4℃)。收集上清并在4℃对0.1M Tris/EDTA透析过夜。随后,从透析腔收集糖蛋白,等分并储存于-80℃直至进一步使用。在OD280测蛋白质浓度,由SDS-PAGE分析G蛋白完整性。
完整的灭活狂犬病病毒或狂犬病病毒G蛋白在磷酸盐缓冲盐水(PBS)中稀释,将2-3ml加至MaxiSorp Nunc-Immuno Tubes(Nunc)并在旋转轮上于4℃保温过夜。一等份噬菌体文库(500μl,约1013cfu,用CT辅助噬菌体扩增(见WO 02/103012))在封闭缓冲液(2%补体素(Protifar)于PBS中)中于室温封闭1-2小时。将封闭的噬菌体文库加到免疫管中(与或未与CR-57scFv预保温以封闭由CR-57识别的表位),在室温保温2小时,并用洗涤缓冲液(0.1%Tween-20(Serva)于PBS中)洗涤以除去未结合的噬菌体。结合的噬菌体然后通过在室温与1ml的50mM甘氨酸-HCl pH2.2保温10分钟而从抗原中洗脱。随后,洗脱的噬菌体与0.5ml的1M Tris-HCl pH7.5混和以中和pH。用混合物感染已在37℃生长至OD600nm约0.3的5mlXL1-Blue大肠杆菌培养物。噬菌体在37℃感染XL1-Blue细菌30分钟。然后,混合物在3200×g于室温离心10分钟,细菌沉淀重悬于0.5ml的2-trypton酵母提取物(2TY)培养基中。获得的细菌悬浮液分在补加了四环素、氨苄青霉素和葡萄糖的两个2TY琼脂平板上。平板在37℃过夜保温后,从平板刮下菌落并用于制备富集的噬菌体文库,基本上如De Kruif et al.(1995a)和WO 02/103012所述。简单地,用刮下的细菌接种含有氨苄青霉素、四环素和葡萄糖的2TY培养基,在37℃生长至OD600nm为约0.3。加入CT辅助噬菌体并感染细菌,之后培养基变为含有氨苄青霉素、四环素和卡那霉素的2TY。继续在30℃保温过夜。第2天,细菌通过离心从2TY培养基中除去,之后培养基中的噬菌体用聚乙二醇(PEG)6000/NaCl沉淀。最后,将噬菌体溶于含有1%牛血清白蛋白(BSA)的2ml PBS中,过滤灭菌并用于下一轮选择。
还用狂犬病病毒糖蛋白转染的细胞进行了噬菌体选择。所用细胞是来自在1996年2月29日保藏在欧洲动物细胞保藏中心(ECACC),CAMR,Salisbury,Wiltshire SP4 OJG,Great Britain的保藏号为96022940的细胞系的细胞,该细胞系以PER.C6_的商标在市场上销售。它们以下被称为PER.C6_细胞。此处,封闭的噬菌体文库(2ml)首先被加到1×107subtractor细胞中(在DMEM/10%FBS中)并在一旋转轮上于4℃保温1小时。Subtractor细胞是在其表面表达与狂犬病病毒跨膜和胞质结构域融合的疱疹性口腔炎病毒(VSV)糖蛋白胞外域(ectodomain)的PER.C6_细胞。随着这一扣除步骤,识别VSV糖蛋白或特异于PER.C6_细胞的抗原的噬菌体被从噬菌体文库中除去。离心噬菌体/细胞混合物(500×g 5分钟,4℃)以除去细胞结合的噬菌体,将上清加入到含有3ml的1×107subtractor细胞的新试管中。这一扣除步骤用各个上清重复2次。随后,在一旋转轮上将扣除的噬菌体与表达狂犬病病毒糖蛋白的转染细胞(PER.C6_细胞(3×106细胞)在4℃保温1.5小时。之前,转染细胞与或未与CR-57scFv预保温以封闭由CR-57识别的表位。保温后,细胞用1ml的DMEM/10%FBS洗5次(每次洗涤细胞均重悬并移至新试管),如上所述洗脱并加工噬菌体。
典型地,在分离各个噬菌体抗体之前进行两轮选择。在第2轮选择后,用各个大肠杆菌菌落制备单克隆噬菌体抗体。基本上,在96孔板中将各个菌落生长至对数期并用VCSM13辅助噬菌体感染,之后使噬菌体抗体产生进行过夜。产生的噬菌体抗体用PEG/NaCl沉淀、过滤灭菌并在ELISA中测试与完整灭活的狂犬病病毒和纯化的狂犬病病毒G蛋白的结合。从选择中获得一大组噬菌体抗体,证实与完整灭活的狂犬病病毒和狂犬病病毒G蛋白均结合(见下述实施例)。用上述免疫文库进行两种选择策略。在第一种策略中,在第一轮和第二轮选择中用灭活病毒或纯化的G蛋白的两轮选择后选择了736种噬菌体抗体。在第二种选择策略中,在第一轮选择用细胞表面表达的重组G蛋白和在第二轮选择中用灭活病毒或纯化的G蛋白的两轮选择后选择了736种噬菌体抗体。用第一种策略获得的独特噬菌体抗体数量是97,而第二种策略产生70种独特噬菌体抗体。第一种策略发现的97种独特噬菌体抗体产生18种中和抗体,第二种策略鉴别的70种独特克隆产生33种中和抗体。这清楚表明包括狂犬病病毒糖蛋白转染的细胞,即细胞表面表达的重组G蛋白作为抗原的选择与仅使用纯化的G蛋白和/或灭活病毒的选择相比似乎产生更多的中和抗体。
实施例4
狂犬病病毒糖蛋白特异性单链噬菌体抗体的确认
在上述筛选中获得的选择的单链噬菌体抗体在ELISA中确认特异性,即与如上所述纯化的狂犬病病毒G蛋白的结合。另外,还测试了单链噬菌体抗体与5%FBS的结合。为此,用狂犬病病毒G蛋白或5%FBS包被MaxisorpTM ELISA平板。包被后,在室温将板在PBS/1%补体素中封闭1小时。选择的单链噬菌体抗体在等体积的PBS/1%补体素中保温15分钟以获得封闭的噬菌体抗体。倒空平板,向孔中加入被封闭的噬菌体抗体。保温1小时,将平板在含有0.1%Tween-20的PBS中洗涤,用与过氧化物酶缀合的抗M13抗体检测结合的噬菌体抗体(用OD492nm测量)。作为对照,不使用单链噬菌体抗体、使用针对CD8的阴性对照单链噬菌体抗体(SC02-007)或使用针对狂犬病病毒糖蛋白的阳性对照单链噬菌体抗体(scFv SO57)同时进行所述程序。如表8所示,称为SC04-001、SC04-004、SC04-008、SC04-010、SC04-018、SC04-021、SC04-026、SC04-031、SC04-038、SC04-040、SC04-060、SC04-073、SC04-097、SC04-098、SC04-103、SC04-104、SC04-108、SC04-120、SC04-125、SC04-126、SC04-140、SC04-144、SC04-146和SC04-164的选择的噬菌体抗体展示与固定化的纯化的狂犬病病毒G蛋白的显著结合,但未观察到与FBS的结合。在使用如上所述制备的完整灭活的狂犬病病毒的ELISA中获得相同结果(数据未示出)。
实施例5
狂犬病病毒特异性scFv的鉴定
从选择的特异性单链噬菌体抗体(scFv)克隆获得质粒DNA并根据标准技术确定核苷酸序列。称为SC04-001、SC04-004、SC04-008、SC04-010、SC04-018、SC04-021、SC04-026、SC04-031、SC04-038、SC04-040、SC04-060、SC04-073、SC04-097、SC04-098、SC04-103、SC04-104、SC04-108、SC04-120、SC04-125、SC04-126、SC04-140、SC04-144、SC04-146和SC04-164的scFv的核苷酸序列(包括用于克隆的限制位点)分别示于SEQ ID NO:157、SEQ ID NO:159、SEQID NO:161、SEQ ID NO:163、SEQ ID NO:165、SEQ ID NO:167、SEQ ID NO:169、SEQ ID NO:171、SEQ ID NO:173、SEQ ID NO:175、SEQ ID NO:177、SEQ ID NO:179、SEQ ID NO:181、SEQ ID NO:183、SEQ ID NO:185、SEQ ID NO:187、SEQ ID NO:189、SEQ ID NO:191、SEQ ID NO:193、SEQ ID NO:195、SEQ ID NO:197、SEQ ID NO:199、SEQ ID NO:201和SEQ ID NO:203。称为SC04-001、SC04-004、SC04-008、SC04-010、SC04-018、SC04-021、SC04-026、SC04-031、SC04-038、SC04-040、SC04-060、SC04-073、SC04-097、SC04-098、SC04-103、SC04-104、SC04-108、SC04-120、SC04-125、SC04-126、SC04-140、SC04-144、SC04-146和SC04-164的scFv的氨基酸序列分别示于SEQ ID NO:158、SEQ ID NO:160、SEQ ID NO:162、SEQID NO:164、SEQ ID NO:166、SEQ ID NO:168、SEQ ID NO:170、SEQ ID NO:172、SEQ ID NO:174、SEQ ID NO:176、SEQ ID NO:178、SEQ ID NO:180、SEQ ID NO:182、SEQ ID NO:184、SEQ ID NO:186、SEQ ID NO:188、SEQ ID NO:190、SEQ ID NO:192、SEQ ID NO:194、SEQ ID NO:196、SEQ ID NO:198、SEQ ID NO:200、SEQ ID NO:202和SEQ ID NO:204。
特异性结合狂犬病病毒G蛋白的scFv的VH和VL基因相同性(参见Tomlinson IM,Williams SC,Ignatovitch O,Corbett SJ,Winter G.V-BASE Sequence Directory.Cambridge United Kingdom:MRC Centrefor Protein Engineering(1997))和重链CDR3组成见表9所示。
实施例6
狂犬病病毒特异性scFv对狂犬病病毒的体外中和(修改的RFFIT)
为了确定选择的scFv是否能阻断狂犬病病毒感染,进行了体外中和分析(修改的RFFIT)。通过用1∶5稀释度开始的系列3倍稀释而稀释scFv制备物。狂犬病病毒(毒株CVS-11)以产生80-100%感染的浓度加入到每一稀释液中。病毒/scFv混合物在加入到MNA细胞上之前在37℃/5%CO2下保温1小时。感染后24小时(在34℃/5%CO2),在4℃用丙酮固定细胞20分钟,用抗狂犬病N-FITC抗体缀合物(Centocor)染色最少3小时。然后在荧光显微镜下分析细胞的狂犬病病毒感染以确定50%终点稀释度。这是在这一分析中病毒感染被阻断50%的稀释度(见实施例1)。鉴别了几种scFv,它们显示出对狂犬病病毒的中和活性(见表10)。
另外,通过如上所述的体外中和分析(修改的RFFIT)研究了是否选择的scFv能中和实施例1制备的E57逃逸病毒(E57A2、E57A3、E57B1、E57B2、E57B3和E57C3)。鉴别了几种scFv,它们显示出对E57逃逸病毒的中和活性(见表11A和11B)。
实施例7
使用scFv的狂犬病病毒G蛋白竞争ELISA
为鉴别与非重叠的非竞争的表位结合的抗体,进行了狂犬病糖蛋白竞争ELISA。用在PBS(50μl)中的1∶1000稀释的纯化狂犬病病毒糖蛋白(1mg/ml;狂犬病病毒ERA毒株)在4℃包被Nunc-ImmunoTMMaxisorp F96板(Nunc)过夜。洗掉未包被的蛋白质,之后孔用100μl的PBS/1%补体素在室温封闭1小时。随后弃掉封闭溶液并加入50μl于PBS/1%补体素中的未纯化的抗狂犬病病毒scFv(2x稀释的)。孔用100μl的PBS/0.05%Tween-20洗5次。然后,向每孔加入50μl生物素化抗狂犬病病毒竞争物IgG,CR-57bio,在室温保温5分钟,孔用100μl的PBS/0.05%Tween-20洗5次。为检测CR-57bio的结合,将50μl的1∶2000稀释的链霉亲和素-HRP抗体(Becton Dickinson)加入到孔中并在室温保温1小时。如上所述再次洗孔,通过加入100μlOPD试剂(Sigma)而进一步显色ELISA。通过加入50μl的1M H2SO4终止反应,在492nm测量OD。
当与scFv SO57,即CR-57的scFv形式(SO57的核苷酸和氨基酸序列分别见SEQ ID NO:205和206)或scFv SOJB,即CR-JB的scFv形式(SOJB的核苷酸和氨基酸序列分别见SEQ ID NO:312和313)共保温时,用CR-57bio单独获得的信号可被降低至背景水平。这表明scFv SO57和SOJB通过与CR-57bio结合相同表位或重叠表位而竞争分别竞争CR-57bio与狂犬病病毒糖蛋白的相互作用。相反,称为SC02-007的无关scFv,即与CD8结合的scFv不竞争结合。称为SC04-004、SC04-010、SC04-024、SC04-060、SC04-073、SC04-097、SC04-098、SC04-103、SC04-104、SC04-120、SC04-125、SC04-127、SC04-140、SC04-144和SC04-146的抗狂犬病病毒scFv不与CR-57bio竞争,提示这些scFv结合与CR-57识别的表位不同的表位(见图4)。
用下述实验获得类似的结果。首先,向用狂犬病病毒G蛋白包被的孔中加入狂犬病病毒抗体CR-57。接着,加入竞争scFv。在这一设置中,抗狂犬病病毒scFv用抗VSV-HRP根据scFv氨基酸序列中VSV-tag的存在而检测(见图5)。
实施例8
从选择的抗狂犬病病毒单链Fv’s构建完全人免疫球蛋白分子(人单克隆抗狂犬病病毒抗体)
称为SC04-001、SC04-008、SC04-018、SC04-040和SC04-126的scFv的重链和轻链可变区用寡核苷酸进行PCR扩增以附加限制位点和/或序列以分别在IgG表达载体pSyn-C03-HCγ1(见SEQ ID No:277)和pSyn-C04-Cλ(见SEQ ID No:278)中表达。分别用表12和13所示寡核苷酸扩增VH和VL基因,将PCR产物分别克隆进载体pSyn-C03-HCγ1和pSyn-C04-Cλ。
称为SC04-004、SC04-010、SC04-021、SC04-026、SC04-031、SC04-038、SC04-060、SC04-073、SC04-097、SC04-098、SC04-103、SC04-104、SC04-108、SC04-120、SC04-125、SC04-140、SC04-144、SC04-146和SC04-164的scFv的重链和轻链可变区也用寡核苷酸进行PCR扩增以附加限制位点和/或序列以分别在IgG表达载体pSyn-C03-HCγ1和pSyn-C05-Cκ(见SEQ ID No:279)中表达。分别用表12和13所示寡核苷酸扩增VH和VL基因,将PCR产物分别克隆进载体pSyn-C03-HCγ1和pSyn-C05-Cκ中。寡核苷酸的设计是使得它们改正来自种系序列的任何偏差,这些偏差是在文库构建过程中由于用来扩增庞大数量的抗体基因的寡核苷酸组数量有限而导入的。根据本领域技术人员已知的标准技术验证了所有构建体的核苷酸序列。
所得到的编码抗狂犬病病毒人IgG1重链的表达构建体pgG104-001C03、pgG104-008C03、pgG104-018C03、pgG104-040C03和pgG104-126C03与编码相应轻链的相关pSyn-C04-Vλ构建体组合在293T细胞中瞬时表达,并获得含有IgG1抗体的上清。编码抗狂犬病病毒人IgG1重链的表达载体pgG104-004C03、pgG104-010C03、pgG104-021C03、pgG104-026C03、pgG104-031C03、pgG104-038C03、pgG104-060C03、pgG104-073C03、pgG104-097C03、pgG104-098C03、pgG104-103C03、pgG104-104C03、pgG104-108C03、pgG104-120C03、pgG104-125C03、pgG104-140C03、pgG104-144C03、pgG104-146C03和pgG104-164C03与编码相应轻链的相关pSyn-C05-Vκ构建体组合在293T细胞中瞬时表达,并获得含有IgG1抗体的上清。
根据标准技术确定了称为CR04-001、CR04-004、CR04-008、CR04-010、CR04-018、CR04-021、CR04-026、CR04-031、CR04-038、CR04-040、CR04-060、CR04-073、CR04-097、CR04-098、CR04-103、CR04-104、CR04-108、CR04-120、CR04-125、CR04-126、CR04-140、CR04-144、CR04-146和CR04-164的抗体的重链和轻链的核苷酸和氨基酸序列。随后,用通常用于免疫球蛋白的标准纯化方法(参见例如WO00/63403,引入本文作参考)在蛋白质-A柱上、随后在脱盐柱上缓冲液交换而纯化所述重组人单克隆抗体。
另外,对于CR04-098,根据针对分别编码CR-57和CR-JB的载体pgSO57C11和pgSOJBC11所述(见实施例1)产生称为pgG104-098C10的单人IgG1表达载体。由载体pgG104-098C10编码的抗体CR04-098的重链和轻链的核苷酸和氨基酸序列分别示于SEQID NO:334-337。载体pgSO57C11(见实施例1)和pgG104-098C10分别用于在细胞中稳定表达CR-57和CR04-098,所述细胞来自在1996年2月29日保藏在欧洲动物细胞保藏中心(ECACC),CAMR,Salisbury,Wiltshire SP4OJG,Great Britain的保藏号为96022940的细胞系,该细胞系以PER.C6_的商标在市场上销售。稳定产生的CR-57和CR04-098的计算等电点分别为8.22和8.46。实验观察到的CR-57的等电点在8.1-8.3之间,CR04-098的在9.0-9.2之间。重组人单克隆抗体如上所述纯化。除非另外描述,对于CR04-001、CR04-004、CR04-008、CR04-010、CR04-018、CR04-021、CR04-026、CR04-031、CR04-038、CR04-040、CR04-060、CR04-073、CR04-097、CR04-098、CR04-103、CR04-104、CR04-108、CR04-120、CR04-125、CR04-126、CR04-140、CR04-144、CR04-146和CR04-164,使用由上述两个载体系统瞬时表达的重组人单克隆抗体,对于CR57,使用由实施例1所述的一个载体系统瞬时表达的重组人单克隆抗体。
实施例9
使用IgG的狂犬病病毒G蛋白竞争ELISA
为确定所述人单克隆抗狂犬病病毒G蛋白IgG是否结合非重叠的非竞争性表位,进行竞争实验。具有包被的狂犬病病毒G蛋白的孔用增加浓度(0-50μg/ml)的未标记的抗狂犬病病毒G蛋白IgG在室温保温1小时。然后,向每孔中加入50μl不同的生物素化的抗狂犬病病毒IgG(1μg/ml),在室温保温5分钟,立即用100μl的PBS/0.05%Tween-20洗5次。随后在室温将孔与50μl的1∶2000稀释的链霉亲和素-HRP(Becton Dickinson)保温1小时,洗涤并如上所述显色。随着未标记IgG浓度增加信号降低,表明这两种抗体互相竞争并识别相同表位或重叠表位。
或者,将用狂犬病病毒G蛋白(ERA毒株)包被的孔与50μg/ml未标记的抗狂犬病病毒G蛋白IgG在室温保温1小时。然后向每孔加入50μl生物素化CR57(0.5-5μg/ml;不完全饱和水平)。如上所述进行进一步的步骤。将获得的信号与仅用生物素化CR57获得的信号进行比较(见图6;无竞争剂)。从图6可以推出使用作为阴性对照的称为CR02-428的抗体的信号不降低。相反,用未标记的CR57(阳性对照)或CR-JB的竞争降低信号至背景水平。从图6可进一步推出抗狂犬病病毒G蛋白IgG无一与CR-57显著竞争,这与实施例7描述的scFv竞争数据一致。
另外,通过流式细胞术在狂犬病病毒G蛋白(ERA毒株)转染的PER.C6细胞上进行竞争实验。转染的细胞与20μl未标记的抗狂犬病病毒G蛋白IgG(50μg/ml)在4℃保温20分钟。在用含1%BSA的PBS洗涤细胞后,向每孔中加入20μl生物素化的CR57(0.5-5μg/ml;在不完全饱和水平),在4℃保温5分钟,立即用100μl含1%BSA的PBS洗2次。随后,将孔与20μl的1∶200稀释的链霉亲和素-PE(Caltag)在4℃保温15分钟,洗涤并如上所述显色。用生物素化CR57获得的信号不能用阴性对照抗体CR02-428显著降低(见图7)。相反,用未标记的CR57(阳性对照)或CR-JB的竞争降低信号至背景水平。抗狂犬病病毒G蛋白IgG无一与CR-57显著竞争,例外是CR04-126,其降低信号至大约30%(见图7)。后者在ELISA中不竞争(见图6)。这可能是由于在FACS实验中糖蛋白被呈递给抗体的方式与ELISA实验不同而导致的。CR04-126的结合可能更依赖于糖蛋白的构象,导致在基于FACS的竞争分析中用CR04-126观察到竞争性作用,而在基于ELISA的分析中未观察到。另外,CR04-008和CR04-010在基于FACS的竞争分析中降低信号至约50%(见图7),说明它们可能与CR57竞争。对于CR04-010,这却没有被scFv竞争数据或基于ELISA的竞争分析证实。对于其它的IgG,FACS数据与各自的scFv和IgG的ELISA数据一致。
实施例10
抗狂犬病IgG在狂犬病病毒的体外中和作用中的加性/协同效应(修改的RFFIT)
为了确定抗狂大病病毒G蛋白IgG在狂犬病病毒中和作用中是否具有加性或协同效应,测试不同组合的IgG。首先,每种抗体的效力(以IU/mg表示)在一修改的RFFIT中确定(见实施例1)。然后,基于等量的IU/mg制备抗体组合并在修改的RFFIT中测试。可确定每种抗体组合的效力并与预期效力进行比较。如果抗体组合的效力等于组合中存在的每种抗体的效力之和,则这些抗体具有加性效应。如果抗体组合的效力更高,则这些抗体在狂犬病病毒中和中具有协同效应。
或者,可通过下述实验确定加性或协同效应。首先,在一标准RFFIT(参见Laboratory techniques in rabies,Edited by:F.-X Meslin,M.M.Kaplan and H.Koprowski(1996),4th edition,Chapter 15,WorldHealth Organization,Geneva)中确定待测抗体例如CR-57和CR04-098的效力。然后,将这些抗体以基于IU/ml为1∶1的比例混合。这一抗体混合物与相同浓度的各个抗体一起在六个独立的RFFIT实验中被测试以确定50%中和终点。随后用由Chou et al.(1984)描述的公式CI=(C1/Cx1)+(C2/Cx2)+(C1C2/Cx1Cx2)确定抗体混合物的组合指数(CI)。C1和C2是当组合应用时导致50%中和的单克隆抗体1和单克隆抗体2的量(以μg表示),Cx1和Cx2是当单独应用时导致50%中和的单克隆抗体1和单克隆抗体2的量(以μg表示)。CI=1表示单克隆抗体的加性效应,CI<1表示单克隆抗体的协同效应,CI>表示单克隆抗体的拮抗效应。
实施例11
通过PEPSCAN-ELISA鉴别由重组人抗狂犬病病毒抗体识别的表位
从狂犬病病毒毒株ERA的G蛋白的胞外结构域(狂犬病病毒毒株ERA的糖蛋白G的完整氨基酸序列见SEQ ID NO:207,胞外结构域由氨基酸20-458组成;在EMBL数据库中狂犬病病毒毒株ERA的糖蛋白的蛋白质id为J02293)合成15-mer线性和环(looped)/环状(cyclic)肽,并如前所述(Slootstra et al.,1996;WO 93/09872)用信用卡(credit-card)形式的mini-PEPSCAN卡(455个肽形式/卡)进行筛选。所有的肽均在氨基末端进行乙酰化。在所有环肽中,第2位和第14位用半胱氨酸置换(乙酰-XCXXXXXXXXXXXCX-minicard)。如果在制备的肽中除了第2位和第4位的半胱氨酸之外还存在其它半胱氨酸,则用丙氨酸置换所述其它半胱氨酸。用标准Fmoc化学合成环肽并用三氟酸和清除剂去保护。随后,去保护的肽在卡上与在碳酸氢铵(20mM,pH7.9/乙腈(1∶1(v/v))中的0.5mM 1,3-双(溴甲基)苯溶液反应。将卡完全浸在溶液中,同时在该溶液中轻轻摇动卡30-60分钟。最后,用过量的H2O彻底洗卡并在含1%SDS/0.1%β-巯基乙醇的PBS(pH7.2)的破坏缓冲液中于70℃超声30分钟,随后在H2O中再超声45分钟。人单克隆抗体如上所述制备。在基于PEPSCAN的酶联免疫测定(ELISA)中测试这些抗体与每一线性和环肽的结合。将含有共价连接的肽的455孔信用卡形式的聚丙烯卡与抗体(10μg/ml;在封闭溶液中稀释,该封闭溶液含有5%马血清(v/v)和5%卵清蛋白(w/v))保温(4℃,过夜)。洗涤后,将肽与抗人抗体过氧化物酶(稀释度1/1000)保温(1小时,25℃),随后,在洗涤后加入过氧化物酶底物2,2′-连氮-二-3-乙基苯并噻唑磺酸(2,2’-azino-di-3-ethylbenzthiazoline sulfonate,ABTS)和2μl/ml 3%H2O2。对照(针对线性和环肽)仅与抗人抗体过氧化物酶保温。1小时后,测量颜色生成。用CCD相机和图像处理系统量化ELISA的颜色生成。设备包括CCD相机和55mm镜头(Sony CCD Video CameraXC-77RR,Nikon micro-nikkor 55mm f/2.8镜头)、相机适配器(SonyCamera adaptor DC-77RR)和图像处理软件包Optimas,版本6.5(Media Cybernetics,Silver Spring,MD 20910,U.S.A.)。Optimas在奔腾II计算机系统上运行。
测试了人抗狂犬病病毒G蛋白单克隆抗体与如上所述合成的15-mer线性和环/环状肽的结合。当OD值等于或高于所有肽的平均OD值(每抗体)的两倍时,该肽被认为是相关地结合一抗体。表14列出了称为CR57、CRJB和CR04-010的人单克隆抗体与狂犬病病毒毒株ERA的糖蛋白G的胞外结构域的线性肽的结合结果。显示与各个抗体显著结合的区域用灰色高亮显示(见表14)。
抗体CR57与具有选自如下一组的氨基酸序列的线性肽结合:SLKGACKLKLCGVLG(SEQ ID NO:314)、LKGACKLKLCGVLGL(SEQ ID NO:315)、KGACKLKLCGVLGLR(SEQ ID NO:316)、GACKLKLCGVLGLRL(SEQ ID NO:317)、ACKLKLCGVLGLRLM(SEQ ID NO:318)、CKLKLCGVLGLRLMD(SEQ ID NO:319)、KLKLCGVLGLRLMDG(SEQ ID NO:320)、LKLCGVLGLRLMDGT(SEQ ID NO:321)和KLCGVLGLRLMDGTW(SEQ ID NO:322)(见表14)。具有氨基酸序列GACKLKLCGVLGLRL(SEQ ID NO:317)、ACKLKLCGVLGLRLM(SEQ ID NO:318)的肽的OD值比平均值的两倍低。但是仍请求保护这些肽,因为它们在由抗体CR57识别的抗原肽区域的邻近。与具有氨基酸序列KLCGVLGLRLMDGTW(SEQID NO:322)的肽的结合是最显著的。
抗体CR04-010与具有选自如下一组的氨基酸序列的线性肽结合:GFGKAYTIFNKTLME(SEQ ID NO:323)、FGKAYTIFNKTLMEA(SEQ ID NO:324)、GKAYTIFNKTLMEAD(SEQ ID NO:325)、KAYTIFNKTLMEADA(SEQ ID NO:326)、AYTIFNKTLMEADAH(SEQ ID NO:327)、YTIFNKTLMEADAHY(SEQ ID NO:328)、TIFNKTLMEADAHYK(SEQ ID NO:329)、IFNKTLMEADAHYKS(SEQ ID NO:330)和FNKTLMEADAHYKSV(SEQ ID NO:331)。具有氨基酸序列AYTIFNKTLMEADAH(SEQ ID NO:327)、YTIFNKTLMEADAHY(SEQ ID NO:328)的肽的OD值比平均值的两倍低。但是仍请求保护这些肽,因为它们在由抗体CR04-010识别的抗原肽区域的邻近。与具有氨基酸序列TIFNKTLMEADAHYK(SEQID NO:329)、IFNKTLMEADAHYKS(SEQ ID NO:330)和FNKTLMEADAHYKSV(SEQ ID NO:331)的肽的结合是最显著的。
CRJB和称为CR04-040、CR04-098和CR04-103的抗体(数据未示出)不识别线性抗原肽的区域。
任何上述肽或其部分均代表狂犬病病毒中和表位的良好候选者,并且可以形成疫苗的基础或者形成产生中和抗体以治疗和/或预防狂犬病病毒感染的基础。
基于它们在PEPSCAN中的高反应性,SLKGACKLKLCGVLGLRLMDGTW(SEQ ID NO:332)和GFGKAYTIFNKTLMEADAHYKSV(SEQ ID NO:333)是特别感兴趣的糖蛋白区域。
从上述PEPSCAN数据可进一步推出称为CR57和CR04-010的人单克隆抗体与狂犬病病毒G蛋白的不同区域结合,表明它们识别非竞争性表位。
实施例12
用体外中和分析(修改的RFFIT)确定抗狂犬病G蛋白IgG的中和效力
在如实施例1所述的修改的RFFIT中确定每种所产生的人单克隆抗体的中和效力。16种IgG中和狂犬病毒株CVS-11的效力高于1000IU/mg,而仅有两种IgG的效力低于2IU/mg(见表15)。16种抗体中有8种比瞬时产生的CR-57的效力强,提示在狂犬病病毒的暴露后预防中比CR-57有更高的效率。瞬时产生的CR-57的效力约为3800IU/mg蛋白质(见表1和表15),而稳定产生的CR-57展示出效力为5400IU/mg蛋白质(数据未示出)。令人感兴趣地,所鉴别的大多数中和人单克隆抗体含有可变重链3-30种系基因(见表9)。
基于抗体对狂犬病病毒的亲和性(数据未示出)和在修改的RFFIT分析中的抗体的100%终点稀释度(数据未示出),选择一组6个独特的IgG,即CR04-010、CR04-040、CR04-098、CR04-103、CR04-104和CR04-144进行进一步开发。在这一组中,抗体CR04-098是特别令人感兴趣的,因为其显示出最高的效力,即约7300IU/mg蛋白质(见表15)。对于稳定产生的CR04-098也发现类似的效力(数据未示出)。
实施例13
用抗狂犬病病毒IgG体外中和E57逃逸病毒
为进一步鉴定新的人单克隆抗狂犬病抗体,在如上所述的修改的RFFIT中测试这些IgG对E57逃逸病毒的中和活性。大多数抗狂犬病病毒IgG有对全部6种E57逃逸病毒的良好中和活性(见表16)。相反,CR04-008、CR04-018和CR04-126分别不中和6/6、2/6和3/6E57逃逸病毒。不中和意味着在1∶100抗体稀释度未达到50%终点(endpoint)。CR04-021、CR04-108、CR04-120、CR04-125和CR04-164显示出对一些逃逸病毒的中和活性显著下降。这提示这些抗体的表位在E57逃逸病毒糖蛋白中已受到直接或间接影响。基于以上,一些抗狂犬病病毒IgG可能与用于暴露后预防治疗的抗狂犬病混合物中的CR-57相容。特别地,如上鉴别的一组6个独特的IgG,即抗体CR04-010、CR04-040、CR04-098、CR04-103、CR04-104和CR04-144,展示了针对E57逃逸病毒的良好中和效力,提示这些抗体识别的表位未被CR-57诱导的氨基酸突变影响。抗体CR04-098似乎是最有前途的,因为它对每种逃逸病毒均具有高于3000IU/mg的效力。
实施例14
抗狂犬病抗体CR-57和CR04-098的表位识别
为了证实称为CR-57和CR04-098的人单克隆抗体识别非重叠的非竞争表位,基本上根据针对CR57的逃逸病毒所描述的那样(见实施例1)产生称为CR04-098的人单克隆抗体的逃逸病毒。简单地说,通过免疫荧光记录每孔转化灶数,选择优选地含有1个转化灶的孔的培养基进行病毒扩增。从1个单转化灶产生除E98-2(2个转化灶)和E98-4(4个转化灶)之外的所有的E98逃逸病毒。如果中和指数<2.5log,则病毒被限定为逃逸变体。中和指数如下确定:从用病毒单独感染的BSR或MNA细胞培养物中产生的感染性病毒颗粒数/ml中减去用病毒加上单克隆抗体(约4IU/ml)感染的BSR细胞培养物中产生的感染性颗粒数/ml([(log在单克隆抗体不存在时的转化灶形成单位/ml病毒)减去(log在单克隆抗体存在时的ffu/ml病毒)])。指数低于2.5log被认为是逃逸的证据。
为进一步研究与CR-57相比,CR04-098与不同的非重叠非竞争性表位结合,在如上所述的修改的RFFIT分析中针对E98逃逸病毒测试CR-57。如表17所示,CR-57针对全部5种E98逃逸病毒均具有良好的中和活性。另外,测试了抗体CR04-010和CR04-144对E98逃逸病毒的中和活性。两种抗体均不中和E98逃逸病毒(数据未示出),提示由两种抗体识别的表位受抗体CR04-098所诱导的氨基酸突变的直接或间接影响。测试了抗体CR04-018和CR04-126对E98逃逸病毒中的一种即E98-4的中和活性。CR04-018能够中和该逃逸病毒,而CR04-126对该逃逸病毒仅有弱的中和效力。这提示由CR04-018识别的表位不受抗体CR04-098所诱导的突变的影响。另外,抗体CR04-010、CR04-038、CR04-040、CR04-073、CR04-103、CR04-104、CR04-108、CR04-120、CR04-125、CR04-164不中和E98-4,提示它们与CR04-098识别相同的表位(数据未示出)。
为了鉴别每种E98逃逸病毒的狂犬病糖蛋白中可能的突变,根据以前针对E57和EJB逃逸病毒所述的那样确定该糖蛋白开放读框(ORF)的核苷酸序列。所有的E98逃逸病毒均显示在狂犬病糖蛋白的第336位氨基酸有N变为D的突变(见图8)。这一糖蛋白区域已被定义为抗原位点III,其包含第330-338位氨基酸(不计信号肽的编号)。相反,CR-57识别位于第226-231位氨基酸(不计信号肽的编号)的表位,其与抗原位点I重叠。除了N336D突变外,称为E98-5的E98逃逸病毒显示在狂犬病糖蛋白第354位氨基酸的H变为Q的突变(CAT变为CAG的密码子改变)(数据未示出)。
另外,对CR57与携带突变的CR57表位的肽结合(如在E57逃逸病毒中观察到的)的pepscan分析确实示出CR57的相互作用被破坏(数据未示出)。令人注目的是,流式细胞术测得CR04-098仍能够与PER.C6_细胞上表达的突变糖蛋白(包含N336D突变)结合(数据未示出),尽管含有这一突变的病毒不再被中和。
另外,用BIAcore3000TM分析系统经表面等离子共振分析进行了表位作图研究和亲和性排序研究。用胺偶联技术将纯化的狂犬病糖蛋白(ERA毒株)作为配体固定化在研究级CM54流路(flow channel,Fc)传感器芯片(Biacore AB,Sweden)上。排序是在25℃用HBS-EP(Biacore AB,Sweden)作为流动缓冲液而进行。将50μl每种抗体以20μl/min的恒定流速注入。然后,加入流动缓冲液750秒,随后用5μl2M NaOH、5μl 45mM HCl和5μl 2mM NaOH再生CM5芯片。将以共振单位(RU)表示的共振信号作为时间的函数作图,确定分别作为缔合和解离测量标准的RU的增加和减少,并用作抗体的排序。通过表面等离子共振测得的CR57和CR04-098的实际KD值分别是2.4nM和4.5nM。表位作图研究进一步证实CR57和CR04-098与狂犬病糖蛋白上的不同表位结合。注入CR57产生了58RU的应答(数据未示出)。在注入CR04-098后,获得了应答水平的额外增加(24RU),提示针对CR04-098的结合位点未被占据(数据未示出)。当采用相反顺序时,观察到类似结果,表明无论注入顺序如何,每一抗体均达到类似RU水平(数据未示出)。这些结果进一步证实CR57和CR04-098可同时结合和识别狂犬病病毒糖蛋白上的不同表位。
总之,上述数据进一步证实抗体CR-57和CR04-098识别不同的非重叠表位,即分别为抗原位点I和III中的表位。这些数据与ELISA/FACS竞争数据非常符合,该竞争数据表明CR-57和CR04-098不竞争结合ERAG以及抗体CR04-098对所有E57逃逸病毒的良好中和活性。基于这些结果以及将狂犬病病毒体外暴露于CR57和CR04-098的组合(在4IU/ml每种抗体存在下的选择)不产生逃逸病毒(数据未示出)这一事实,得出如下结论:抗体CR-57和CR04-098识别非重叠的非竞争性表位,并且可以被有利地用于抗狂犬病病毒抗体混合物中以进行暴露后预防治疗。
实施例15
评估由CR57和CR04-098识别的表位的保守性
将CR-57的最小结合区(SEQ ID NO:332内的氨基酸KLCGVL,由PEPSCAN和丙氨酸扫描技术确定的由CR57识别的狂犬病病毒糖蛋白区域)与229个基因型1狂犬病病毒分离株的核苷酸序列进行序列比对以评估该表位的保守性(见表18)。样品组含有人分离株、蝙蝠分离株和来自犬类的或来自最易受患有狂犬病的犬类攻击的家畜的分离株。在该最小结合区内每一位置的氨基酸的频率分析揭示了组成该表位的关键残基是高度保守的。在第1位的赖氨酸在99.6%的分离株中是保守的,而仅在1/229分离株中观察到保守的K>R突变。第2位和第3位(L和C)是完全保守的。据信中心的半胱氨酸残基在结构上参与糖蛋白折叠并且在所有狂犬病属病毒中是保守的(参见Badrane and Tordo,2001)。第4位的甘氨酸在98.7%的分离株中是保守的,而在3/229分离株中观察到朝向带电荷氨基酸的突变(在1/229中有G>R;在2/229中有G>E)。第5位也是保守的,只在一个分离株中有例外,在该分离株中观察到保守的V>I突变。在由丙氨酸置换扫描确定为非关键残基的第6位,在街毒分离株中观察到显著的异质性:在70.7%毒株中为L,在26.7%毒株中为P,在2.6%毒株中为S。加在一起,预计约99%的可以遇到的狂犬病病毒被CR-57抗体识别。
对这229个病毒分离株中的123个分析了CR-57和CR04-098表位中突变的存在。这123个街毒分离株中无一在两个表位中含有突变。在E98逃逸病毒中观察到的N>D突变仅在5个病毒分离株中存在。这些病毒地域上是独立的并分离自非洲的动物(参见图9的系统发生树;这5个病毒分离株即AF325483、AF325482、AF325481、AF325480和AF325485,以粗体示出)。糖蛋白序列的系统发生分析揭示具有突变的CR57表位的狂犬病病毒仅与携带突变的CR04-098表位的狂犬病病毒远缘相关。因此,遇到对CR-57和CR04-098的混合物所致的中和作用有抗性的狂犬病病毒的可能性基本上是不存在的。
表1:CR-57和CR-JB对野生型和逃逸病毒的中和效力
病毒 | 效力CR-57(IU/mg) | 效力CR-JB(IU/mg) | 病毒 | 效力CR-57(IU/mg) | 效力CR-JB(IU/mg) | |
CVS-11 | 3797 | 605 | CVS-11 | 3797 | 605 | |
E57A2 | 0 | <0.2 | EJB2B | 0.004 | 0.6 | |
E57A3 | 0 | 419 | EJB2C | <0.004 | 2 | |
E57B1 | 0 | 93 | EJB2D | <0.004 | 3 | |
E57B2 | 0 | <0.3 | EJB2E | <0.2 | <0.3 | |
E57B3 | 0 | 419 | EJB2F | <0.06 | 3 | |
E57C3 | 0 | 31 | EJB3F | <0.04 | 0.06 |
表2:人λ链可变区引物(有义)
引物名称 | 引物核苷酸序列 | SEQ ID NO |
HuVλ1A | 5′-CAGTCTGTGCTGACTCAGCCACC-3′ | SEQ ID NO:208 |
HuVλ1B | 5′-CAGTCTGTGYTGACGCAGCCGCC-3′ | SEQ ID NO:209 |
HuVλ1C | 5′-CAGTCTGTCGTGACGCAGCCGCC-3′ | SEQ ID NO:210 |
HuVλ2 | 5′-CARTCTGCCCTGACTCAGCCT-3′ | SEQ ID NO:211 |
HuVλ3A | 5′-TCCTATGWGCTGACTCAGCCACC-3′ | SEQ ID NO:212 |
HuVλ3B | 5′-TCTTCTGAGCTGACTCAGGACCC-3′ | SEQ ID NO:213 |
HuVλ4 | 5′-CACGTTATACTGACTCAACCGCC-3′ | SEQ ID NO:214 |
HuVλ5 | 5′-CAGGCTGTGCTGACTCAGCCGTC-3′ | SEQ ID NO:215 |
HuVλ6 | 5′-AATTTTATGCTGACTCAGCCCCA-3′ | SEQ ID NO:216 |
HuVλ7/8 | 5′-CAGRCTGTGGTGACYCAGGAGCC-3′ | SEQ ID NO:217 |
HuVλ9 | 5′-CWGCCTGTGCTGACTCAGCCMCC-3′ | SEQ ID NO:218 |
表3:人κ链可变区引物(有义)
引物名称 | 引物核苷酸序列 | SEQ ID NO |
HuVκ1B | 5′-GACATCCAGWTGACCCAGTCTCC-3′ | SEQ ID NO:219 |
HuVκ2 | 5′-GATGTTGTGATGACTCAGTCTCC-3′ | SEQ ID NO:220 |
HuVκ3 | 5′-GAAATTGTGWTGACRCAGTCTCC-3′ | SEQ ID NO:221 |
HuVκ4 | 5′-GATATTGTGATGACCCACACTCC-3′ | SEQ ID NO:222 |
HuVκ5 | 5′-GAAACGACACTCACGCAGTCTCC-3′ | SEQ ID NO:223 |
HuVκ6 | 5′-GAAATTGTGCTGACTCAGTCTCC-3′ | SEQ ID NO:224 |
表4:用SalI限制位点延伸的人k链可变区引物(有义),用NotI限制位点延伸的人k链J-区引物(反义),用SalI限制位点延伸的人λ链可变区引物(有义)和用NotI限制位点延伸的人λ链J-区引物(反义)
引物名称 | 引物核苷酸序列 | SEQ ID NO |
HuVκ1B-SalI | 5′-TGAGCACACAGGTCGACGGACATCCAGWTGACCCAGTCTCC-3′ | SEQ ID NO:225 |
HuVκ2-SalI | 5′-TGAGCACACAGGTCGACGGATGTTGTGATGACTCAGTCTCC-3′ | SEQ ID NO:226 |
HuVκ3B-SalI | 5′-TGAGCACACAGGTCGACGGAAATTGTGWTGACRCAGTCTCC-3′ | SEQ ID NO:227 |
HuVκ4B-SalI | 5′-TGAGCACACAGGTCGACGGATATTGTGATGACCCACACTCC-3′ | SEQ ID NO:228 |
HuVκ5-SalI | 5′-TGAGCACACAGGTCGACGGAAACGACACTCACGCAGTCTCC-3′ | SEQ ID NO:229 |
HuVκ6-SalI | 5′-TGAGCACACAGGTCGACGGAAATTGTGCTGACTCAGTCTCC-3′ | SEQ ID NO:230 |
HuJκ1-NotI | 5′-GAGTCATTCTCGACTTGCGGCCGCACGTTTGATTTCCACCTTGGTCCC-3′ | SEQ ID NO:231 |
HuJκ2-NotI | 5′-GAGTCATTCTCGACT | SEQ ID NO:232 |
TGCGGCCGCACGTTTGATCTCCAGCTTGGTCCC-3′ | ||
HuJκ3-NotI | 5′-GAGTCATTCTCGACTTGCGGCCGCACGTTTGATATCCACTTTGGTCCC-3′ | SEQ ID NO:233 |
HuJκ4-NotI | 5′-GAGTCATTCTCGACTTGCGGCCGCACGTTTGATCTCCACCTTGGTCCC-3′ | SEQ ID NO:234 |
HuJκ5-NotI | 5′-GAGTCATTCTCGACTTGCGGCCGCACGTTTAATCTCCAGTCGTGTCCC-3′ | SEQ ID NO:235 |
HuVλ1A-SalI | 5′-TGAGCACACAGGTCGACGCAGTCTGTGCTGACTCAGCCACC-3′ | SEQ ID NO:236 |
HuVλ1B-SalI | 5′-TGAGCACACAGGTCGACGCAGTCTGTGYTGACGCAGCCGCC-3′ | SEQ ID NO:237 |
HuVλ1C-SalI | 5′-TGAGCACACAGGTCGACGCAGTCTGTCGTGACGCAGCCGCC-3′ | SEQ ID NO:238 |
HuVλ2-SalI | 5′-TGAGCACACAGGTCGACGCARTCTGCCCTGACTCAGCCT-3′ | SEQ ID NO:239 |
HuVλ3A-SalI | 5′-TGAGCACACAGGTCGACGTCCTATGWGCTGACTCAGCCACC-3′ | SEQ ID NO:240 |
HuVλ3B-SalI | 5′-TGAGCACACAGGTCGACGTCTTCTGAGCTGACTCAGGACCC-3′ | SEQ ID NO:241 |
HuVλ4-SalI | 5′-TGAGCACACAGGTCGACGCACGTTATACTGACTCAACCG | SEQ ID NO:242 |
CC-3′ | ||
HuVλ5-SalI | 5′-TGAGCACACAGGTCGACGCAGGCTGTGCTGACTCAGCCGTC-3′ | SEQ ID NO:243 |
HuVλ6-SalI | 5′-TGAGCACACAGGTCGACGAATTTTATGCTGACTCAGCCCCA-3′ | SEQ ID NO:244 |
HuVλ7/8-SalI | 5′-TGAGCACACAGGTCGACGCAGRCTGTGGTGACYCAGGAGCC-3′ | SEQ ID NO:245 |
HuVλ9-SalI | 5′-TGAGCACACAGGTCGACGCWGCCTGTGCTGACTCAGCCMCC-3′ | SEQ ID NO:246 |
HuJλ1-NotI | 5′-GAGTCATTCTCGACTTGCGGCCGCACCTAGGACGGTGACCTTGGTCCC-3′ | SEQ ID NO:247 |
HuJλ2/3-NotI | 5′-GAGTCATTCTCGACTTGCGGCCGCACCTAGGACGGTCAGCTTGGTCCC-3′ | SEQ ID NO:248 |
HuJλ4/5-NotI | 5′-GAGTCATTCTCGACTTGCGGCCGCACYTAAAACGGTGAGCTGGGTCCC-3′ | SEQ ID NO:249 |
表5:10个级分中不同轻链产物的分布
轻链产物 | 等位基因数 | 级分数 | 等位基因/级分 |
Vk1B/Jk1-5 | 19 | 1and 2 | 9.5 |
Vk2/Jk1-5 | 9 | 3 | 9 |
Vk3B/Jk1-5 | 7 | 4 | 7 |
Vk4B/Jk1-5 | 1 | 5 | 5 |
Vk5/Jk1-5 | 1 | ||
Vk6/Jk1-5 | 3 | ||
Vλ1A/J11-3 | 5 | 6 | 5 |
Vλ1B/J11-3 | |||
Vλ1C/J11-3 | |||
Vλ2/J11-3 | 5 | 7 | 5 |
Vλ3A/J11-3 | 9 | 8 | 9 |
Vλ3B/J11-3 | |||
Vλ4/J11-3 | 3 | 9 | 5 |
Vλ5/J11-3 | 1 | ||
Vλ6/J11-3 | 1 | ||
Vλ7/8/J11-3 | 3 | 10 | 6 |
Vλ9/J11-3 | 3 |
表6:人IgG重链可变区引物(有义)
引物名称 | 引物核苷酸序列 | SEQ ID NO |
HuVH1B/7A | 5′-CAGRTGCAGCTGGTGCARTCTGG-3′ | SEQ ID NO:250 |
HuVH1C | 5′-SAGGTCCAGCTGGTRCAGTCTGG-3′ | SEQ ID NO:251 |
HuVH2B | 5′-SAGGTGCAGCTGGTGGAGTCTGG-3′ | SEQ ID NO:252 |
HuVH3B | 5′-SAGGTGCAGCTGGTGGAGTCTGG-3′ | SEQ ID NO:253 |
HuVH3C | 5′-GAGGTGCAGCTGGTGGAGWCYGG-3′ | SEQ ID NO:254 |
HuVH4B | 5′-CAGGTGCAGCTACAGCAGTGGGG-3′ | SEQ ID NO:255 |
HuVH4C | 5′-CAGSTGCAGCTGCAGGAGTCSGG-3′ | SEQ ID NO:256 |
HuVH5B | 5′-GARGTGCAGCTGGTGCAGTCTGG-3′ | SEQ ID NO:257 |
HuVH6A | 5′-CAGGTACAGCTGCAGCAGTCAGG-3′ | SEQ ID NO:258 |
表7:用SfiI/NcoI限制位点延伸的人IgG重链可变区引物(有义)和用XhoI/BstEII限制位点延伸的人IgG重链J-区引物(反义)
引物名称 | 引物核苷酸序列 | SEQ ID NO |
HuVH1B/7A-SfiI | 5′-GTCCTCGCAACTGCGGCCCAGCCGGCCATGGCCCAGRTGCAGCTGGTGCARTCTGG-3′ | SEQ ID NO:259 |
HuVH1C-SfiI | 5′-GTCCTCGCAACTGCGGCCCAGCCGGCCATGGCCSAGGTCCAGCTGGTRCAGTCTGG-3′ | SEQ ID NO:260 |
HuVH2B-SfiI | 5′-GTCCTCGCAACTGCGGCCCAGCCGGCCATGGCCCAGRTCACCTTGAAGGAGTCTGG-3′ | SEQ ID NO:261 |
HuVH3B-SfiI | 5′-GTCCTCGCAACTGCGGCCCAGCCGGCCATGGCCSAGGTGCAGCTGGTGGAGTCTGG-3′ | SEQ ID NO:262 |
HuVH3C-SfiI | 5′-GTCCTCGCAACTGCGGCCCAGCCGGCCATGGCCGAGGTGCAGCTGGTGGAGWCYGG-3′ | SEQ ID NO:263 |
HuVH4B-SfiI | 5′-GTCCTCGCAACTGCGGCCCAGCCGGCCATGGCCCAGGTGCAGCTACAGCAGTGGGG-3′ | SEQ ID NO:264 |
HuVH4C-SfiI | 5′-GTCCTCGCAACTGCGGCCCAGCCGGCCATGGCCCAGSTG | SEQ ID NO:265 |
CAGCTGCAGGAGTCSGG-3′ | ||
HuVH5B-SfiI | 5′-GTCCTCGCAACTGCGGCCCAGCCGGCCATGGCCGARGTGCAGCTGGTGCAGTCTGG-3′ | SEQ ID NO:266 |
HuVH6A-SfiI | 5′-GTCCTCGCAACTGCGGCCCAGCCGGCCATGGCCCAGGTACAGCTGCAGCAGTCAGG-3′ | SEQ ID NO:267 |
HuJH1/2-XhoI | 5′-GAGTCATTCTCGACTCGAGACGGTGACCAGGGTGCC-3′ | SEQ ID NO:268 |
HuJH3-XhoI | 5′-GAGTCATTCTCGACTCGAGACGGTGACCATTGTCCC-3′ | SEQ ID NO:269 |
HuJH4/5-XhoI | 5′-GAGTCATTCTCGACTCGAGACGGTGACCAGGGTTCC-3′ | SEQ ID NO:270 |
HuJH6-XhoI | 5′-GAGTCATTCTCGACTCGAGACGGTGACCGTGGTCCC-3′ | SEQ ID NO:271 |
表8:ELISA测定的单链(scFv)噬菌体抗体与狂犬病病毒G蛋白(ERA株)和与FBS的结合
噬菌体抗体名称 | 狂犬病病毒G蛋白(OD492nm) | FBS(OD492nm) |
SC04-001 | 0.828 | 0.053 |
SC04-004 | 0.550 | 0.054 |
SC04-008 | 0.582 | 0.058 |
SC04-010 | 0.915 | 0.043 |
SC04-018 | 0.247 | 0.052 |
SC04-021 | 0.278 | 0.052 |
SC04-026 | 0.212 | 0.054 |
SC04-031 | 0.721 | 0.065 |
SC04-038 | 0.653 | 0.061 |
SC04-040 | 0.740 | 0.053 |
SC04-060 | 0.923 | 0.056 |
SC04-073 | 0.657 | 0.054 |
SC04-097 | 0.835 | 0.056 |
SC04-098 | 0.798 | 0.060 |
SC04-103 | 0.606 | 0.059 |
SC04-104 | 0.566 | 0.063 |
SC04-108 | 0.363 | 0.052 |
SC04-120 | 0.571 | 0.052 |
SC04-125 | 0.735 | 0.049 |
SC04-126 | 0.232 | 0.051 |
SC04-140 | 0.865 | 0.057 |
SC04-144 | 0.775 | 0.054 |
SC04-146 | 0.484 | 0.057 |
SC04-164 | 0.547 | 0.057 |
control(SO57) | 0.650 | 0.055 |
control(02-007) | 0.063 | 0.052 |
表9:能结合狂犬病病毒G蛋白的单链Fv′s的数据
名称scFv(libr.) | 核苷酸序列SEQ ID NO | 氨基酸序列SEQ ID NO | HCDR3(SEQ ID NO:) | VH-基因座 | VL-基因座 |
sc04-001(JK1994) | 157 | 158 | GLYGELFDY(SEQ ID NO:1) | 3-20(DP32) | V13(31-V2-13) |
sc04-004(WT2000) | 159 | 160 | DYLYPTTDFDY(SEQ ID NO:2) | 3-23(DP47) | VkI(O12/O2-DPK9) |
sc04-008(RAB-03-G01) | 161 | 162 | MGFTGTYFDY(SEQ ID NO:3) | 2-70(DP28) | V13(3h-V2-14) |
sc04-010(RAB-03-G01) | 163 | 164 | DGLDLTGTIQPFGY(SEQ ID NO:4) | 3-30(DP49) | VkI(L11-DPK3) |
sc04-018(RAB-03-G01) | 165 | 166 | VSVTTGAFNI(SEQ ID NO:5) | 4-04(DP70) | V11(1c-V1-16) |
sc04-021(RAB-03-G01) | 167 | 168 | GSVLGDAFDI(SEQ ID NO:6) | 3-30(DP49) | VkI(L8) |
sc04-026(RAB-03-G01) | 169 | 170 | TSNWNYLDRFDP(SEQ ID NO:7) | 5-51(DP73) | VkII(A19/03-DPK15) |
sc04-031(RAB-03-G01) | 171 | 172 | GSVLGDAFDI(SEQ ID NO:8) | 3-30(DP49) | VkI(L5-DPK5) |
sc04-038(RAB-03-G01) | 173 | 174 | GSVLGDAFDI(SEQ ID NO:9) | 3-30(DP49) | VkI(L5-DPK5) |
sc04-040(RAB-03-G01) | 175 | 176 | GSKVGDFDY(SEQ ID NO:10) | 3-30(DP49) | V13(3h-V2-14) |
sc04-060(RAB-04-G01) | 177 | 178 | EKEKYSDRSGYSYYYYYMDV(SEQ ID NO:11) | 4-59(DP71) | VkI(O12/O2-DPK9) |
sc04-073(RAB-04-G01) | 179 | 180 | DGLDLTGTIQPFGY(SEQ ID NO:12) | 3-30(DP49) | VkI(L12) |
sc04-097(RAB-04-G01) | 181 | 182 | TASNLGRGGMDV(SEQ ID NO:13) | 3-23(DP47) | VkI(L8) |
sc04-098(RAB-04-G01) | 183 | 184 | VAVAGTHFDY(SEQ ID NO:14) | 3-30(DP49) | VkI(A30) |
sc04-103(RAB-04-G01) | 185 | 186 | VAVAGESFDS(SEQ ID NO:15) | 3-30(DP49) | VkI(L5-DPK5) |
sc04-104(RAB-04-G01) | 187 | 188 | IVVVTALDAFDI(SEQ ID NO:16) | 3-30(DP49) | VkI(L12) |
sc04-108(RAB-04-G01) | 189 | 190 | FMIVADDAFDI(SEQ ID NO:17) | 3-30(DP49) | VkI(L1) |
sc04-120(RAB-04-G01) | 191 | 192 | GGKTGEFDY(SEQ ID NO:18) | 3-30(DP49) | VkI(L8) |
sc04-125(RAB-04-G01) | 193 | 194 | IATAGTGFDY(SEQ ID NO:19) | 3-30(DP49) | VkI(L8) |
sc04-126(RAB-04-G01) | 195 | 196 | MGFTGTYFDY(SEQ ID NO:20) | 2-70(DP28) | V13(3h-V2-14) |
sc04-140(RAB-04-G01) | 197 | 198 | VTNPGDAFDI(SEQ ID NO:21) | 3-30(DP49) | VkI(L4/18a) |
sc04-144(RAB-04-G01) | 199 | 200 | GGKTGEFDY(SEQ ID NO:22) | 3-30(DP49) | VkI(L8) |
sc04-146(RAB-04-G01) | 201 | 202 | GGKTGEFDY(SEQ ID NO:23) | 3-30(DP49) | VkIII(L2-DPK21) |
sc04-164(RAB-04-G01) | 203 | 204 | GSVLGDAFDI(SEQ ID NO:24) | 3-30(DP49) | VkI(L19-DPK6) |
SO57 | 205 | 206 | ENLDNSGTYYYFSGWFDP(SEQ ID NO:25) | 1-69(DP10) | V12(2e-V1-3) |
SOJB | 312 | 313 | RQHISSFPWFDS(SEQ IDNO:276) | 2-05 | V13(3h-V2-14) |
表10:scFv狂犬病病毒中和活性分析数据
名称scFv | 50%终点稀释 | 50%终点稀释WHO标准(2IU/ml) | 效力(IU/ml) |
SC04-001 | 270 | 405 | 1.3 |
SC04-004 | 3645 | 405 | 18 |
SC04-008 | >10935 | 405 | >54 |
SC04-010 | 810 | 405 | 4 |
SC04-018 | 15 | 405 | 0.1 |
SC04-021 | 270 | 405 | 1.3 |
SC04-026 | 45 | 270 | 0.3 |
SC04-031 | 90 | 270 | 0.7 |
SC04-038 | 270 | 270 | 2 |
SC04-040 | 45 | 270 | 0.3 |
SC04-060 | 30 | 270 | 0.2 |
SC04-073 | 405 | 270 | 3 |
SC04-097 | 30 | 270 | 0.2 |
SC04-098 | 1215 | 270 | 9 |
SC04-103 | 45 | 270 | 0.3 |
SC04-104 | 135 | 270 | 1 |
SC04-108 | 135 | 270 | 1 |
SC04-120 | 810 | 270 | 6 |
SC04-125 | 405 | 270 | 3 |
SC04-126 | 10 | 270 | 0.1 |
SC04-140 | 135 | 270 | 1 |
SC04-144 | 810 | 270 | 6 |
SC04-146 | 405 | 270 | 3 |
SC04-164 | 45 | 270 | 0.3 |
表11A:测量scFv对E57逃逸病毒E57A2、E57A3和E57B1的中和活性的分析数据
名称scFv | E57A2 | E57A3 | E57B1 | ||||||
1* | 2* | 3* | 1* | 2* | 3* | 1* | 2* | 3* | |
SC04-001 | 10 | 90 | 0.2 | 10 | 90 | 0.2 | 30 | 45 | 1.3 |
SC04-004 | 810 | 90 | 18.0 | 1215 | 90 | 27.0 | 810 | 45 | 36.0 |
SC04-008 | 10 | 90 | 0.2 | 15 | 90 | 0.3 | 270 | 45 | 12.0 |
SC04-010 | 270 | 90 | 6.0 | 270 | 90 | 6.0 | 270 | 45 | 12.0 |
SC04-018 | 5 | 90 | 0.1 | 15 | 90 | 0.3 | 15 | 45 | 0.7 |
SC04-021 | 10 | 90 | 0.2 | 30 | 90 | 0.7 | 10 | 90 | 0.2 |
SC04-026 | <5 | 90 | 0.0 | <5 | 45 | 0.0 | <5 | 90 | 0.0 |
SC04-031 | 10 | 90 | 0.2 | 30 | 90 | 0.7 | 10 | 90 | 0.2 |
SC04-038 | 90 | 90 | 2.0 | 90 | 90 | 2.0 | 45 | 90 | 1.0 |
SC04-040 | 15 | 90 | 0.3 | 5 | 90 | 0.1 | 5 | 90 | 0.1 |
SC04-060 | 5 | 90 | 0.1 | 5 | 90 | 0.1 | <5 | 90 | 0.0 |
SC04-073 | 135 | 90 | 3.0 | 90 | 30 | 6.0 | 30 | 30 | 2.0 |
SC04-097 | <5 | 90 | 0.0 | <5 | 90 | 0.0 | <5 | 90 | 0.0 |
SC04-098 | 810 | 90 | 18.0 | 270 | 30 | 18.0 | 270 | 30 | 18.0 |
SC04-103 | <5 | 90 | 0.0 | 10 | 90 | 0.2 | 5 | 90 | 0.1 |
SC04-104 | 90 | 90 | 2.0 | 30 | 30 | 2.0 | 30 | 30 | 2.0 |
SC04-108 | 15 | 90 | 0.3 | <5 | 90 | 0.0 | <5 | 90 | 0.0 |
SC04-120 | 45 | 90 | 1.0 | 30 | 30 | 2.0 | 10 | 30 | 0.7 |
SC04-125 | 135 | 90 | 3.0 | 135 | 30 | 9.0 | 90 | 30 | 6.0 |
SC04-126 | <5 | 90 | 0.0 | <5 | 45 | 0.0 | <5 | 90 | 0.0 |
SC04-140 | 30 | 45 | 1.3 | 90 | 30 | 6.0 | 45 | 90 | 1.0 |
SC04-144 | 270 | 45 | 12.0 | 270 | 30 | 18.0 | 135 | 90 | 3.0 |
SC04-146 | 90 | 45 | 4.0 | 90 | 30 | 6.0 | 90 | 90 | 2.0 |
SC04-164 | 15 | 45 | 0.7 | 30 | 30 | 2.0 | 15 | 90 | 0.3 |
1*是50%终点稀释
2*是50%终点稀释WHO标准(2IU/ml)
3*是效力(IU/ml)
表11B:测量scFv对E57逃逸病毒E57B2、E57B3和E57C3的中和活性的分析数据
名称scFv | E57B2 | E57B3 | E57C3 | ||||||
1* | 2* | 3* | 1* | 2* | 3* | 1* | 2* | 3* | |
SC04-001 | 30 | 45 | 1.3 | 90 | 270 | 0.7 | 5 | 90 | 0.1 |
SC04-004 | 5 | 45 | 0.2 | 2430 | 270 | 18.0 | 270 | 90 | 6.0 |
SC04-008 | 5 | 45 | 0.2 | 45 | 270 | 0.3 | 10 | 90 | 0.2 |
SC04-010 | 45 | 45 | 2.0 | 405 | 270 | 3.0 | 270 | 90 | 6.0 |
SC04-018 | 15 | 45 | 0.7 | 15 | 270 | 0.1 | 30 | 90 | 0.7 |
SC04-021 | 10 | 90 | 0.2 | 30 | 270 | 0.2 | 10 | 90 | 0.2 |
SC04-026 | <5 | 45 | 0.0 | <5 | 45 | 0.0 | <5 | 30 | 0.0 |
SC04-031 | 10 | 90 | 0.2 | 30 | 270 | 0.2 | 30 | 90 | 0.7 |
SC04-038 | 30 | 90 | 0.7 | 90 | 270 | 0.7 | 90 | 90 | 2.0 |
SC04-040 | 5 | 90 | 0.1 | 15 | 135 | 0.2 | 10 | 90 | 0.2 |
SC04-060 | <5 | 90 | 0.0 | 10 | 135 | 0.1 | 5 | 90 | 0.1 |
SC04-073 | 30 | 90 | 0.7 | 90 | 270 | 0.7 | 90 | 90 | 2.0 |
SC04-097 | <5 | 90 | 0.0 | <5 | 135 | 0.0 | <5 | 90 | 0.0 |
SC04-098 | 90 | 90 | 2.0 | 810 | 270 | 6.0 | 270 | 90 | 6.0 |
SC04-103 | <5 | 90 | 0.0 | 10 | 135 | 0.1 | 10 | 90 | 0.2 |
SC04-104 | 45 | 90 | 1.0 | 45 | 270 | 0.3 | 90 | 90 | 2.0 |
SC04-108 | 10 | 90 | 0.2 | <5 | 135 | 0.0 | 15 | 90 | 0.3 |
SC04-120 | 15 | 90 | 0.3 | 45 | 270 | 0.3 | 30 | 90 | 0.7 |
SC04-125 | 90 | 90 | 2.0 | 270 | 270 | 2.0 | 270 | 90 | 6.0 |
SC04-126 | <5 | 45 | 0.0 | <5 | 45 | 0.0 | <5 | 30 | 0.0 |
SC04-140 | 30 | 90 | 0.7 | 90 | 90 | 2.0 | 270 | 90 | 6.0 |
SC04-144 | 90 | 90 | 2.0 | 270 | 90 | 6.0 | 405 | 90 | 9.0 |
SC04-146 | 30 | 90 | 0.7 | 90 | 90 | 2.0 | 90 | 90 | 2.0 |
SC04-164 | 15 | 90 | 0.3 | 15 | 90 | 0.3 | 30 | 90 | 0.7 |
1*是50%终点稀释
2*是50%终点稀释WHO标准(2IU/ml)
3*是效力(IU/ml)
表12:用于PCR扩增VH基因的寡核苷酸
名称和核苷酸序列 | VH基因 | SEQ ID NO: |
5H-B:acctgtcttgaattctccatggccgaggtgcagctggtggagtctg | SC04-001 | 280 |
5H-C:acctgtcttgaattctccatggcccaggtgcagctggtggagtctgg | SC04-021SC04-031SC04-125SC04-164 | 281 |
5H-C-long:acctgtcttgaattctccatggcccaggtgcagctggtggagtctgggg | SC04-010SC04-038SC04-040SC04-073SC04-098SC04-103SC04-104SC04-108SC04-120SC04-140SC04-144SC04-146 | 282 |
5H-F:acctgtcttgaattctccatggcccaggtgcagctgcaggagtccggccc | SC04-018SC04-060 | 283 |
5H-H:acctgtcttgaattctccatggccgaggtgcagctggtgcagtctgg | SC04-026 | 284 |
5H-I:acctgtcttgaattctccatggccgaggtgcagctgctggagtctgg | SC04-004SC04-097 | 285 |
5H-M:acctgtcttgaattctccatggcccaggtgaccttgaaggagtctgg | SC04-008SC04-126 | 286 |
sy3H-A:gcccttggtgctagcgctggagacggtcaccagggtgccctggcccc | SC04-001SC04-004SC04-008SC04-010SC04-026SC04-040SC04-073SC04-098SC04-120SC04-125SC04-126SC04-144SC04-146 | 287 |
sy3H-C:gcccttggtgctagcgctggagacggtcacggtggtgccctggcccc | SC04-097 | 288 |
sy3H-C-long:gcccttggtgctagcgctggagacggtcacggtggtgcccttgccccagacgtc | SC04-060 | 289 |
sy3H-D:gcccttggtgctagcgctggacacggtcaccatggtgccctggcccc | SC04-018SC04-021SC04-031SC04-038SC04-104SC04-108SC04-140SC04-164 | 290 |
sy3H-E: | SC04-103 | 291 |
gcccttggtgctagcgctggacacggtcaccagggtgccccggcccc |
表13:用于PCR扩增VL基因的寡核苷酸
名称和核苷酸序列 | VL基因 | SEQ ID NO: |
3L-B:ttttccttagcggccgcgactcacctaggacggtcagcttggtc | SC04-001 | 292 |
5K-B:acctgtctcgagttttccatggctgacatccagatgacccagtc | SC04-031SC04-060SC04-073SC04-098SC04-103SC04-104SC04-108SC04-164 | 293 |
5K-C:acctgtctcgagttttccatggctgacatccagatgacccagtctccatcctccc | SC04-004 | 294 |
5K-G:acctgtctcgagttttccatggctgacatcgtgatgacccagtctcc | SC04-026 | 295 |
5K-K:acctgtctcgagttttccatggctgccatccagatgacccagtctcc | SC04-010 | 296 |
5K-M:acctgtctcgagttttccatggctgacatccagctgacccagtc | SC04-021SC04-097SC04-120SC04-125SC04-144 | 297 |
5K-N:acctgtctcgagttttccatggctgacatccagatgactcagtc | SC04-038 | 298 |
5K-O:acctgtctcgagttttccatggctgccatccagctgacccagtc | SC04-140 | 299 |
5K-Q:acctgtctcgagttttccatggctgagatcgtgatgactcagtc | SC04-146 | 300 |
5L-E:acctgtctcgagttttccatggcttcctacgtgctgactcagccg | SC04-008 | 301 |
5L-F:acctgtctcgagttttccatggctcagtccgtgctgactcagcc | SC04-018 | 302 |
5L-G:acctgtctcgagttttccatggcttcctacgtgctgactcagcc | SC04-040SC04-126 | 303 |
sy3K-F:gctgggggcggccacggtccgcttgatctccaccttggtccc | SC04-004SC04-010SC04-021SC04-031SC04-098SC04-104SC04-125SC04-140SC04-144SC04-164 | 304 |
sy3K-I:gctgggggcggccacggtccgcttgatctccagccgtgtccc | SC04-038SC04-097SC04-103SC04-108SC04-146 | 305 |
sy3K-J: | SC04-026 | 306 |
gctgggggcggccacggtccgcttgatctccagcttggtccc | SC04-060SC04-073 | |
sy3K-K:gctgggggcggccacggtccgcttgatgtccaccttggtccc | SC04-120 | 307 |
sy3L-A:ccagcacggtaagcttcagcacggtcaccttggtgccagttcc | SC04-018SC04-126 | 308 |
sy3L-C:ccagcacggtaagcttcagcacggtcagcttggtgcctccgcc | SC04-040 | 309 |
sy3L-D:ccagcacggtaagcttcaacacggtcagctgggtccc | SC04-008 | 310 |
sy5L-A:acctgtctcgagttttccatggcttcctccgagctgacccaggaccctgctg | SC04-001 | 311 |
表14:人单克隆抗体CR57、CRJB和CR04-010(10μg/ml)与狂犬病病毒株ERA的糖蛋白G的胞外结构域的线性肽的结合
线性肽的氨基酸序列 | CR57 | CRJB | CR04-010 |
KFPIYTILDKLGPWS | 71 | 97 | 1 |
FPIYTILDKLGPWSP | 42 | 105 | 39 |
PIYTILDKLGPWSPI | 36 | 89 | 87 |
IYTILDKLGPWSPID | 44 | 97 | 104 |
YTILDKLGPWSPIDI | 48 | 114 | 91 |
TILDKLGPWSPIDIH | 76 | 96 | 88 |
ILDKLGPWSPIDIHH | 54 | 104 | 69 |
LDKLGPWSPIDIHHL | 55 | 99 | 107 |
DKLGPWSPIDIHHLS | 62 | 103 | 93 |
KLGPWSPIDIHHLSC | 72 | 105 | 45 |
LGPWSPIDIHHLSCP | 69 | 112 | 19 |
GPWSPIDIHHLSCPN | 68 | 114 | 33 |
PWSPIDIHHLSCPNN | 62 | 104 | 47 |
WSPIDIHHLSCPNNL | 80 | 106 | 11 |
SPIDIHHLSCPNNLV | 74 | 85 | 1 |
PIDIHHLSCPNNLVV | 46 | 93 | 90 |
IDIHHLSCPNNLVVE | 69 | 102 | 55 |
DIHHLSCPNNLVVED | 38 | 96 | 78 |
IHHLSCPNNLVVEDE | 37 | 85 | 113 |
HHLSCPNNLVVEDEG | 56 | 76 | 117 |
HLSCPNNLVVEDEGC | 65 | 119 | 111 |
LSCPNNLVVEDEGCT | 69 | 117 | 127 |
SCPNNLVVEDEGCTN | 83 | 114 | 91 |
CPNNLVVEDEGCTNL | 77 | 97 | 49 |
PNNLVVEDEGCTNLS | 78 | 107 | 97 |
NNLVVEDEGCTNLSG | 72 | 99 | 97 |
NLVVEDEGCTNLSGF | 75 | 119 | 55 |
LVVEDEGCTNLSGFS | 76 | 103 | 52 |
VVEDEGCTNLSGFSY | 73 | 107 | 91 |
VEDEGCTNLSGFSYM | 74 | 103 | 31 |
EDEGCTNLSGFSYME | 54 | 90 | 7 |
DEGCTNLSGFSYMEL | 1 | 23 | 1 |
EGCTNLSGFSYMELK | 51 | 114 | 129 |
GCTNLSGFSYMELKV | 55 | 114 | 118 |
CTNLSGFSYMELKVG | 47 | 110 | 137 |
TNLSGFSYMELKVGY | 43 | 106 | 161 |
NLSGFSYMELKVGYI | 61 | 115 | 170 |
LSGFSYMELKVGYIL | 71 | 132 | 169 |
SGFSYMELKVGYILA | 79 | 132 | 161 |
GFSYMELKVGYILAI | 65 | 111 | 141 |
FSYMELKVGYILAIK | 89 | 112 | 192 |
SYMELKVGYILAIKM | 65 | 123 | 152 |
YMELKVGYILAIKMN | 78 | 114 | 150 |
MELKVGYILAIKMNG | 76 | 141 | 107 |
ELKVGYILAIKMNGF | 87 | 132 | 76 |
LKVGYILAIKMNGFT | 78 | 112 | 118 |
KVGYILAIKMNGFTC | 78 | 118 | 68 |
VGYILAIKMNGFTCT | 77 | 93 | 1 |
GYILAIKMNGFTCTG | 75 | 90 | 1 |
YILAIKMNGFTCTGV | 47 | 107 | 107 |
ILAIKMNGFTCTGVV | 79 | 103 | 104 |
LAIKMNGFTCTGVVT | 68 | 130 | 159 |
AIKMNGFTCTGVVTE | 47 | 103 | 152 |
IKMNGFTCTGVVTEA | 68 | 108 | 138 |
KMNGFTCTGVVTEAE | 76 | 104 | 133 |
MNGFTCTGVVTEAEN | 69 | 99 | 148 |
NGFTCTGVVTEAENY | 69 | 101 | 138 |
GFTCTGVVTEAENYT | 71 | 86 | 129 |
FTCTGVVTEAENYTN | 83 | 125 | 154 |
TCTGVVTEAENYTNF | 92 | 112 | 129 |
CTGVVTEAENYTNFV | 76 | 123 | 150 |
TGVVTEAENYTNFVG | 85 | 110 | 154 |
GVVTEAENYTNFVGY | 86 | 111 | 110 |
VVTEAENYTNFVGYV | 87 | 106 | 114 |
VTEAENYTNFVGYVT | 79 | 90 | 73 |
TEAENYTNFVGYVTT | 68 | 84 | 8 |
EAENYTNFVGYVTTT | 69 | 117 | 142 |
AENYTNFVGYVTTTF | 66 | 106 | 110 |
ENYTNFVGYVTTTFK | 44 | 112 | 183 |
NYTNFVGYVTTTFKR | 49 | 114 | 174 |
YTNFVGYVTTTFKRK | 51 | 104 | 138 |
TNFVGYVTTTFKRKH | 71 | 125 | 165 |
NFVGYVTTTFKRKHF | 65 | 107 | 154 |
FVGYVTTTFKRKHFR | 70 | 111 | 152 |
VGYVTTTFKRKHFRP | 75 | 113 | 155 |
GYVTTTFKRKHFRPT | 70 | 123 | 160 |
YVTTTFKRKHFRPTP | 85 | 106 | 160 |
VTTTFKRKHFRPTPD | 79 | 105 | 119 |
TTTFKRKHFRPTPDA | 80 | 108 | 137 |
TTFKRKHFRPTPDAC | 74 | 99 | 110 |
TFKRKHFRPTPDACR | 96 | 111 | 108 |
FKRKHFRPTPDACRA | 64 | 92 | 62 |
KRKHFRPTPDACRAA | 65 | 93 | 1 |
RKHFRPTPDACRAAY | 64 | 107 | 99 |
KHFRPTPDACRAAYN | 73 | 112 | 124 |
HFRPTPDACRAAYNW | 46 | 113 | 118 |
FRPTPDACRAAYNWK | 43 | 112 | 148 |
RPTPDACRAAYNWKM | 77 | 101 | 129 |
PTPDACRAAYNWKMA | 99 | 125 | 143 |
TPDACRAAYNWKMAG | 92 | 132 | 160 |
PDACRAAYNWKMAGD | 61 | 124 | 147 |
DACRAAYNWKMAGDP | 84 | 113 | 136 |
ACRAAYNWKMAGDPR | 82 | 116 | 138 |
CRAAYNWKMAGDPRY | 87 | 118 | 137 |
RAAYNWKMAGDPRYE | 90 | 130 | 120 |
AAYNWKMAGDPRYEE | 68 | 106 | 120 |
AYNWKMAGDPRYEES | 96 | 94 | 77 |
YNWKMAGDPRYEESL | 83 | 118 | 116 |
NWKMAGDPRYEESLH | 58 | 101 | 69 |
WKMAGDPRYEESLHN | 69 | 101 | 1 |
KMAGDPRYEESLHNP | 62 | 102 | 84 |
MAGDPRYEESLHNPY | 64 | 116 | 112 |
AGDPRYEESLHNPYP | 40 | 101 | 125 |
GDPRYEESLHNPYPD | 36 | 98 | 123 |
DPRYEESLHNPYPDY | 57 | 110 | 118 |
PRYEESLHNPYPDYR | 73 | 115 | 129 |
RYEESLHNPYPDYRW | 69 | 112 | 125 |
YEESLHNPYPDYRWL | 58 | 106 | 120 |
EESLHNPYPDYRWLR | 76 | 123 | 141 |
ESLHNPYPDYRWLRT | 92 | 132 | 125 |
SLHNPYPDYRWLRTV | 78 | 111 | 137 |
LHNPYPDYRWLRTVK | 79 | 106 | 142 |
HNPYPDYRWLRTVKT | 86 | 108 | 146 |
NPYPDYRWLRTVKTT | 85 | 102 | 151 |
PYPDYRWLRTVKTTK | 65 | 93 | 103 |
YPDYRWLRTVKTTKE | 72 | 97 | 97 |
PDYRWLRTVKTTKES | 76 | 85 | 27 |
DYRWLRTVKTTKESL | 54 | 111 | 105 |
YRWLRTVKTTKESLV | 46 | 117 | 125 |
RWLRTVKTTKESLVI | 40 | 110 | 120 |
WLRTVKTTKESLVII | 41 | 104 | 125 |
LRTVKTTKESLVIIS | 65 | 104 | 161 |
RTVKTTKESLVIISP | 82 | 120 | 150 |
TVKTTKESLVIISPS | 76 | 116 | 150 |
VKTTKESLVIISPSV | 71 | 120 | 154 |
KTTKESLVIISPSVA | 101 | 112 | 147 |
TTKESLVIISPSVAD | 78 | 121 | 141 |
TKESLVIISPSVADL | 86 | 112 | 132 |
KESLVIISPSVADLD | 86 | 117 | 111 |
ESLVIISPSVADLDP | 88 | 125 | 143 |
SLVIISPSVADLDPY | 68 | 105 | 125 |
LVIISPSVADLDPYD | 85 | 107 | 93 |
VIISPSVADLDPYDR | 59 | 98 | 50 |
IISPSVADLDPYDRS | 83 | 125 | 14 |
ISPSVADLDPYDRSL | 50 | 119 | 91 |
SPSVADLDPYDRSLH | 59 | 114 | 118 |
PSVADLDPYDRSLHS | 44 | 114 | 118 |
SVADLDPYDRSLHSR | 49 | 106 | 129 |
VADLDPYDRSLHSRV | 71 | 113 | 141 |
ADLDPYDRSLHSRVF | 70 | 121 | 141 |
DLDPYDRSLHSRVFP | 111 | 152 | 127 |
LDPYDRSLHSRVFPS | 99 | 142 | 106 |
DPYDRSLHSRVFPSG | 90 | 120 | 134 |
PYDRSLHSRVFPSGK | 86 | 120 | 130 |
YDRSLHSRVFPSGKC | 364 | 818 | 127 |
DRSLHSRVFPSGKCS | 98 | 142 | 141 |
RSLHSRVFPSGKCSG | 87 | 141 | 156 |
SLHSRVFPSGKCSGV | 69 | 111 | 141 |
LHSRVFPSGKCSGVA | 78 | 114 | 129 |
HSRVFPSGKCSGVAV | 97 | 118 | 111 |
SRVFPSGKCSGVAVS | 100 | 125 | 24 |
RVFPSGKCSGVAVSS | 69 | 110 | 106 |
VFPSGKCSGVAVSST | 74 | 114 | 142 |
FPSGKCSGVAVSSTY | 64 | 134 | 146 |
PSGKCSGVAVSSTYC | 56 | 112 | 132 |
SGKCSGVAVSSTYCS | 64 | 121 | 120 |
GKCSGVAVSSTYCST | 92 | 143 | 145 |
KCSGVAVSSTYCSTN | 88 | 130 | 130 |
CSGVAVSSTYCSTNH | 110 | 165 | 143 |
SGVAVSSTYCSTNHD | 79 | 110 | 115 |
GVAVSSTYCSTNHDY | 79 | 114 | 108 |
VAVSSTYCSTNHDYT | 85 | 114 | 118 |
AVSSTYCSTNHDYTI | 71 | 105 | 102 |
VSSTYCSTNHDYTIW | 78 | 107 | 121 |
SSTYCSTNHDYTIWM | 76 | 107 | 121 |
STYCSTNHDYTIWMP | 86 | 99 | 119 |
TYCSTNHDYTIWMPE | 96 | 107 | 74 |
YCSTNHDYTIWMPEN | 47 | 92 | 29 |
CSTNHDYTIWMPENP | 52 | 106 | 86 |
STNHDYTIWMPENPR | 60 | 112 | 107 |
TNHDYTIWMPENPRL | 69 | 129 | 119 |
NHDYTIWMPENPRLG | 71 | 119 | 130 |
HDYTIWMPENPRLGM | 82 | 125 | 123 |
DYTIWMPENPRLGMS | 93 | 127 | 123 |
YTIWMPENPRLGMSC | 97 | 132 | 143 |
TIWMPENPRLGMSCD | 69 | 106 | 134 |
IWMPENPRLGMSCDI | 98 | 110 | 101 |
WMPENPRLGMSCDIF | 88 | 113 | 120 |
MPENPRLGMSCDIFT | 105 | 121 | 143 |
PENPRLGMSCDIFTN | 83 | 111 | 104 |
ENPRLGMSCDIFTNS | 71 | 118 | 111 |
NPRLGMSCDIFTNSR | 90 | 113 | 138 |
PRLGMSCDIFTNSRG | 72 | 112 | 105 |
RLGMSCDIFTNSRGK | 88 | 106 | 113 |
LGMSCDIFTNSRGKR | 76 | 110 | 114 |
GMSCDIFTNSRGKRA | 54 | 120 | 101 |
MSCDIFTNSRGKRAS | 46 | 110 | 106 |
SCDIFTNSRGKRASK | 44 | 111 | 98 |
CDIFTNSRGKRASKG | 42 | 104 | 117 |
DIFTNSRGKRASKGS | 70 | 107 | 111 |
IFTNSRGKRASKGSE | 77 | 125 | 87 |
FTNSRGKRASKGSET | 83 | 111 | 119 |
TNSRGKRASKGSETC | 68 | 108 | 110 |
NSRGKRASKGSETCG | 92 | 100 | 119 |
SRGKRASKGSETCGF | 64 | 93 | 90 |
RGKRASKGSETCGFV | 75 | 104 | 115 |
GKRASKGSETCGFVD | 92 | 124 | 118 |
KRASKGSETCGFVDE | 92 | 106 | 129 |
RASKGSETCGFVDER | 86 | 110 | 134 |
ASKGSETCGFVDERG | 97 | 108 | 103 |
SKGSETCGFVDERGL | 92 | 102 | 76 |
KGSETCGFVDERGLY | 90 | 97 | 44 |
GSETCGFVDERGLYK | 57 | 115 | 92 |
SETCGFVDERGLYKS | 33 | 116 | 86 |
ETCGFVDERGLYKSL | 64 | 120 | 138 |
TCGFVDERGLYKSLK | 47 | 120 | 125 |
CGFVDERGLYKSLKG | 72 | 115 | 120 |
GFVDERGLYKSLKGA | 84 | 120 | 129 |
FVDERGLYKSLKGAC | 86 | 121 | 124 |
VDERGLYKSLKGACK | 50 | 108 | 110 |
DERGLYKSLKGACKL | 90 | 119 | 54 |
ERGLYKSLKGACKLK | 90 | 118 | 106 |
RGLYKSLKGACKLKL | 90 | 121 | 121 |
GLYKSLKGACKLKLC | 94 | 129 | 92 |
LYKSLKGACKLKLCG | 93 | 136 | 141 |
YKSLKGACKLKLCGV | 80 | 112 | 110 |
KSLKGACKLKLCGVL | 129 | 113 | 110 |
SLKGACKLKLCGVLG | 200 | 111 | 124 |
LKGACKLKLCGVLGL | 340 | 90 | 23 |
KGACKLKLCGVLGLR | 181 | 111 | 100 |
GACKLKLCGVLGLRL | 123 | 134 | 129 |
ACKLKLCGVLGLRLM | 148 | 117 | 142 |
CKLKLCGVLGLRLMD | 410 | 111 | 147 |
KLKLCGVLGLRLMDG | 273 | 120 | 114 |
LKLCGVLGLRLMDGT | 918 | 145 | 148 |
KLCGVLGLRLMDGTW | 3152 | 132 | 86 |
LCGVLGLRLMDGTWV | 83 | 138 | 129 |
CGVLGLRLMDGTWVA | 99 | 117 | 104 |
GVLGLRLMDGTWVAM | 89 | 148 | 117 |
VLGLRLMDGTWVAMQ | 90 | 141 | 127 |
LGLRLMDGTWVAMQT | 102 | 115 | 97 |
GLRLMDGTWVAMQTS | 104 | 138 | 120 |
LRLMDGTWVAMQTSN | 103 | 114 | 118 |
RLMDGTWVAMQTSNE | 100 | 113 | 130 |
LMDGTWVAMQTSNET | 96 | 106 | 106 |
MDGTWVAMQTSNETK | 97 | 97 | 110 |
DGTWVAMQTSNETKW | 69 | 114 | 92 |
GTWVAMQTSNETKWC | 58 | 113 | 82 |
TWVAMQTSNETKWCP | 78 | 118 | 107 |
WVAMQTSNETKWCPP | 50 | 114 | 116 |
VAMQTSNETKWCPPD | 86 | 104 | 151 |
AMQTSNETKWCPPDQ | 104 | 114 | 128 |
MQTSNETKWCPPDQL | 104 | 132 | 125 |
QTSNETKWCPPDQLV | 92 | 120 | 155 |
TSNETKWCPPDQLVN | 97 | 111 | 90 |
SNETKWCPPDQLVNL | 99 | 129 | 110 |
NETKWCPPDQLVNLH | 90 | 128 | 107 |
ETKWCPPDQLVNLHD | 105 | 120 | 118 |
TKWCPPDQLVNLHDF | 85 | 125 | 125 |
KWCPPDQLVNLHDFR | 89 | 113 | 121 |
WCPPDQLVNLHDFRS | 101 | 119 | 99 |
CPPDQLVNLHDFRSD | 93 | 137 | 127 |
PPDQLVNLHDFRSDE | 107 | 120 | 56 |
PDQLVNLHDFRSDEI | 35 | 106 | 63 |
DQLVNLHDFRSDEIE | 54 | 117 | 97 |
QLVNLHDFRSDEIEH | 60 | 113 | 106 |
LVNLHDFRSDEIEHL | 47 | 104 | 100 |
VNLHDFRSDEIEHLV | 83 | 129 | 98 |
MLHDFRSDEIEHLVV | 83 | 113 | 110 |
LHDFRSDEIEHLVVE | 93 | 115 | 121 |
HDFRSDEIEHLVVEE | 69 | 107 | 150 |
DFRSDEIEHLVVEEL | 99 | 103 | 110 |
FRSDEIEHLVVEELV | 86 | 114 | 116 |
RSDEIEHLVVEELVR | 100 | 138 | 104 |
SDEIEHLVVEELVRK | 101 | 117 | 118 |
DEIEHLVVEELVRKR | 94 | 123 | 143 |
EIEHLVVEELVRKRE | 82 | 113 | 121 |
IEHLVVEELVRKREE | 90 | 129 | 118 |
EHLVVEELVRKREEC | 82 | 114 | 106 |
HLVVEELVRKREECL | 82 | 123 | 46 |
LVVEELVRKREECLD | 64 | 100 | 79 |
VVEELVRKREECLDA | 62 | 108 | 97 |
VEELVRKREECLDAL | 58 | 111 | 101 |
EELVRKREECLDALE | 69 | 112 | 123 |
ELVRKREECLDALES | 82 | 113 | 117 |
LVRKREECLDALESI | 86 | 130 | 124 |
VRKREECLDALESIM | 58 | 181 | 151 |
RKREECLDALESIMT | 73 | 110 | 137 |
KREECLDALESIMTT | 102 | 113 | 97 |
REECLDALESIMTTK | 94 | 110 | 106 |
EECLDALESIMTTKS | 82 | 120 | 133 |
ECLDALESIMTTKSV | 91 | 112 | 125 |
CLDALESIMTTKSVS | 101 | 146 | 155 |
LDALESIMTTKSVSF | 97 | 116 | 152 |
DALESIMTTKSVSFR | 104 | 120 | 188 |
ALESIMTTKSVSFRR | 97 | 132 | 137 |
LESIMTTKSVSFRRL | 48 | 114 | 130 |
ESIMTTKSVSFRRLS | 62 | 111 | 114 |
SIMTTKSVSFRRLSH | 54 | 130 | 97 |
IMTTKSVSFRRLSHL | 43 | 101 | 111 |
MTTKSVSFRRLSHLR | 59 | 116 | 125 |
TTKSVSFRRLSHLRK | 66 | 118 | 111 |
TKSVSFRRLSHLRKL | 83 | 125 | 123 |
KSVSFRRLSHLRKLV | 108 | 124 | 129 |
SVSFRRLSHLRKLVP | 64 | 123 | 117 |
VSFRRLSHLRKLVPG | 90 | 111 | 105 |
SFRRLSHLRKLVPGF | 92 | 110 | 96 |
FRRLSHLRKLVPGFG | 90 | 108 | 111 |
RRLSHLRKLVPGFGK | 92 | 143 | 118 |
RLSHLRKLVPGFGKA | 93 | 123 | 148 |
LSHLRKLVPGFGKAY | 96 | 139 | 150 |
SHLRKLVPGFGKAYT | 113 | 132 | 132 |
HLRKLVPGFGKAYTI | 99 | 111 | 102 |
LRKLVPGFGKAYTIF | 83 | 118 | 82 |
RKLVPGFGKAYTIFN | 47 | 115 | 86 |
KLVPGFGKAYTIFNK | 47 | 114 | 123 |
LVPGFGKAYTIFNKT | 54 | 112 | 139 |
VPGFGKAYTIFNKTL | 58 | 114 | 138 |
PGFGKAYTIFNKTLM | 78 | 113 | 157 |
GFGKAYTIFNKTLME | 78 | 123 | 380 |
FGKAYTIFNKTLMEA | 90 | 151 | 356 |
GKAYTIFNKTLMEAD | 76 | 127 | 418 |
KAYTIFNKTLMEADA | 101 | 123 | 559 |
AYTIFNKTLMEADAH | 86 | 121 | 192 |
YTIFNKTLMEADAHY | 104 | 147 | 161 |
TIFNKTLMEADAHYK | 107 | 123 | 1405 |
IFNKTLMEADAHYKS | 100 | 118 | 1828 |
FNKTLMEADAHYKSV | 111 | 141 | 2736 |
NKTLMEADAHYKSVR | 104 | 116 | 141 |
KTLMEADAHYKSVRT | 91 | 98 | 123 |
TLMEADAHYKSVRTW | 100 | 114 | 90 |
LMEADAHYKSVRTWN | 73 | 107 | 97 |
MEADAHYKSVRTWNE | 62 | 129 | 83 |
EADAHYKSVRTWNEI | 58 | 97 | 106 |
ADAHYKSVRTWNEIL | 56 | 100 | 100 |
DAHYKSVRTWNEILP | 59 | 121 | 112 |
AHYKSVRTWNEILPS | 112 | 160 | 125 |
HYKSVRTWNEILPSK | 80 | 130 | 123 |
YKSVRTWNEILPSKG | 66 | 137 | 116 |
KSVRTWNEILPSKGC | 115 | 125 | 114 |
SVRTWNEILPSKGCL | 106 | 138 | 118 |
VRTWNEILPSKGCLR | 90 | 124 | 133 |
RTWNEILPSKGCLRV | 120 | 127 | 120 |
TWNEILPSKGCLRVG | 97 | 146 | 127 |
WNEILPSKGCLRVGG | 102 | 136 | 117 |
NEILPSKGCLRVGGR | 104 | 130 | 163 |
EILPSKGCLRVGGRC | 104 | 112 | 128 |
ILPSKGCLRVGGRCH | 79 | 113 | 107 |
LPSKGCLRVGGRCHP | 77 | 119 | 100 |
PSKGCLRVGGRCHPH | 69 | 138 | 91 |
SKGCLRVGGRCHPHV | 72 | 121 | 103 |
KGCLRVGGRCHPHVN | 68 | 130 | 115 |
GCLRVGGRCHPHVNG | 85 | 125 | 123 |
CLRVGGRCHPHVNGV | 102 | 132 | 134 |
LRVGGRCHPHVNGVF | 104 | 143 | 133 |
RVGGRCHPHVNGVFF | 86 | 143 | 99 |
VGGRCHPHVNGVFFN | 120 | 136 | 120 |
GGRCHPHVNGVFFNG | 86 | 119 | 119 |
GRCHPHVNGVFFNGI | 117 | 113 | 117 |
RCHPHVNGVFFNGII | 98 | 141 | 143 |
CHPHVNGVFFNGIIL | 97 | 150 | 151 |
HPHVNGVFFNGIILG | 104 | 138 | 164 |
PHVNGVFFNGIILGP | 93 | 173 | 146 |
HVNGVFFNGIILGPD | 97 | 123 | 114 |
VNGVFFNGIILGPDG | 68 | 116 | 85 |
NGVFFNGIILGPDGN | 66 | 117 | 97 |
GVFFNGIILGPDGNV | 58 | 116 | 100 |
VFFNGIILGPDGNVL | 55 | 132 | 108 |
FFNGIILGPDGNVLI | 92 | 143 | 105 |
FNGIILGPDGNVLIP | 61 | 139 | 130 |
NGIILGPDGNVLIPE | 102 | 146 | 141 |
GIILGPDGNVLIPEM | 107 | 132 | 123 |
IILGPDGNVLIPEMQ | 85 | 118 | 93 |
ILGPDGNVLIPEMQS | 125 | 134 | 119 |
LGPDGNVLIPEMQSS | 100 | 134 | 150 |
GPDGNVLIPEMQSSL | 86 | 154 | 157 |
PDGNVLIPEMQSSLL | 87 | 129 | 139 |
DGNVLIPEMQSSLLQ | 123 | 134 | 169 |
GNVLIPEMQSSLLQQ | 96 | 120 | 168 |
NVLIPEMQSSLLQQH | 72 | 120 | 150 |
VLIPEMQSSLLQQHM | 92 | 104 | 142 |
LIPEMQSSLLQQHME | 89 | 111 | 85 |
IPEMQSSLLQQHMEL | 89 | 128 | 129 |
PEMQSSLLQQHMELL | 62 | 133 | 93 |
EMQSSLLQQHMELLE | 58 | 129 | 142 |
MQSSLLQQHMELLES | 65 | 113 | 117 |
QSSLLQQHMELLESS | 82 | 114 | 132 |
SSLLQQHMELLESSV | 90 | 128 | 132 |
SLLQQHMELLESSVI | 124 | 163 | 133 |
LLQQHMELLESSVIP | 78 | 111 | 121 |
LQQHMELLESSVIPL | 106 | 134 | 128 |
QQHMELLESSVIPLV | 103 | 134 | 133 |
QHMELLESSVIPLVH | 98 | 146 | 139 |
HMELLESSVIPLVHP | 110 | 129 | 134 |
MELLESSVIPLVHPL | 90 | 125 | 152 |
ELLESSVIPLVHPLA | 90 | 133 | 155 |
LLESSVIPLVHPLAD | 72 | 117 | 118 |
LESSVIPLVHPLADP | 90 | 128 | 128 |
ESSVIPLVHPLADPS | 104 | 138 | 143 |
SSVIPLVHPLADPST | 73 | 104 | 93 |
SVIPLVHPLADPSTV | 72 | 137 | 107 |
VIPLVHPLADPSTVF | 69 | 141 | 123 |
IPLVHPLADPSTVFK | 96 | 156 | 188 |
PLVHPLADPSTVFKD | 93 | 112 | 138 |
LVHPLADPSTVFKDG | 164 | 174 | 188 |
VHPLADPSTVFKDGD | 98 | 138 | 125 |
HPLADPSTVFKDGDE | 74 | 141 | 117 |
PLADPSTVFKDGDEA | 99 | 125 | 90 |
LADPSTVFKDGDEAE | 68 | 116 | 113 |
ADPSTVFKDGDEAED | 147 | 152 | 110 |
DPSTVFKDGDEAEDF | 98 | 147 | 137 |
PSTVFKDGDEAEDFV | 104 | 143 | 141 |
STVFKDGDEAEDFVE | 104 | 120 | 125 |
TVFKDGDEAEDFVEV | 107 | 124 | 96 |
VFKDGDEAEDFVEVH | 100 | 106 | 93 |
FKDGDEAEDFVEVHL | 65 | 76 | 119 |
KDGDEAEDFVEVHLP | 72 | 93 | 76 |
DGDEAEDFVEVHLPD | 85 | 123 | 91 |
GDEAEDFVEVHLPDV | 46 | 124 | 113 |
DEAEDFVEVHLPDVH | 68 | 136 | 123 |
EAEDFVEVHLPDVHN | 76 | 117 | 114 |
AEDFVEVHLPDVHNQ | 123 | 138 | 123 |
EDFVEVHLPDVHNQV | 90 | 141 | 123 |
DFVEVHLPDVHNQVS | 96 | 141 | 118 |
FVEVHLPDVHNQVSG | 92 | 143 | 102 |
VEVHLPDVHNQVSGV | 106 | 141 | 123 |
EVHLPDVHNQVSGVD | 91 | 150 | 139 |
VHLPDVHNQVSGVDL | 110 | 114 | 137 |
HLPDVHNQVSGVDLG | 104 | 150 | 129 |
LPDVHNQVSGVDLGL | 104 | 154 | 154 |
PDVHNQVSGVDLGLP | 106 | 129 | 115 |
DVHNQVSGVDLGLPN | 117 | 133 | 113 |
VHNQVSGVDLGLPNW | 100 | 119 | 38 |
HNQVSGVDLGLPNWG | 76 | 106 | 38 |
NQVSGVDLGLPNWGK | 78 | 138 | 98 |
Average | 91.9 | 119.5 | 130.9 |
StDV | 157.9 | 37.6 | 169.8 |
表15:抗狂犬病病毒G蛋白IgG的中和效力
名称IgG | IU/mg |
CR04-001 | 89 |
CR04-004 | 5 |
CR04-008 | 1176 |
CR04-010 | 3000 |
CR04-018 | 1604 |
CR04-021 | 1500 |
CR04-026 | <2 |
CR04-031 | 272 |
CR04-038 | 2330 |
CR04-040 | 3041 |
CR04-060 | 89 |
CR04-073 | 6116 |
CR04-097 | <1 |
CR04-098 | 7317 |
CR04-103 | 3303 |
CR04-104 | 4871 |
CR04-108 | 4871 |
CR04-120 | 4938 |
CR04-125 | 4718 |
CR04-126 | 2655 |
CR04-140 | 478 |
CR04-144 | 6250 |
CR04-146 | ND |
CR04-164 | 4724 |
CR57 | 3800 |
CRJB | 605 |
ND=未确定
表16:针对E57逃逸病毒,抗狂犬病病毒G蛋白IgG的中和效力
名称IgG | E57A2(IU/mg) | E57A3(IU/mg) | E57B1(IU/mg) | E57B2(IU/mg) | E57B3(IU/mg) | E57C3(IU/mg) |
CR04-008 | 0* | 0 | 0 | 0 | 0 | 0 |
CR04-010 | 8127 | 1355 | 5418 | 1355 | 2709 | 4064 |
CR04-018 | 1604 | 0 | 1604 | 0 | 59 | 535 |
CR04-021 | 450 | 2 | 150 | 8 | 50 | 50 |
CR04-038 | 9437 | 1573 | 9437 | 1049 | 6291 | 1573 |
CR04-040 | 8209 | 2736 | 24628 | 1368 | 5473 | 912 |
CR04-073 | 8256 | 1835 | 11008 | 1835 | 3669 | 1835 |
CR04-098 | 9878 | 3293 | 9878 | 3293 | 3293 | 3293 |
CR04-103 | 8917 | 2972 | 17835 | 2972 | 5945 | 2972 |
CR04-104 | 3288 | 2192 | 6576 | 2192 | 4384 | 1096 |
CR04-108 | 3288 | 731 | 4384 | 731 | 2192 | 731 |
CR04-120 | 1111 | 14 | 741 | 82 | 247 | 41 |
CR04-125 | 708 | 39 | 236 | 79 | 157 | 79 |
CR04-126 | 88 | 0 | 18 | 0 | 18 | 0 |
CR04-144 | 5625 | 2813 | 11250 | 2813 | 5625 | 1875 |
CR04-164 | 4252 | 472 | 4252 | 472 | 945 | 709 |
*0表示是抗体1∶100稀释时没有50%终点
表17:针对E98逃逸病毒CR57的中和效力
E98-2(IU/mg) | E98-4(IU/mg) | E98-5(IU/mg) | E98-6(IU/mg) | E98-7(IU/mg) | |
CR-57 | 2813 | 8438 | 4219 | 2813 | 8438 |
CR04-098 | 0* | 0 | 0 | 0 | 0 |
*0表示是抗体1∶1000稀释时没有50%终点
表18:I型基因型狂犬病病毒中CR57的最小结合区域中的氨基酸残基的出现
野生型 | K | L | C | G | V | L |
K(99.6%)* | L(100%) | C(100%) | G(98.7%) | V(99.6%) | L(70.7%) | |
R(0.4%) | E(0.9%) | I(0.4%) | P(26.7%) | |||
R(0.4%) | S(2.6%) |
*229种狂犬病病毒分离物中示出每种氨基酸出现的百分比
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Seif I,Coulon P,Rollin E,and Flamand A(1985)Rabies virulence:effect onpathogenicicty and sequence characterization of rabies virus mutations affectingantigenic site III of the glycoprotein.J.Virol.53:926-934.
Slootstra JW,Puijk WC,Ligtvoet GJ,Langeveld JP,Meloen RH 1996.Structuralaspects of antibody-antigen interaction revealed through small random peptidelibraries.Mol.Divers.1:87-96.
Tordo N(1996),Characteristics and molecular biology of rabies virus.In Meslin F-X,Kaplan MM,Koprowski H,editors.Laboratory Techniques in rabies,4th editionGeneva,Switzerland:World Health Organization.
White LA and Chappell WA(1982),Inactivation of rabies virus in reagents used forthe fluorescent rabies antibody test.J.Clin.Microbiol.16:253-256.
序列表
序列表
<110>克鲁塞尔荷兰公司
<120>能中和狂犬病病毒的结合分子及其应用
<130>0110 WO 00 ORD
<160>337
<170>PatentIn version 3.1
<210>1
<211>9
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-001
<400>1
Gly Leu Tyr Gly Glu Leu Phe Asp Tyr
1 5
<210>2
<211>11
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-004
<400>2
Asp Tyr Leu Tyr Pro Thr Thr Asp Phe Asp Tyr
1 5 10
<210>3
<211>10
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-008
<400>3
Met Gly Phe Thr Gly Thr Tyr Phe Asp Tyr
1 5 10
<210>4
<211>14
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-010
<400>4
Asp Gly Leu Asp Leu Thr Gly Thr Ile Gln Pro Phe Gly Tyr
1 5 10
<210>5
<211>10
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-018
<400>5
Val Ser Val Thr Thr Gly Ala Phe Asn Ile
1 5 10
<210>6
<211>10
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-021
<400>6
Gly Ser Val Leu Gly Asp Ala Phe Asp Ile
1 5 10
<210>7
<211>12
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-026
<400>7
Thr Ser Asn Trp Asn Tyr Leu Asp Arg Phe Asp Pro
1 5 10
<210>8
<211>10
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-031
<400>8
Gly Ser Val Leu Gly Asp Ala Phe Asp Ile
1 5 10
<210>9
<211>10
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-038
<400>9
Gly Ser Val Leu Gly Asp Ala Phe Asp Ile
1 5 10
<210>10
<211>9
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-040
<400>10
Gly Ser Lys Val Gly Asp Phe Asp Tyr
1 5
<210>11
<211>20
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-060
<400>11
Glu Lys Glu Lys Tyr Ser Asp Arg Ser Gly Tyr Ser Tyr Tyr Tyr Tyr
1 5 10 15
Tyr Met Asp Val
20
<210>12
<211>14
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-073
<400>12
Asp Gly Leu Asp Leu Thr Gly Thr Ile Gln Pro Phe Gly Tyr
1 5 10
<210>13
<211>12
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-097
<400>13
Thr Ala Ser Asn Leu Gly Arg Gly Gly Met Asp Val
1 5 10
<210>14
<211>10
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-098
<400>14
Val Ala Val Ala Gly Thr His Phe Asp Tyr
1 5 10
<210>15
<211>10
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-103
<400>15
Val Ala Val Ala Gly Glu Ser Phe Asp Ser
1 5 10
<210>16
<211>12
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-104
<400>16
Ile Val Val Val Thr Ala Leu Asp Ala Phe Asp Ile
1 5 10
<210>17
<211>11
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-108
<400>17
Phe Met Ile Val Ala Asp Asp Ala Phe Asp Ile
1 5 10
<210>18
<211>9
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-120
<400>18
Gly Gly Lys Thr Gly Glu Phe Asp Tyr
1 5
<210>19
<211>10
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-125
<400>19
Ile Ala Thr Ala Gly Thr Gly Phe Asp Tyr
1 5 10
<210>20
<211>10
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-126
<400>20
Met Gly Phe Thr Gly Thr Tyr Phe Asp Tyr
1 5 10
<210>21
<211>10
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-140
<400>21
Val Thr Asn Pro Gly Asp Ala Phe Asp Ile
1 5 10
<210>22
<211>9
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-144
<400>22
Gly Gly Lys Thr Gly Glu Phe Asp Tyr
1 5
<210>23
<211>9
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-146
<400>23
Gly Gly Lys Thr Gly Glu Phe Asp Tyr
1 5
<210>24
<211>10
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of SC04-164
<400>24
Gly Ser Val Leu Gly Asp Ala Phe Asp Ile
1 5 10
<210>25
<211>18
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of S057
<400>25
Glu Asn Leu Asp Asn Ser Gly Thr Tyr Tyr Tyr Phe Ser Gly Trp Phe
1 5 10 15
Asp Pro
<210>26
<211>117
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-001
<400>26
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Leu Tyr Gly Glu Leu Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser
115
<210>27
<211>118
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-004
<400>27
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Tyr Leu Tyr Pro Thr Thr Asp Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val
115
<210>28
<211>120
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-008
<400>28
Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu
35 40 45
Trp Leu Ala Arg Ile Asp Trp Asp Asp Asp Lys Tyr Tyr Ser Thr Ser
50 55 60
Leu Lys Thr Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Met Gly Phe Thr Gly Thr Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>29
<211>123
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-010
<400>29
Gln Val Gln Leu Val Gln Ser Gly Gly Asp Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Gly Leu Asp Leu Thr Gly Thr Ile Gln Pro Phe Gly Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>30
<211>119
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-018
<400>30
Glu Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Ser Val Thr Thr Gly Ala Phe Asn Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210>31
<211>119
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-021
<400>31
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Ser Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Ser Val Leu Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210>32
<211>121
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-026
<400>32
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Asn Phe Pro Tyr Ser
20 25 30
Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Phe Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Pro Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Asn Ser Lys Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Thr Ser Asn Trp Asn Tyr Leu Asp Arg Phe Asp Pro Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>33
<211>119
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-031
<400>33
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Ser Val Leu Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210>34
<211>119
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-038
<400>34
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Ser Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Ser Val Leu Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210>35
<211>118
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04040
<400>35
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Phe Tyr Asp Gly Ser Tyr Lys Asp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Ser Lys Val Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210>36
<211>128
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-060
<400>36
Gln Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys Ala Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Ile Ser Ser Phe
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Glu Ile Gln Asp Thr Gly Arg Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Thr Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Glu Lys Glu Lys Tyr Ser Asp Arg Ser Gly Tyr Ser Tyr Tyr Tyr
100 105 110
Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210>37
<211>123
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-073
<400>37
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Ala Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Gly Leu Asp Leu Thr Gly Thr Ile Gln Pro Phe Gly Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>38
<211>121
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-097
<400>38
Glu Val Gln Leu Val Gln Ser Gly Gly His Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Ile Gly Ser Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Thr Ala Ser Asn Leu Gly Arg Gly Gly Met Asp Val Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210>39
<211>119
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-098
<400>39
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Ala Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Leu Tyr Asp Gly Ser Asp Lys Phe Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Ala Val Ala Gly Thr His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210>40
<211>119
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-103
<400>40
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Leu Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Ala Val Ala Gly Glu Ser Phe Asp Ser Trp Gly Arg Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210>41
<211>121
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-104
<400>41
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Tyr Asp Gly Asn Val Lys Asp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ile Val Val Val Thr Ala Leu Asp Ala Phe Asp Ile Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210>42
<211>120
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain varaible region of SC04-108
<400>42
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Leu Tyr Asp Gly Ser Asp Lys Phe Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Met Ile Val Ala Asp Asp Ala Phe Asp Ile Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser
115 120
<210>43
<211>118
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-120
<400>43
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Tyr Asp Gly Ser Ile Lys Asp Tyr Ala Asp Ser Glu
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Gly Lys Thr Gly Glu Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210>44
<211>119
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-125
<400>44
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ile Ala Thr Ala Gly Thr Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210>45
<211>120
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-126
<400>45
Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Asn Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Gly
20 25 30
Gly Val Gly Val Gly Trp Phe Arg Gln Pro Pro Gly Lys Ala Leu Glu
35 40 45
Trp Leu Ala Arg Ile Asp Trp Asp Asp Asp Lys Tyr Tyr Ser Thr Ser
50 55 60
Leu Lys Thr Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Ile Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Met Gly Phe Thr Gly Thr Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210>46
<211>119
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-140
<400>46
Gln Met Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Leu Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ala Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Thr Asn Pro Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<21O>47
<211>118
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-144
<400>47
Gln Val Gln Leu Gln Glu Leu Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Tyr Asp Gly Ser Ile Lys Asp Tyr Ala Asp Ser Glu
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Gly Lys Thr Gly Glu Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210>48
<211>118
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-146
<400>48
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Tyr Asp Gly Ser Ile Lys Asp Tyr Ala Asp Ser Glu
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Gly Lys Thr Gly Glu Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210>49
<211>119
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-164
<400>49
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Ser Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Ser Val Leu Gly Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210>50
<211>108
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-001
<400>50
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210>51
<211>103
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-004
<400>51
Thr Gln Ser Pro Ser Ser Leu SerAla Ser Val Gly Asp Arg Val Thr
1 5 10 15
Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr
20 25 30
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser
35 40 45
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
50 55 60
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
65 70 75 80
Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro Thr Phe Gly Gln
85 90 95
Gly Thr Lys Val Glu Ile Lys
100
<210>52
<211>109
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-008
<400>52
Gln Ala Val Leu Thr Gln Pro Ser Ser Val Ser Val Ala Pro Gly Glu
1 5 10 15
Thr Ala Ser Val Thr Cys Gly Gly Asp Asn Ile Gly Ser Lys Ser Val
20 25 30
His Trp Tyr Gln Lys Lys Pro Gly Gln Ala Pro Val Leu Val Val Phe
35 40 45
Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Thr Ser Gly Asn Thr Ala Ala Leu Thr Ile Ser Arg Val Glu Ala Gly
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Asn Asp His
85 90 95
Leu Tyr Val Phe Gly Pro Gly Thr Gln Leu Thr Val Leu
100 105
<210>53
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-010
<400>53
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Asn Tyr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210>54
<211>110
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-018
<400>54
Gln Pro Val Leu Thr Gln Pro Leu Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Asp Thr Ser Asn Ile Gly Ser Asn
20 25 30
Thr Val His Trp Tyr Gln Arg Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile His Asn Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ala Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Phe Cys Ala Ala Trp Asp Asp Asn Leu
85 90 95
Asn Gly Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105 110
<210>55
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-021
<400>55
Asp Ile Gln Met Thr Gln Ser Pro Phe Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Scr Gln Gly Ile Gly Ser Ser
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Leu Gln His His Asp Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210>56
<211>112
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-026
<400>56
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly His Asp Tyr Leu Asp Trp Tyr Val Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Pro Leu Ile Tyr Leu Gly Ser Asp Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr His Phe Thr Leu Asn Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser
85 90 95
Leu Gln Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210>57
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-031
<400>57
Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210>58
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-038
<400>58
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Gly Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Arg Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210>59
<211>108
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-040
<400>59
Gln Pro Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln
1 5 10 15
Thr Ala Arg Ile Ser Cys Gly Gly Asp Asn Ile Gly Thr Asn Thr Val
20 25 30
Gln Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr
35 40 45
Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asp Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Asp Ser Ser Asp Leu
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu
100 105
<210>60
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-060
<400>60
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Thr Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Glu Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Phe Thr Thr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210>61
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-073
<400>61
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser His Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Asn Tyr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210>62
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-097
<400>62
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser His
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210>63
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-098
<400>63
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210>64
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-103
<400>64
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln GlyIle Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Arg Ser Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asp Ser Phe Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210>65
<211>109
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-104
<400>65
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ile Leu Gly His Trp
20 25 30
Leu Pro Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
35 40 45
Leu Ile Ser Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Pro Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Ser Asp Phe Thr Leu Thr Ile Ser Ser Leu
65 70 75 80
Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr His Glu Tyr
85 90 95
Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210>66
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-108
<400>66
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser His
20 25 30
Leu Val Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg phe Ser Gly
50 55 60
Ser Glu Ser Ala Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Tyr Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210>67
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-120
<400>67
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Glu Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210>68
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-125
<400>68
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210>69
<211>109
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-126
<400>69
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys
1 5 10 15
Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Tyr Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His
85 90 95
Pro Tyr Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu
100 105
<210>70
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-140
<400>70
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210>71
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-144
<400>71
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Gly Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210>72
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-146
<400>72
Asp Val Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Ser Ala Thr Leu Phe Cys Arg Ala Ser Glu Ser Val Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln His Lys Pro Gly Arg Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Asp Gly
50 55 60
Thr Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asp Trp Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210>73
<211>107
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-164
<400>73
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys
100 105
<210>74
<211>351
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region SC04-001
<400>74
gaggtgcagc tggtggagtc tgggggaggt gtggtacggc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttgat gattatggca tgagctgggt ccgccaagct 120
ccagggaagg ggctggagtg ggtctctggt attaattgga atggtggtag cacaggttat 180
gcagactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agccgaggac acggccgtgt attactgtgc aaagggcctt 300
tatggggagc tttttgacta ctggggccaa ggtaccctgg tcaccgtctc g 351
<210>75
<211>354
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-004
<400>75
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagc aactactgga tgaactgggt ccgccaggcg 120
cccgggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac 180
gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc caaagactac 300
ctctacccca ccaccgactt cgattactgg ggccagggca ccctggtgac cgtg 354
<210>76
<211>360
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain varaible region of SC04-008
<400>76
caggtcacct tgaaggagtc tggtcctacg ctggtgaaac ccacacagac cctcacgctg 60
acctgcacct tctctgggtt ctcactcagc actagtggag tgggtgtggg ctggatccgt 120
cagcccccag gaaaggccct ggagtggctt gcacgcattg attgggatga tgataaatac 180
tacagcacat ctctgaagac caggctcacc atctccaagg acacctccaa aaaccaggtg 240
gtccttacaa tgaccaacat ggaccctgtg gacacagcca cgtattactg tgcacggatg 300
ggtttcactg gaacctactt tgactactgg ggccagggca ccctggtcac cgtctcgagc 360
<210>77
<211>369
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-010
<400>77
caggtgcagc tggtgcagtc tgggggagac ttggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagat atatcatatg atggaagtaa taaatactat 180
gcagactccg tgaagggccg attcaccatt tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagatggg 300
ctggatttaa ctggaacgat tcagccattt ggctactggg gccagggaac cctggtcacc 360
gtctcgagc 369
<210>78
<211>357
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-018
<400>78
gaggtgcagc tggtggagtc tggcccagga ctggtgaggc cttcggggac cctgtccctc 60
acctgcgctg tctctggtgg ctccatcagc agtagtaact ggtggagttg ggtccgccag 120
cccccaggga aggggctgga gtggattggg gaaatctatc atagtgggag caccaactac 180
aacccgtccc tcaagagtcg agtcaccata tcagtagaca agtccaagaa ccagttctcc 240
ctgaagctga gctctgtgac cgccgcggac acggccgtgt attactgtgc gagagtttct 300
gtgactacgg gtgcttttaa tatctggggc caagggacaa tggtcaccgt ctcgagc 357
<210>79
<211>357
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain varaible region SC04-021
<400>79
gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtag taaatattat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagggtcc 300
gtcctcggtg atgcttttga tatctggggc caagggacaa tggtcaccgt ctcgagc 357
<210>80
<211>363
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-026
<400>80
gaggtgcagc tggtggagtc tggagcagag gtgaagaagc cgggggaatc tctgaagatc 60
tcctgtaagg gttctggata caactttccc tactcctgga tcgcctgggt gcgccagatg 120
cccgggaaag gcctggagtg gatggggatc atctttcctg gtgactctga caccagatat 180
agtccgccct tccaaggcca ggtcaccatc tcagccgaca actccaaaag caccgcctac 240
ctgcagtgga gtagcctgaa ggcctcggac accgccatgt attactgtgc gcggacctcg 300
aactggaact atttggaccg gttcgacccc tggggccagg gcaccctggt caccgtctcg 360
agc 363
<210>81
<211>357
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain varaible region of SC04-031
<400>81
gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagggtcc 300
gtcctcggtg atgcttttga tatctggggc caagggacaa tggtcaccgt ctcgagc 357
<210>82
<211>357
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain varaible region of SC04-038
<400>82
caggtgcagc tggtgcaatc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtag taaatattat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagggtcc 300
gtcctcggtg atgcttttga tatctggggc caagggacaa tggtcaccgt ctcgagc 357
<210>83
<211>354
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-040
<400>83
caggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcggt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcaact atattctatg atggaagtta taaagactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaaggcagt 300
aaggtaggcg actttgacta ctggggccag ggaaccctgg tcaccgtctc gagc 354
<210>84
<211>384
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-060
<400>84
caggtgcagc tggtggagtc tggcccagga ctggtgaagg cttcggagac cctgtccctc 60
acttgcacgg tctctgatgg ctccatcagt agtttctact ggagctggat ccggcagccc 120
cccgggaagg gactggagtg ggttggggaa atccaggaca ctgggaggac caattacaac 180
ccctccctca agagtcgagt cactatatca ctagacacgt ccaagaacca gttctccctg 240
acgttgagct ctgtgaccgc tgcggacacg gccgtgtatt actgcgcgag agagaaggag 300
aaatactctg atagaagcgg ttattcgtac tactactatt acatggacgt ctggggcaaa 360
gggaccacgg tcaccgtctc gagc 384
<210>85
<211>369
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-073
<400>85
caggtgcagc tggtgcagtc tgggggaggc gtggcccagc ctgggaggtc cctgagactc 60
tcctgtgcag cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagat atatcatatg atggaagtaa taaatactat 180
gcagactccg tgaagggccg attcaccatt tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagatggg 300
ctggatttaa ctggaacgat tcagccattt ggctactggg gccagggcac cctggtcacc 360
gtctcgagc 369
<210>86
<211>369
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-097
<400>86
caggtgcagc tggtgcagtc tgggggagac ttggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagat atatcatatg atggaagtaa taaatactat 180
gcagactccg tgaagggccg attcaccatt tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagatggg 300
ctggatttaa ctggaacgat tcagccattt ggctactggg gccagggaac cctggtcacc 360
gtctcgagc 369
<210>87
<211>357
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-098
<400>87
gaagtgcagc tggtgcagtc tgggggaggc gcggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggctgtt atattatatg atggaagtga taaattctat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcagatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagtagca 300
gtggctggta cgcactttga ctactggggc cagggaaccc tggtcaccgt ctcgagc 357
<210>88
<211>357
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-103
<400>88
caggtgcagc tgcaggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atattatatg atggaagtga taaatactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagtcgct 300
gtggctgggg aaagctttga ctcctggggc cggggcaccc tggtcaccgt ctcgagc 357
<210>89
<211>363
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-104
<400>89
caggtgcagc tgcaggagtc ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcaact atatcatatg atggaaatgt taaagactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag aactgaggac acggctgtgt attactgtgc gaaaatagtg 300
gtggtgaccg ccctcgatgc ttttgatatc tggggccaag ggacaatggt caccgtctcg 360
agc 363
<210>90
<211>360
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain varaible region of SC04-108
<400>90
gaagtgcagc tggtgcagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atattatatg atggaagtga taagttctat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagga cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaatttatg 300
atagtagcag atgatgcttt tgatatctgg ggccaaggga caatggtcac cgtctcgagc 360
<210>91
<211>354
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-120
<400>91
gaggtgcagc tggtgcagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt acctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcaact atatcatatg atggaagtat taaagactat 180
gcagactccg agaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagggggg 300
aagactggag agtttgacta ctggggccag ggaaccctgg tcaccgtctc gagc 354
<210>92
<211>357
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-125
<400>92
caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtga taaatactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctctat 240
ctgcaaatga acagcttgag agctgaggac acggctgtgt attactgtgc gaagatagca 300
acagctggta ccgggtttga ctactggggc cagggaaccc tggtcaccgt ctcgagc 357
<210>93
<211>360
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-126
<400>93
caggtcacct tgaaggagtc tggtcccacg ctggtgaacc ccacacagac cctcacgttg 60
acctgcacct tctctgggtt ctcgctcagc actggtggag tgggtgtggg ctggttccgt 120
cagcccccag ggaaggccct ggagtggctt gcacgcattg attgggatga tgataaatac 180
tacagcacat ctctgaagac caggctcacc atctccaagg acacctccaa aatccaggtg 240
gtccttacaa tgaccaacat ggaccctgtg gacacagcca cgtattactg tgcacggatg 300
ggtttcactg gaacctactt tgactactgg ggccagggca ccctggtcac cgtctcgagc 360
<210>94
<211>357
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-140
<400>94
cagatgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atattatatg atggaagtaa taaatactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cgcgttgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaggtgacc 300
aaccccggag atgcttttga tatctggggc caagggacca tggtcaccgt ctcgagc 357
<210>95
<211>354
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-144
<400>95
caggtgcagc tgcaggagtt ggggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcggt agctatggca tgcactgggt ccgccaggct 120
ccgggcaagg ggctggagtg ggtggcaact atatcatatg atggaagtat taaagactat 180
gcagactccg agaagggccg attcaccatc tccagagaca attccaagaa cacactgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagggggg 300
aagactggag agtttgacta ctggggccag ggaaccctgg tcaccgtctc gagc 354
<210>96
<211>354
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-146
<400>96
gaagtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccgggcaagg ggctggagtg ggtggcaact atatcatatg atggaagtat taaagactat 180
gcagactccg aggagggccg attcaccatc tccagagaca attccaagaa cacactgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagggggg 300
aagactggag agtttgacta ctggggccag ggcaccctgg tcaccgtctc gagc 354
<210>97
<211>357
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of SC04-164
<400>97
gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagcag taaatactac 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagggtcc 300
gtcctcggtg atgcttttga tatctggggc caagggacaa tggtcaccgt ctcgagc 357
<210>98
<211>324
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain varaible region of SC04-001
<400>98
tcgtctgagc tgactcagga ccctgctgtg tctgtggcct tgggacagac agtcaggatc 60
acatgccaag gagacagcct cagaagctat tatgcaagct ggtaccagca gaagccagga 120
caggcccctg tacttgtcat ctatggtaaa aacaaccggc cctcagggat cccagaccga 180
ttctctggct ccagctcagg aaacacagct tccttgacca tcactggggc tcaggcggaa 240
gatgaggctg actattactg taactcccgg gacagcagtg gtaaccatgt ggtattcggc 300
ggagggacca agctgaccgt ccta 324
<210>99
<211>309
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-004
<400>99
acccagtctc catcctccct gtctgcatct gtaggagaca gagtcaccat cacttgccgg 60
gcaagtcaga gcattagcag ctacttaaat tggtatcagc agaaaccagg gaaagcccct 120
aagctcctga tctatgctgc atccagtttg caaagtgggg tcccatcaag gttcagtggc 180
agtggatctg ggacagattt cactctcacc atcagcagtc tgcaacctga agattttgca 240
acttactact gtcaacagag ttacagtacc cctccaacgt tcggccaagg gaccaaggtg 300
gagatcaaa 309
<210>100
<211>327
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-008
<400>100
caggctgtgc tgactcagcc gtcctcggtg tcagtggccc caggagagac ggccagcgtt 60
acctgtgggg gagacaacat tgggagtaag agtgtgcact ggtaccaaaa gaagccaggc 120
caggcccctg tgctggtcgt ctttgatgat agcgaccggc cctcagggat ccctgagcga 180
ttctctggct ccacctctgg gaacacggcc gccctgacca tcagcagggt cgaagccggg 240
gatgaggccg actattactg tcaggtgtgg gatagtagta atgatcatct ttatgtcttc 300
ggacccggga cccagctcac cgtttta 327
<210>101
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-010
<400>101
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tacaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tggcacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtctacaa gattacaatt accctcggac gttcggccaa 300
gggaccaagg tggagatcaa a 321
<210>102
<211>330
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-018
<400>102
cagcctgtgc tgactcagcc cctctcagcg tctgggaccc ccgggcagag ggtcaccatc 60
tcttgttctg gagacacctc caacatcgga agtaatactg tacactggta ccagcgcctc 120
ccaggaacgg cccccaaact cctcatccat aataataatc agcggccctc aggggtccct 180
gaccggttct ctggcgccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240
tctgaggatg aggctgatta tttctgtgca gcatgggatg acaacctgaa tggttatgtc 300
ttcggaactg ggaccaaggt caccgtccta 330
<210>103
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variablre region of SC04-021
<400>103
gacatccaga tgacccagtc tccattctcc ctgtctgctt ctgtcggaga cagagttacc 60
atcacttgcc gggccagtca gggcattggc agttccttag cctggtatca gcaaaaacca 120
gggaaagccc ctaaactcct gatctacgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttattt ctgtctgcag catcatgatt acccgctcac tttcggcgga 300
gggaccaagc tggagatcaa a 321
<210>104
<211>336
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SCO4-026
<400>104
gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
atctcctgca ggtctagtca gagcctcctg catagtaatg gacatgatta cttggattgg 120
tacgtgcaga agccagggca gtctccacag cccctgatct atttgggttc tgatcgggcc 180
tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cacattttac actgaatatc 240
agcagagtgg aggctgagga tgttggggtt tattactgca tgcaatctct acaaactcct 300
tggacttttg gccaggggac caagctggag atcaaa 336
<210>105
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-031
<400>105
gacatccaga tgacccagtc tccatctttc gtgtctgcat ctgtaggaga cagagtcacc 60
atcacttgtc gggcgagtca gggtattagc agttggttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttacta ttgtcaacag gctaacagtt tcccactcac tttcggcgga 300
gggaccaagg tggagatcaa a 321
<210>106
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-038
<400>106
gacatccagt tgactcagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60
atcacttgtc gggcgagtca gggtattagc ggctggttag cctggtatca gcagaaacca 120
gagaaagccc ctaagctcct gatctatgcg gcatccagtt tgcaacgtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttacta ttgtcaacag gctaacagtt tcccccccac cttcggccaa 300
gggacacgac tggagattaa a 321
<210>107
<211>324
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-040
<400>107
cagcctgtgc tgactcagcc cccctcggtg tcagtggccc caggacagac ggccaggatt 60
tcctgtgggg gagacaacat tggaactaat actgtgcagt ggtaccagca gaagccaggc 120
caggcccctg tcctggtcgt ctatgatgat agcgaccggc cctcagggat ccctgagcga 180
ttctctggct ccaactctgg ggacacggcc accctgacca tcagcagggt cgaggccggg 240
gatgaggccg attattactg tcaggtgtgg gatgacagta gtgatctggt ggtattcggc 300
ggagggacca aggtcaccgt ccta 324
<210>108
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-060
<400>108
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattagc acctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaacctcct gatctacggt gcatctaatt tgcaaagtgg ggtcccatca 180
aggttcagtg gcagtgaatc tgggacagat ttcactctca ccatcagcag tctacaacct 240
gaagattttg caacttacta ctgtcagcag agtttcacta cccctcgcac gttcggccaa 300
gggaccaagc tggagatcaa a 321
<210>109
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-073
<400>109
gacatccagt tgacccagtc gccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca cagtattagt agctggttgg cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctataag gcatctagtt tagaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtctacaa gattacaatt accctcggac gttcggccaa 300
gggaccaagc tggagatcaa a 321
<210>110
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-097
<400>110
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tacaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tggcacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtctacaa gattacaatt accctcggac gttcggccaa 300
gggaccaagg tggagatcaa a 321
<210>111
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-098
<400>111
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaacag cttaatagtt accctcccac tttcggcgga 300
gggaccaagg tggaaatcaa a 321
<210>112
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-103
<400>112
gacatccagt tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60
atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaagcca 120
gggaaagccc ctaggtccct gatctatgat gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagac tttactctca ccatcagcag cctgcagcct 240
gaagattttg caacttacta ttgtcaacag gctgacagtt tcccgatcac cttcggccaa 300
gggacacgac tggagattaa a 321
<210>113
<211>327
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-104
<400>113
gacatccagt tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gattcttggt cactggttgc ccttgtcctg gtatcagcag 120
aaaccaggta aagcccctaa actcctgatc tctaaggcgt ctagtttaga aagtggagtc 180
ccaccaaggt tcagcggcag tggatctggg tcagatttca ctctcaccat cagcagcctg 240
cagcccgatg attttgcaac ttattactgc ctccaatatc atgagtaccc gctcaccttc 300
ggcggaggga ccaagctgga gatcaaa 327
<210>114
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-108
<400>114
gacatccagt tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgtc gggcgagtca gggcattagc agtcatttag tctggtatca gcagaaacca 120
gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtgaatc tgcgacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgccaacag tattacagtt accctatcac cttcggccaa 300
gggacacgac tggagattaa a 321
<210>115
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-120
<400>115
gacatccagt tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gggcattaac agttatttag cctggtatca gcaagaacca 120
gggaaagccc ctaaactcct gatctatgct gcatccactt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaacag cttaatagtt accccttcac tttcggccct 300
gggaccaaag tggatatcaa a 321
<210>116
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-125
<400>116
gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60
atcacttgtc gggcgagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120
gggaaagccc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgtcaacaa cttaacagtt acccactcac tttcggcgga 300
gggaccaagg tggagatcaa a 321
<210>117
<211>327
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-126
<400>117
cagtctgtgc tgactcagcc accctcagtg tcagtggccc caggaaagac ggccaggatt 60
acctgtgggg gaaacaacat tggaagtaaa agtgtgcact ggtaccagca gaagccaggc 120
caggcccctg tgctggtcat ctattatgat agcgaccggc cctcagggat ccctgagcga 180
ttctctggct ccaactctgg gaacacggcc accctgacca tcagcagggt cgaagccggg 240
gatgaggctg actattactg tcaggtgtgg gatagtagta gtgatcatcc ctatgtcttc 300
ggaactggga ccaagctgac cgtccta 327
<210>118
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-140
<400>118
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtcggaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattagc agtgctttag cctggtatca gcagaaacca 120
gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaacag tttaatagtt acccgctcac tttcggcgga 300
gggaccaagg tggaaatcaa a 321
<210>119
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-144
<400>119
gacatccagt tgacgcagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120
gggaaaggcc ctaagctcct gatctatgct gcatccactt tacaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagac ttcagtctca ccatcagtag cctgcagcct 240
gaagatttag caacttatta ctgccaacag tatgatagtt accctctcac tttcggcgga 300
gggaccaagg tggaaatcaa a 321
<210>120
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-146
<400>120
gatgttgtga tgactcagtc tccagccacc ctgtctgtgt ctccagggga aagcgccaca 60
ctcttctgca gggccagtga gagtgtttat agcaacttgg cctggtatca gcacaaacct 120
ggccgggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180
aggttcgatg gcactgggtc tgggacagac ttcacactca ccatcagcag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcaa tataatgact ggccgatcac cttcggccaa 300
gggacacgac tggagattaa a 321
<210>121
<211>321
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of SC04-164
<400>121
gacatccagt tgacccagtc tccatcttct gtgtctgcat ctgtaggaga cagagtcacc 60
atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ctatcagcag cctgcagcct 240
gaagattttg caacttacta ttgtcaacag gctaacagtt tcccgctcac tttcggcgga 300
gggaccaaag tggatatcaa a 321
<210>122
<211>2107
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain CR57
<220>
<221>Intron
<222>(382)..(508)
<223>
<220>
<221>Intron
<222>(1687)..(1783)
<223>
<220>
<221>Intron
<222>(1239)..(1356)
<223>
<220>
<221>Intron
<222>(803)..(1193)
<223>
<400>122
caggtgcagc tggtgcagag cggagccgag gtgaagaagc ccggcagcag cgtgaaggtg 60
agctgcaagg ccagcggcgg caccttcaac aggtacaccg tgaactgggt gagacaggcc 120
ccaggccagg gcctggagtg gatgggcggc atcatcccta tcttcggcac cgccaactac 180
gcccagagat tccagggcag gctcaccatc accgccgacg agagcaccag caccgcctac 240
atggagctga gcagcctgag aagcgatgac accgccgtgt acttctgcgc cagggagaac 300
ctggataaca gcggcaccta ctactacttc agcggctggt tcgacccctg gggccagggc 360
accctggtga ccgtgagctc aggtgagtgc ggccgcgagc ccagacactg gacgctgaac 420
ctcgcggaca gttaagaacc caggggcctc tgcgccctgg gcccagctct gtcccacacc 480
gcggtcacat ggcaccacct ctcttgcagc ctccaccaag ggcccatcgg tcttccccct 540
ggcaccctcc tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga 600
ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca 660
caccttcccg gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt 720
gccctccagc agcttgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa 780
caccaaggtg gacaagagag ttggtgagag gccagcacag ggagggaggg tgtctgctgg 840
aagccaggct cagcgctcct gcctggacgc atcccggcta tgcagtccca gtccagggca 900
gcaaggcagg ccccgtctgc ctcttcaccc ggaggcctct gcccgcccca ctcatgctca 960
gggagagggt cttctggctt tttccccagg ctctgggcag gcacaggcta ggtgccccta 1020
acccaggccc tgcacacaaa ggggcaggtg ctgggctcag acctgccaag agccatatcc 1080
gggaggaccc tgcccctgac ctaagcccac cccaaaggcc aaactctcca ctccctcagc 1140
tcggacacct tctctcctcc cagattccag taactcccaa tcttctctct gcagagccca 1200
aatcttgtga caaaactcac acatgcccac cgtgcccagg taagccagcc caggcctcgc 1260
cctccagctc aaggcgggac aggtgcccta gagtagcctg catccaggga caggccccag 1320
ccgggtgctg acacgtccac ctccatctct tcctcagcac ctgaactcct ggggggaccg 1380
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 1440
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 1500
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 1560
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 1620
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1680
gccaaaggtg ggacccgtgg ggtgcgaggg ccacatggac agaggccggc tcggcccacc 1740
ctctgccctg agagtgaccg ctgtaccaac ctctgtccct acagggcagc cccgagaacc 1800
acaggtgtac accctgcccc catcccggga ggagatgacc aagaaccagg tcagcctgac 1860
ctgcctggtc aaaggcttct atcccagcga catcgccgtg gagtgggaga gcaatgggca 1920
gccggagaac aactacaaga ccacgcctcc cgtgctggac tccgacggct ccttcttcct 1980
ctatagcaag ctcaccgtgg acaagagcag gtggcagcag gggaacgtct tctcatgctc 2040
cgtgatgcat gaggctctgc acaaccacta cacgcagaag agcctctccc tgtctccggg 2100
taaatga 2107
<210>123
<211>457
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain CR57
<400>123
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 51 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Asn Arg Tyr
20 25 30
Thr Val Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Arg Phe
50 55 60
Gln Gly Arg Leu Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Glu Asn Leu Asp Asn Ser Gly Thr Tyr Tyr Tyr Phe Ser Gly
100 105 110
Trp Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
115 120 125
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
130 135 140
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
145 150 155 160
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
165 170 175
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
180 185 190
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
195 200 205
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg
210 215 220
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
225 230 235 240
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
245 250 255
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
260 265 270
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
275 280 285
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
290 295 300
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
305 310 315 320
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
325 330 335
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
340 345 350
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
355 360 365
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
370 375 380
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
385 390 395 400
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
405 410 415
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
420 425 430
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
435 440 445
Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210>124
<211>859
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain of CR57
<220>
<221>Intron
<222>(337)..(538)
<223>
<400>124
cagagcgccc tcacccagcc cagaagcgtg agcggcagcc ctggccagag cgtgaccatc 60
agctgcaccg gcaccagcag cgacatcggc ggctacaact tcgtgagctg gtatcagcag 120
caccccggca aggcccctaa gctcatgatc tacgacgcca ccaagagacc cagcggcgtg 180
cccgacagat tcagcggcag caagagcggc aacaccgcca gcctcaccat cagcggactg 240
caggccgagg acgaggccga ctactactgc tgcagctacg ccggcgacta cacccctggc 300
gtggtgttcg gcggaggcac caagcttacc gtcctaggta agtgcacttt gcggccgcta 360
ggaagaaact caaaacatca agattttaaa tacgcttctt ggtctccttg ctataattat 420
ctgggataag catgctgttt tctgtctgtc cctaacatgc cctgtgatta tccgcaaaca 480
acacacccaa gggcagaact ttgttactta aacaccatcc tgtttgcttc tttcctcagg 540
acagcccaag gctgcaccat ctgtgaccct gttccccccc tcctccgagg agctgcaggc 600
caacaaggcc accctggtgt gcctcatcag cgacttctac cctggcgccg tgaccgtggc 660
ctggaaggcc gacagcagcc ccgtgaaggc cggcgtggag accaccaccc ccagcaagca 720
gagcaacaac aagtacgccg ccagcagcta cctgagcctc acccccgagc agtggaagag 780
ccaccggagc tacagctgcc aggtgaccca cgagggcagc accgtggaga agaccgtggc 840
ccccaccgag tgcagctag 859
<210>125
<211>218
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain of CR57
<400>125
Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Gly Tyr
20 25 30
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Ala Thr Lys Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Asp
85 90 95
Tyr Thr Pro Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
115 120 125
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
130 135 140
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
145 150 155 160
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
165 170 175
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
180 185 190
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
195 200 205
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215
<210>126
<211>2089
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain of CRJB
<400>126
cagatcaccc tgaaggagac cggccccacc ctggtgaagc ccacccagac cctcaccctc 60
acctgcacct tcagcggctt cagcctgagc accagcggcg tgggcgtggg ctggatcaga 120
cagccccctg gcaaggccct ggagtgggtg accctcatct actgggacga cgacaagaga 180
tacagcccca gcctggagaa cagggtgacc atccggaagg acaccagcaa gaaccaggtg 240
gccctcacca tgaccaacat ggaccccctg gataccggca cctactactg cgcccacagg 300
cagcacatca gcagcttccc ctggttcgac agctggggcc agggcacact ggtgaccgtg 360
agctcaggtg agtgcggccg cgagcccaga cactggacgc tgaacctcgc ggacagttaa 420
gaacccaggg gcctctgcgc cctgggccca gctctgtccc acaccgcggt cacatggcac 480
cacctctctt gcagcctcca ccaagggccc atcggtcttc cccctggcac cctcctccaa 540
gagcacctct gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc 600
ggtgacggtg tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt 660
cctacagtcc tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt 720
gggcacccag acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa 780
gagagttggt gagaggccag cacagggagg gagggtgtct gctggaagcc aggctcagcg 840
ctcctgcctg gacgcatccc ggctatgcag tcccagtcca gggcagcaag gcaggccccg 900
tctgcctctt cacccggagg cctctgcccg ccccactcat gctcagggag agggtcttct 960
ggctttttcc ccaggctctg ggcaggcaca ggctaggtgc ccctaaccca ggccctgcac 1020
acaaaggggc aggtgctggg ctcagacctg ccaagagcca tatccgggag gaccctgccc 1080
ctgacctaag cccaccccaa aggccaaact ctccactccc tcagctcgga caccttctct 1140
cctcccagat tccagtaact cccaatcttc tctctgcaga gcccaaatct tgtgacaaaa 1200
ctcacacatg cccaccgtgc ccaggtaagc cagcccaggc ctcgccctcc agctcaaggc 1260
gggacaggtg ccctagagta gcctgcatcc agggacaggc cccagccggg tgctgacacg 1320
tccacctcca tctcttcctc agcacctgaa ctcctggggg gaccgtcagt cttcctcttc 1380
cccccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg 1440
gtggacgtga gccacgaaga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag 1500
gtgcataatg ccaagacaaa gccgcgggag gagcagtaca acagcacgta ccgtgtggtc 1560
agcgtcctca ccgtcctgca ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc 1620
tccaacaaag ccctcccagc ccccatcgag aaaaccatct ccaaagccaa aggtgggacc 1680
cgtggggtgc gagggccaca tggacagagg ccggctcggc ccaccctctg ccctgagagt 1740
gaccgctgta ccaacctctg tccctacagg gcagccccga gaaccacagg tgtacaccct 1800
gcccccatcc cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg 1860
cttctatccc agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta 1920
caagaccacg cctcccgtgc tggactccga cggctccttc ttcctctata gcaagctcac 1980
cgtggacaag agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc 2040
tctgcacaac cactacacgc agaagagcct ctccctgtct ccgggtaaa 2089
<210>127
<211>452
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain of CRJB
<400>127
Gln Ile Thr Leu Lys Glu Thr Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu
35 40 45
Trp Val Thr Leu Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Ser Pro Ser
50 55 60
Leu Glu Asn Arg Val Thr Ile Arg Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Ala Leu Thr Met Thr Asn Met Asp Pro Leu Asp Thr Gly Thr Tyr Tyr
85 90 95
Cys Ala His Arg Gln His Ile Ser Ser Phe Pro Trp Phe Asp Ser Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210>128
<211>841
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain of CRJB
<400>128
agctacgtgc tcacccagcc ccccagcgtg agcgtggccc ctggcaagac cgccagaatc 60
aactgcggcg gcaacaacat cgagtaccgg agcgtgcact ggtatcagca gaagagcggc 120
caggcccccg tggccgtgat ctacgacaac agcgacagac ctagcggcat ccccgagaga 180
ttcagcggca gcaagagcgg caacaccgcc accctcacca tcagcagagt ggaggccggc 240
gacgaggccg actactactg ccaggtgtgg gacatcagca gcgatgtggt gttcggcgga 300
ggcaccaagc ttaccgtcct aggtaagtgc actttgcggc cgctaggaag aaactcaaaa 360
catcaagatt ttaaatacgc ttcttggtct ccttgctata attatctggg ataagcatgc 420
tgttttctgt ctgtccctaa catgccctgt gattatccgc aaacaacaca cccaagggca 480
gaactttgtt acttaaacac catcctgttt gcttctttcc tcaggacagc ccaaggctgc 540
accatctgtg accctgttcc ccccctcctc cgaggagctg caggccaaca aggccaccct 600
ggtgtgcctc atcagcgact tctaccctgg cgccgtgacc gtggcctgga aggccgacag 660
cagccccgtg aaggccggcg tggagaccac cacccccagc aagcagagca acaacaagta 720
cgccgccagc agctacctga gcctcacccc cgagcagtgg aagagccacc ggagctacag 780
ctgccaggtg acccacgagg gcagcaccgt ggagaagacc gtggccccca ccgagtgcag 840
c 841
<210>129
<211>213
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain of CRJB
<400>129
Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys
1 5 10 15
Thr Ala Arg Ile Asn Cys Gly Gly Asn Asn Ile Glu Tyr Arg Ser Val
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Gln Ala Pro Val Ala Val Ile Tyr
35 40 45
Asp Asn Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Lys Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ile Ser Ser Asp Val
85 90 95
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala
100 105 110
Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala
115 120 125
Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala
130 135 140
Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val
145 150 155 160
Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser
165 170 175
Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr
180 185 190
Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala
195 200 205
Pro Thr Glu Cys Ser
210
<210>130
<211>12
<212>DNA
<213>Rabies virus
<220>
<221>misc_feature
<223>Part of glycoprotein of CVS-11,E57A2,E57B1,E57B2,E57B3 and E5
7C3
<400>130
atacaccatc tc 12
<210>131
<211>12
<212>DNA
<213>Rabies virus
<220>
<221>misc_feature
<223>Part of glycoprotein of E57A3
<400>131
atacaacatc tc 12
<210>132
<211>18
<212>DNA
<213>Rabies virus
<220>
<221>misc_feature
<223>Part of glycoprotein of CVS-11
<400>132
ctcaagttat gtggagtt 18
<210>133
<211>18
<212>DNA
<213>Rabies virus
<220>
<221>misc_feature
<223>Part of glycoprotein of E57A2
<400>133
ctcaagttat gtgaagtt 18
<210>134
<211>18
<212>DNA
<213>Rabies virus
<220>
<221>misc_feature
<223>Part of glycoprotein of E57A3,E57B1 and E57B3
<400>134
ctcgagttat gtggagtt 18
<210>135
<211>18
<212>DNA
<213>Rabies virus
<220>
<221>misc_feature
<223>Part of glycoprotein of E57B2 and E57C3
<400>135
ctcaatttat gtggagtt 18
<210>136
<211>16
<212>PRT
<213>Rabies virus
<220>
<221>MISC_FEATURE
<223>Part of glycoprotein of CVS-11,E57A2,E57B1,E57B2,E57B3 and E5
7C3
<400>136
Gly Pro Trp Ser Pro Ile Asp Ile His His Leu Ser Cys Pro Asn Asn
1 5 10 15
<210>137
<211>16
<212>PRT
<213>Rabies virus
<220>
<221>MISC_FEATURE
<223>Part of glycoprotein of E57A3
<400>137
Gly Pro Trp Ser Pro Ile Asp Ile Gln His Leu Ser Cys Pro Asn Asn
1 5 10 15
<210>138
<211>23
<212>PRT
<213>Rabies virus
<220>
<221>MISC_FEATURE
<223>Part of glycoprotein of CVS-11
<400>138
Ser Leu Lys Gly Ala Cys Arg Leu Lys Leu Cys Gly Val Leu Gly Leu
1 5 10 15
Arg Leu Met Asp Gly Thr Trp
20
<210>139
<211>23
<212>PRT
<213>Rabies virus
<220>
<221>MISC_FEATURE
<223>Part of glycoprotein of E57A2
<400>139
Ser Leu Lys Gly Ala Cys Arg Leu Lys Leu Cys Glu Val Leu Gly Leu
1 5 10 15
Arg Leu Met Asp Gly Thr Trp
20
<210>140
<211>23
<212>PRT
<213>Rabies virus
<220>
<221>MISC_FEATURE
<223>Part of glycoprotein of E57A3,E57B1 and E57B3
<400>140
Ser Leu Lys Gly Ala Cys Arg Leu Glu Leu Cys Gly Val Leu Gly Leu
1 5 10 15
Arg Leu Met Asp Gly Thr Trp
20
<210>141
<211>23
<212>PRT
<213>Rabies virus
<220>
<221>MISC_FEATURE
<223>Part of glycoprotein of E57B2 and E57C3
<400>141
Ser Leu Lys Gly Ala Cys Arg Leu Asn Leu Cys Gly Val Leu Gly Leu
1 5 10 15
Arg Leu Met Asp Gly Thr Trp
20
<210>142
<211>15
<212>DNA
<213>Rabies virus
<220>
<221>misc_feature
<223>Part of glycoprotein of CVS-11
<400>142
cccgagaatc cgaga 15
<210>143
<211>15
<212>DNA
<213>Rabies virus
<220>
<221>misc_feature
<223>Part of glycoprotein of EJB2B,EJB2C,EJB2D,EJB2E,EJB2F and EJB
3F
<400>143
cccgaggatc cgaga 15
<210>144
<211>15
<212>DNA
<213>Rabies virus
<220>
<221>misc_feature
<223>Part of glycoprotein of CVS-11
<400>144
tgtggagttc ttgga 15
<210>145
<211>15
<212>DNA
<213>Rabies virus
<220>
<221>misc_feature
<223>Part of glycoprotein of EJB2B,EJB2C and EJB2F
<400>145
tgtgaagttc ctgga 15
<210>146
<211>15
<212>DNA
<213>Rabies virus
<220>
<221>misc_feature
<223>Part of glycoprotein of EJB2D,EJB2E and EJB3F
<400>146
tgtggagttc ctgga 15
<210>147
<211>13
<212>PRT
<213>Rabies virus
<220>
<221>MISC FEATURE
<223>Part of glycoprotein of CVS-11
<400>147
Tyr Thr Ile Trp Met Pro Glu Asn Pro Arg Leu Gly Met
1 5 10
<210>148
<211>13
<212>PRT
<213>Rabies virus
<220>
<221>MISC_FEATURE
<223>Part of glycoprotein of EJB2B,EJB2C,EJB2D,EJB2E,EJB2F and EJB
3F
<400>148
Tyr Thr Ile Trp Met Pro Glu Asp Pro Arg Leu Gly Met
1 5 10
<210>149
<211>23
<212>PRT
<213>Rabies virus
<220>
<221>MISC_FEATURE
<223>Part of glycoprotein of CVS-11
<400>149
Ser Leu Lys Gly Ala Cys Arg Leu Lys Leu Cys Gly Val Leu Gly Leu
1 5 10 15
Arg Leu Met Asp Gly Thr Trp
20
<210>150
<211>23
<212>PRT
<213>Rabies virus
<220>
<221>MISC_FEATURE
<223>Part of glycoprotein of EJB2B,EJB2C and EJB2F
<400>150
Ser Leu Lys Gly Ala Cys Arg Leu Lys Leu Cys Glu Val Pro Gly Leu
1 5 10 15
Arg Leu Met Asp Gly Thr Trp
20
<210>151
<211>23
<212>PRT
<213>Rabies virus
<220>
<221>MISC_FEATURE
<223>Part of glycoprotein of EJB2D,EJB2E and EJB3F
<400>151
Ser Leu Lys Gly Ala Cys Arg Leu Lys Leu Cys Gly Val Pro Gly Leu
1 5 10 15
Arg Leu Met Asp Gly Thr Trp
20
<210>152
<211>24
<212>DNA
<213>Artificial sequence
<220>
<223>Anti-sense primer HuCkappa
<400>152
acactctccc ctgttgaagc tctt 24
<210>153
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Anti-sense primer HuClambda2
<400>153
tgaacattct gtaggggcca ctg 23
<210>154
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Anti-sense primer HuClambda7
<400>154
agagcattct gcaggggcca ctg 23
<210>155
<211>4941
<212>DNA
<213>Artificial sequence
<220>
<223>Vector PDV-C06
<400>155
aagcttgcat gcaaattcta tttcaaggag acagtcataa tgaaatacct attgcctacg 60
gcagccgctg gattgttatt actcgcggcc cagccggcca tggccgaggt gtttgactaa 120
tggggcgcgc ctcagggaac cctggtcacc gtctcgagcg gtacgggcgg ttcaggcgga 180
accggcagcg gcactggcgg gtcgacggaa attgtgctca cacagtctcc agccaccctg 240
tctttgtctc caggggaaag agccaccctc tcctgcaggg ccagtcagag tgttagcagc 300
tacttagcct ggtaccaaca gaaacctggc caggctccca ggctcctcat ctatgatgca 360
tccaacaggg ccactggcat cccagccagg ttcagtggca gtgggtctgg gacagacttc 420
actctcacca tcagcagcct agagcctgaa gattttgcag tttattactg tcagcagcgt 480
agcaactggc ctccggcttt cggcggaggg accaaggtgg agatcaaacg tgcggccgca 540
catcatcatc accatcacgg ggccgcatat accgatattg aaatgaaccg cctgggcaaa 600
ggggccgcat agactgttga aagttgttta gcaaaacctc atacagaaaa ttcatttact 660
aacgtctgga aagacgacaa aactttagat cgttacgcta actatgaggg ctgtctgtgg 720
aatgctacag gcgttgtggt ttgtactggt gacgaaactc agtgttacgg tacatgggtt 780
cctattgggc ttgctatccc tgaaaatgag ggtggtggct ctgagggtgg cggttctgag 840
ggtggcggtt ctgagggtgg cggtactaaa cctcctgagt acggtgatac acctattccg 900
ggctatactt atatcaaccc tctcgacggc acttatccgc ctggtactga gcaaaacccc 960
gctaatccta atccttctct tgaggagtct cagcctctta atactttcat gtttcagaat 1020
aataggttcc gaaataggca gggtgcatta actgtttata cgggcactgt tactcaaggc 1080
actgaccccg ttaaaactta ttaccagtac actcctgtat catcaaaagc catgtatgac 1140
gcttactgga acggtaaatt cagagactgc gctttccatt ctggctttaa tgaggatcca 1200
ttcgtttgtg aatatcaagg ccaatcgtct gacctgcctc aacctcctgt caatgctggc 1260
ggcggctctg gtggtggttc tggtggcggc tctgagggtg gcggctctga gggtggcggt 1320
tctgagggtg gcggctctga gggtggcggt tccggtggcg gctccggttc cggtgatttt 1380
gattatgaaa aaatggcaaa cgctaataag ggggctatga ccgaaaatgc cgatgaaaac 1440
gcgctacagt ctgacgctaa aggcaaactt gattctgtcg ctactgatta cggtgctgct 1500
atcgatggtt tcattggtga cgtttccggc cttgctaatg gtaatggtgc tactggtgat 1560
tttgctggct ctaattccca aatggctcaa gtcggtgacg gtgataattc acctttaatg 1620
aataatttcc gtcaatattt accttctttg cctcagtcgg ttgaatgtcg cccttatgtc 1680
tttggcgctg gtaaaccata tgaattttct attgattgtg acaaaataaa cttattccgt 1740
ggtgtctttg cgtttctttt atatgttgcc acctttatgt atgtattttc gacgtttgct 1800
aacatactgc gtaataagga gtcttaataa gaattcactg gccgtcgttt tacaacgtcg 1860
tgactgggaa aaccctggcg ttacccaact taatcgcctt gcagcacatc cccctttcgc 1920
cagctggcgt aatagcgaag aggcccgcac cgatcgccct tcccaacagt tgcgcagcct 1980
gaatggcgaa tggcgcctga tgcggtattt tctccttacg catctgtgcg gtatttcaca 2040
ccgcatacgt caaagcaacc atagtacgcg ccctgtagcg gcgcattaag cgcggcgggt 2100
gtggtggtta cgcgcagcgt gaccgctaca cttgccagcg ccctagcgcc cgctcctttc 2160
gctttcttcc cttcctttct cgccacgttc gccggctttc cccgtcaagc tctaaatcgg 2220
gggctccctt tagggttccg atttagtgct ttacggcacc tcgaccccaa aaaacttgat 2280
ttgggtgatg gttcacgtag tgggccatcg ccctgataga cggtttttcg ccctttgacg 2340
ttggagtcca cgttctttaa tagtggactc ttgttccaaa ctggaacaac actcaaccct 2400
atctcgggct attcttttga tttataaggg attttgccga tttcggccta ttggttaaaa 2460
aatgagctga tttaacaaaa atttaacgcg aattttaaca aaatattaac gtttacaatt 2520
ttatggtgca ctctcagtac aatctgctct gatgccgcat agttaagcca gccccgacac 2580
ccgccaacac ccgctgacgc gccctgacgg gcttgtctgc tcccggcatc cgcttacaga 2640
caagctgtga ccgtctccgg gagctgcatg tgtcagaggt tttcaccgtc atcaccgaaa 2700
cgcgcgagac gaaagggcct cgtgatacgc ctatttttat aggttaatgt catgataata 2760
atggtttctt agacgtcagg tggcactttt cggggaaatg tgcgcggaac ccctatttgt 2820
ttatttttct aaatacattc aaatatgtat ccgctcatga gacaataacc ctgataaatg 2880
cttcaataat attgaaaaag gaagagtatg agtattcaac atttccgtgt cgcccttatt 2940
cccttttttg cggcattttg ccttcctgtt tttgctcacc cagaaacgct ggtgaaagta 3000
aaagatgctg aagatcagtt gggtgcacga gtgggttaca tcgaactgga tctcaacagc 3060
ggtaagatcc ttgagagttt tcgccccgaa gaacgttttc caatgatgag cacttttaaa 3120
gttctgctat gtggcgcggt attatcccgt attgacgccg ggcaagagca actcggtcgc 3180
cgcatacact attctcagaa tgacttggtt gagtactcac cagtcacaga aaagcatctt 3240
acggatggca tgacagtaag agaattatgc agtgctgcca taaccatgag tgataacact 3300
gcggccaact tacttctgac aacgatcgga ggaccgaagg agctaaccgc ttttttgcac 3360
aacatggggg atcatgtaac tcgccttgat cgttgggaac cggagctgaa tgaagccata 3420
ccaaacgacg agcgtgacac cacgatgcct gtagcaatgg caacaacgtt gcgcaaacta 3480
ttaactggcg aactacttac tctagcttcc cggcaacaat taatagactg gatggaggcg 3540
gataaagttg caggaccact tctgcgctcg gcccttccgg ctggctggtt tattgctgat 3600
aaatctggag ccggtgagcg tgggtctcgc ggtatcattg cagcactggg gccagatggt 3660
aagccctccc gtatcgtagt tatctacacg acggggagtc aggcaactat ggatgaacga 3720
aatagacaga tcgctgagat aggtgcctca ctgattaagc attggtaact gtcagaccaa 3780
gtttactcat atatacttta gattgattta aaacttcatt tttaatttaa aaggatctag 3840
gtgaagatcc tttttgataa tctcatgacc aaaatccctt aacgtgagtt ttcgttccac 3900
tgagcgtcag accccgtaga aaagatcaaa ggatcttctt gagatccttt ttttctgcgc 3960
gtaatctgct gcttgcaaac aaaaaaacca ccgctaccag cggtggtttg tttgccggat 4020
caagagctac caactctttt tccgaaggta actggcttca gcagagcgca gataccaaat 4080
actgtccttc tagtgtagcc gtagttaggc caccacttca agaactctgt agcaccgcct 4140
acatacctcg ctctgctaat cctgttacca gtggctgctg ccagtggcga taagtcgtgt 4200
cttaccgggt tggactcaag acgatagtta ccggataagg cgcagcggtc gggctgaacg 4260
gggggttcgt gcacacagcc cagcttggag cgaacgacct acaccgaact gagataccta 4320
cagcgtgagc tatgagaaag cgccacgctt cccgaaggga gaaaggcgga caggtatccg 4380
gtaagcggca gggtcggaac aggagagcgc acgagggagc ttccaggggg aaacgcctgg 4440
tatctttata gtcctgtcgg gtttcgccac ctctgacttg agcgtcgatt tttgtgatgc 4500
tcgtcagggg ggcggagcct atggaaaaac gccagcaacg cggccttttt acggttcctg 4560
gccttttgct ggccttttgc tcacatgttc tttcctgcgt tatcccctga ttctgtggat 4620
aaccgtatta ccgcctttga gtgagctgat accgctcgcc gcagccgaac gaccgagcgc 4680
agcgagtcag tgagcgagga agcggaagag cgcccaatac gcaaaccgcc tctccccgcg 4740
cgttggccga ttcattaatg cagctggcac gacaggtttc ccgactggaa agcgggcagt 4800
gagcgcaacg caattaatgt gagttagctc actcattagg caccccaggc tttacacttt 4860
atgcttccgg ctcgtatgtt gtgtggaatt gtgagcggat aacaatttca cacaggaaac 4920
agctatgacc atgattacgc c 4941
<210>156
<211>24
<212>DNA
<213>Artificial sequence
<220>
<223>Anti-sense primer HuCIgG
<400>156
gtccaccttg gtgttgctgg gctt 24
<210>157
<211>741
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-001
<220>
<221>CDS
<222>(1)..(741)
<223>
<400>157
gcc atg gcc gag gtg cag ctg gtg gag tct ggg gga ggt gtg gta cgg 48
Ala Met Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg
1 5 10 15
cct ggg ggg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttt 96
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
gat gat tat ggc atg agc tgg gtc cgc caa gct cca ggg aag ggg ctg 144
Asp Asp Tyr Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtc tct ggt att aat tgg aat ggt ggt agc aca ggt tat gca 192
Glu Trp Val Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala
50 55 60
gac tct gtg aag ggc cga ttc acc atc tcc aga gac aac gcc aag aac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
65 70 75 80
tcc ctg tat ctg caa atg aac agt ctg aga gcc gag gac acg gcc gtg 288
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gca aag ggc ctt tat ggg gag ctt ttt gac tac tgg ggc 336
Tyr Tyr Cys Ala Lys Gly Leu Tyr Gly Glu Leu Phe Asp Tyr Trp Gly
100 105 110
caa ggt acc ctg gtc acc gtc tcg aga ggt gga ggc ggt tca ggc gga 384
Gln Gly Thr Leu Val Thr Val Ser Arg Gly Gly Gly Gly Ser Gly Gly
115 120 125
ggt ggc tct ggc ggt ggc gga tcg tct gag ctg act cag gac cct gct 432
Gly Gly Ser Gly Gly Gly Gly Ser Ser Glu Leu Thr Gln Asp Pro Ala
130 135 140
gtg tct gtg gcc ttg gga cag aca gtc agg atc aca tgc caa gga gac 480
Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys Gln Gly Asp
145 150 155 160
agc ctc aga agc tat tat gca agc tgg tac cag cag aag cca gga cag 528
Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln
165 170 175
gcc cct gta ctt gtc atc tat ggt aaa aac aac cgg ccc tca ggg atc 576
Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile
180 185 190
cca gac cga ttc tct ggc tcc agc tca gga aac aca gct tcc ttg acc 624
Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr
195 200 205
atc act ggg gct cag gcg gaa gat gag gct gac tat tac tgt aac tcc 672
Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser
210 215 220
cgg gac agc agt ggt aac cat gtg gta ttc ggc gga ggg acc aag ctg 720
Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
acc gtc cta ggt gcg gcc gca 741
Thr Val Leu Gly Ala Ala Ala
245
<210>158
<211>247
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-001
<400>158
Ala Met Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg
1 5 10 15
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Asp Asp Tyr Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
65 70 75 80
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Gly Leu Tyr Gly Glu Leu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Arg Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Ser Glu Leu Thr Gln Asp Pro Ala
130 135 140
Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys Gln Gly Asp
145 150 155 160
Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln
165 170 175
Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr
195 200 205
Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser
210 215 220
Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Thr Val Leu Gly Ala Ala Ala
245
<210>159
<211>741
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-004
<220>
<221>CDS
<222>(1)..(741)
<223>
<400>159
tcc atg gct gag gtg cag ctg gtg gag tct ggg gga ggc ttg gtc cag 48
Ser Met Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
1 5 10 15
cct ggg ggg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc 96
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agc aac tac tgg atg aac tgg gtc cgc cag gcg ccc ggg aag ggg ctg 144
Ser Asn Tyr Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtc tca gct att agt ggt agt ggt ggt agc aca tac tac gca 192
Glu Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
50 55 60
gac tcc gtg aag ggc cgg ttc acc atc tcc aga gac aat tcc aag aac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
acg ctg tat ctg caa atg aac agc ctg aga gcc gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcc aaa gac tac ctc tac ccc acc acc gac ttc gat tac 336
Tyr Tyr Cys Ala Lys Asp Tyr Leu Tyr Pro Thr Thr Asp Phe Asp Tyr
100 105 110
tgg ggc cag ggc acc ctg gtg acc gtg ctc gag ggt acc gga ggt tcc 384
Trp Gly Gln Gly Thr Leu Val Thr Val Leu Glu Gly Thr Gly Gly Ser
115 120 125
ggc gga acc ggg tct ggg act ggt acg agc gag ctc acc cag tct cca 432
Gly Gly Thr Gly Ser Gly Thr Gly Thr Ser Glu Leu Thr Gln Ser Pro
130 135 140
tcc tcc ctg tct gca tct gta gga gac aga gtc acc atc act tgc cgg 480
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
145 150 155 160
gca agt cag agc att agc agc tac tta aat tgg tat cag cag aaa cca 528
Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
ggg aaa gcc cct aag ctc ctg atc tat gct gca tcc agt ttg caa agt 576
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser
180 185 190
ggg gtc cca tca agg ttc agt ggc agt gga tct ggg aca gat ttc act 624
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
ctc acc atc agc agt ctg caa cct gaa gat ttt gca act tac tac tgt 672
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
caa cag agt tac agt acc cct cca acg ttc ggc caa ggg acc aag gtg 720
Gln Gln Ser Tyr Ser Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val
225 230 235 240
gag atc aaa cgt gcg gcc gca 741
Glu Ile Lys Arg Ala Ala Ala
245
<210>160
<211>247
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-004
<400>160
Ser Met Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
1 5 10 15
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Asn Tyr Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Asp Tyr Leu Tyr Pro Thr Thr Asp Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Leu Glu Gly Thr Gly Gly Ser
115 120 125
Gly Gly Thr Gly Ser Gly Thr Gly Thr Ser Glu Leu Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
145 150 155 160
Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Ser Tyr Ser Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val
225 230 235 240
Glu Ile Lys Arg Ala Ala Ala
245
<210>161
<211>756
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-008
<220>
<221>CDS
<222>(1)..(756)
<223>
<400>161
gcc atg gcc cag gtc acc ttg aag gag tct ggt cct acg ctg gtg aaa 48
Ala Met Ala Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys
1 5 10 15
ccc aca cag acc ctc acg ctg acc tgc acc ttc tct ggg ttc tca ctc 96
Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu
20 25 30
agc act agt gga gtg ggt gtg ggc tgg atc cgt cag ccc cca gga aag 144
Ser Thr Ser Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys
35 40 45
gcc ctg gag tgg ctt gca cgc att gat tgg gat gat gat aaa tac tac 192
Ala Leu Glu Trp Leu Ala Arg Ile Asp Trp Asp Asp Asp Lys Tyr Tyr
50 55 60
agc aca tct ctg aag acc agg ctc acc atc tcc aag gac acc tcc aaa 240
Ser Thr Ser Leu Lys Thr Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys
65 70 75 80
aac cag gtg gtc ctt aca atg acc aac atg gac cct gtg gac aca gcc 288
Asn Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala
85 90 95
acg tat tac tgt gca cgg atg ggt ttc act gga acc tac ttt gac tac 336
Thr Tyr Tyr Cys Ala Arg Met Gly Phe Thr Gly Thr Tyr Phe Asp Tyr
100 105 110
tgg ggc cag ggc acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca 384
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser
115 120 125
ggc gga acc ggc agc ggc act ggc ggg tcg acg cag gct gtg ctg act 432
Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Gln Ala Val Leu Thr
130 135 140
cag ccg tcc tcg gtg tca gtg gcc cca gga gag acg gcc agc gtt acc 480
Gln Pro Ser Ser Val Ser Val Ala Pro Gly Glu Thr Ala Ser Val Thr
145 150 155 160
tgt ggg gga gac aac att ggg agt aag agt gtg cac tgg tac caa aag 528
Cys Gly Gly Asp Asn Ile Gly Ser Lys Ser Val His Trp Tyr Gln Lys
165 170 175
aag cca ggc cag gcc cct gtg ctg gtc gtc ttt gat gat agc gac cgg 576
Lys Pro Gly Gln Ala Pro Val Leu Val Val Phe Asp Asp Ser Asp Arg
180 185 190
ccc tca ggg atc cct gag cga ttc tct ggc tcc acc tct ggg aac acg 624
Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Thr Ser Gly Asn Thr
195 200 205
gcc gcc ctg acc atc agc agg gtc gaa gcc ggg gat gag gcc gac tat 672
Ala Ala Leu Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp Tyr
210 215 220
tac tgt cag gtg tgg gat agt agt aat gat cat ctt tat gtc ttc gga 720
Tyr Cys Gln Val Trp Asp Ser Ser Asn Asp His Leu Tyr Val Phe Gly
225 230 235 240
ccc ggg acc cag ctc acc gtt tta agt gcg gcc gca 756
Pro Gly Thr Gln Leu Thr Val Leu Ser Ala Ala Ala
245 250
<210>162
<211>252
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-008
<400>162
Ala Met Ala Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys
1 5 10 15
Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu
20 25 30
Ser Thr Ser Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys
35 40 45
Ala Leu Glu Trp Leu Ala Arg Ile Asp Trp Asp Asp Asp Lys Tyr Tyr
50 55 60
Ser Thr Ser Leu Lys Thr Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys
65 70 75 80
Asn Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala
85 90 95
Thr Tyr Tyr Cys Ala Arg Met Gly Phe Thr Gly Thr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser
115 120 125
Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Gln Ala Val Leu Thr
130 135 140
Gln Pro Ser Ser Val Ser Val Ala Pro Gly Glu Thr Ala Ser Val Thr
145 150 155 160
Cys Gly Gly Asp Asn Ile Gly Ser Lys Ser Val His Trp Tyr Gln Lys
165 170 175
Lys Pro Gly Gln Ala Pro Val Leu Val Val Phe Asp Asp Ser Asp Arg
180 185 190
Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Thr Ser Gly Asn Thr
195 200 205
Ala Ala Leu Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Gln Val Trp Asp Ser Ser Asn Asp His Leu Tyr Val Phe Gly
225 230 235 240
Pro Gly Thr Gln Leu Thr Val Leu Ser Ala Ala Ala
245 250
<210>163
<211>759
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-010
<220>
<221>CDS
<222>(1)..(759)
<223>
<400>163
gcc atg gcc cag gtg cag ctg gtg cag tct ggg gga gac ttg gtc cag 48
Ala Met Ala Gln Val Gln Leu Val Gln Ser Gly Gly Asp Leu Val Gln
1 5 10 15
cct ggg agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc 96
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agt agc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg 144
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gca gat ata tca tat gat gga agt aat aaa tac tat gca 192
Glu Trp Val Ala Asp Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
50 55 60
gac tcc gtg aag ggc cga ttc acc att tcc aga gac aat tcc aag aac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
acg ctg tat ctg caa atg aac agc ctg aga gct gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aaa gat ggg ctg gat tta act gga acg att cag cca 336
Tyr Tyr Cys Ala Lys Asp Gly Leu Asp Leu Thr Gly Thr Ile Gln Pro
100 105 110
ttt ggc tac tgg ggc cag gga acc ctg gtc acc gtc tcg agc ggt acg 384
Phe Gly Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr
115 120 125
ggc ggt tca ggc gga acc ggc agc ggc act ggc ggg tcg acg gac atc 432
Gly Gly Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile
130 135 140
cag atg acc cag tct cca tcc tcc ctg tct gca tct gta gga gac aga 480
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
145 150 155 160
gtc acc atc act tgc cgg gca agt cag ggc att aga aat gat tta ggc 528
Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly
165 170 175
tgg tat cag cag aaa cca ggg aaa gcc cct aag ctc ctg atc tat gct 576
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala
180 185 190
gca tcc agt tta caa agt ggg gtc cca tca agg ttc agc ggc agt gga 624
Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
tct ggc aca gat ttc act ctc acc atc agc agc ctg cag cct gaa gat 672
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
ttt gca act tat tac tgt cta caa gat tac aat tac cct cgg acg ttc 720
Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Asn Tyr Pro Arg Thr Phe
225 230 235 240
ggc caa ggg acc aag gtg gag atc aaa cgt gcg gcc gca 759
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ala Ala Ala
245 250
<210>164
<211>253
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-010
<400>164
Ala Met Ala Gln Val Gln Leu Val Gln Ser Gly Gly Asp Leu Val Gln
1 5 10 15
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Asp Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Asp Gly Leu Asp Leu Thr Gly Thr Ile Gln Pro
100 105 110
Phe Gly Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr
115 120 125
Gly Gly Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala
180 185 190
Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Asn Tyr Pro Arg Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ala Ala Ala
245 250
<210>165
<211>756
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-018
<220>
<221>CDS
<222>(1)..(756)
<223>
<400>165
gcc atg gcc gag gtg cag ctg gtg gag tct ggc cca gga ctg gtg agg 48
Ala Met Ala Glu Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Arg
1 5 10 15
cct tcg ggg acc ctg tcc ctc acc tgc gct gtc tct ggt ggc tcc atc 96
Pro Ser Gly Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile
20 25 30
agc agt agt aac tgg tgg agt tgg gtc cgc cag ccc cca ggg aag ggg 144
Ser Ser Ser Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly
35 40 45
ctg gag tgg att ggg gaa atc tat cat agt ggg agc acc aac tac aac 192
Leu Glu Trp Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn
50 55 60
ccg tcc ctc aag agt cga gtc acc ata tca gta gac aag tcc aag aac 240
Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn
65 70 75 80
cag ttc tcc ctg aag ctg agc tct gtg acc gcc gcg gac acg gcc gtg 288
Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
85 90 95
tat tac tgt gcg aga gtt tct gtg act acg ggt gct ttt aat atc tgg 336
Tyr Tyr Cys Ala Arg Val Ser Val Thr Thr Gly Ala Phe Asn Ile Trp
100 105 110
ggc caa ggg aca atg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc 384
Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
gga acc ggc agc ggc act ggc ggg tcg acg cag cct gtg ctg act cag 432
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Gln Pro Val Leu Thr Gln
130 135 140
ccc ctc tca gcg tct ggg acc ccc ggg cag agg gtc acc atc tct tgt 480
Pro Leu Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys
145 150 155 160
tct gga gac acc tcc aac atc gga agt aat act gta cac tgg tac cag 528
Ser Gly Asp Thr Ser Asn Ile Gly Ser Asn Thr Val His Trp Tyr Gln
165 170 175
cgc ctc cca gga acg gcc ccc aaa ctc ctc atc cat aat aat aat cag 576
Arg Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile His Asn Asn Asn Gln
180 185 190
cgg ccc tca ggg gtc cct gac cgg ttc tct ggc gcc aag tct ggc acc 624
Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ala Lys Ser Gly Thr
195 200 205
tca gcc tcc ctg gcc atc agt ggg ctc cag tct gag gat gag gct gat 672
Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp
210 215 220
tat ttc tgt gca gca tgg gat gac aac ctg aat ggt tat gtc ttc gga 720
Tyr Phe Cys Ala Ala Trp Asp Asp Asn Leu Asn Gly Tyr Val Phe Gly
225 230 235 240
act ggg acc aag gtc acc gtc cta ggt gcg gcc gca 756
Thr Gly Thr Lys Val Thr Val Leu Gly Ala Ala Ala
245 250
<210>166
<211>252
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-018
<400>166
Ala Met Ala Glu Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Arg
1 5 10 15
Pro Ser Gly Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile
20 25 30
Ser Ser Ser Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly
35 40 45
Leu Glu Trp Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn
50 55 60
Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn
65 70 75 80
Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Arg Val Ser Val Thr Thr Gly Ala Phe Asn Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Gln Pro Val Leu Thr Gln
130 135 140
Pro Leu Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys
145 150 155 160
Ser Gly Asp Thr Ser Asn Ile Gly Ser Asn Thr Val His Trp Tyr Gln
165 170 175
Arg Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile His Asn Asn Asn Gln
180 185 190
Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ala Lys Ser Gly Thr
195 200 205
Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp
210 215 220
Tyr Phe Cys Ala Ala Trp Asp Asp Asn Leu Asn Gly Tyr Val Phe Gly
225 230 235 240
Thr Gly Thr Lys Val Thr Val Leu Gly Ala Ala Ala
245 250
<210>167
<211>747
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-021
<220>
<221>CDS
<222>(1)..(747)
<223>
<400>167
gcc atg gcc gag gtg cag ctg gtg gag tct ggg gga ggc gtg gtc cag 48
Ala Met Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
1 5 10 15
cct ggg agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc 96
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agt agc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg 144
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gca gtt ata tca tat gat gga agt agt aaa tat tat gca 192
Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Ser Ser Lys Tyr Tyr Ala
50 55 60
gac tcc gtg aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
acg ctg tat ctg caa atg aac agc ctg aga gct gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aaa ggg tcc gtc ctc ggt gat gct ttt gat atc tgg 336
Tyr Tyr Cys Ala Lys Gly Ser Val Leu Gly Asp Ala Phe Asp Ile Trp
100 105 110
ggc caa ggg aca atg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc 384
Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
gga acc ggc agc ggc act ggc ggg tcg acg gac atc cag atg acc cag 432
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Met Thr Gln
130 135 140
tct cca ttc tcc ctg tct gct tct gtc gga gac aga gtt acc atc act 480
Ser Pro Phe Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
tgc cgg gcc agt cag ggc att ggc agt tcc tta gcc tgg tat cag caa 528
Cys Arg Ala Ser Gln Gly Ile Gly Ser Ser Leu Ala Trp Tyr Gln Gln
165 170 175
aaa cca ggg aaa gcc cct aaa ctc ctg atc tac gct gca tcc agt ttg 576
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
180 185 190
caa agt ggg gtc cca tca agg ttc agc ggc agt gga tct ggg aca gat 624
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
ttc act ctc acc atc agc agc ctg cag cct gaa gat ttt gca act tat 672
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
ttc tgt ctg cag cat cat gat tac ccg ctc act ttc ggc gga ggg acc 720
Phe Cys Leu Gln His His Asp Tyr Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
aag ctg gag atc aaa cgt gcg gcc gca 747
Lys Leu Glu Ile Lys Arg Ala Ala Ala
245
<210>168
<211>249
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-021
<400>168
Ala Met Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
1 5 10 15
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Ser Ser Lys Tyr Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Gly Ser Val Leu Gly Asp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Met Thr Gln
130 135 140
Ser Pro Phe Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Arg Ala Ser Gln Gly Ile Gly Ser Ser Leu Ala Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
180 185 190
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
Phe Cys Leu Gln His His Asp Tyr Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Leu Glu Ile Lys Arg Ala Ala Ala
245
<210>169
<211>768
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-026
<220>
<221>CDS
<222>(1)..(768)
<223>
<400>169
gcc atg gcc gag gtg cag ctg gtg gag tct gga gca gag gtg aag aag 48
Ala Met Ala Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys
1 5 10 15
ccg ggg gaa tct ctg aag atc tcc tgt aag ggt tct gga tac aac ttt 96
Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Asn Phe
20 25 30
ccc tac tcc tgg atc gcc tgg gtg cgc cag atg ccc ggg aaa ggc ctg 144
Pro Tyr Ser Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu
35 40 45
gag tgg atg ggg atc atc ttt cct ggt gac tct gac acc aga tat agt 192
Glu Trp Met Gly Ile Ile Phe Pro Gly Asp Ser Asp Thr Arg Tyr Ser
50 55 60
ccg ccc ttc caa ggc cag gtc acc atc tca gcc gac aac tcc aaa agc 240
Pro Pro Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Asn Ser Lys Ser
65 70 75 80
acc gcc tac ctg cag tgg agt agc ctg aag gcc tcg gac acc gcc atg 288
Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met
85 90 95
tat tac tgt gcg cgg acc tcg aac tgg aac tat ttg gac cgg ttc gac 336
Tyr Tyr Cys Ala Arg Thr Ser Asn Trp Asn Tyr Leu Asp Arg Phe Asp
100 105 110
ccc tgg ggc cag ggc acc ctg gtc acc gtc tcg agc ggt acg ggc ggt 384
Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly
115 120 125
tca ggc gga acc ggc agc ggc act ggc ggg tcg acg gat gtt gtg atg 432
Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Val Val Met
130 135 140
act cag tct cca ctc tcc ctg ccc gtc acc cct gga gag ccg gcc tcc 480
Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser
145 150 155 160
atc tcc tgc agg tct agt cag agc ctc ctg cat agt aat gga cat gat 528
Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly His Asp
165 170 175
tac ttg gat tgg tac gtg cag aag cca ggg cag tct cca cag ccc ctg 576
Tyr Leu Asp Trp Tyr Val Gln Lys Pro Gly Gln Ser Pro Gln Pro Leu
180 185 190
atc tat ttg ggt tct gat cgg gcc tcc ggg gtc cct gac agg ttc agt 624
Ile Tyr Leu Gly Ser Asp Arg Ala Ser Gly Val Pro Asp Arg Phe Ser
195 200 205
ggc agt gga tca ggc aca cat ttt aca ctg aat atc agc aga gtg gag 672
Gly Ser Gly Ser Gly Thr His Phe Thr Leu Asn Ile Ser Arg Val Glu
210 215 220
gct gag gat gtt ggg gtt tat tac tgc atg caa tct cta caa act cct 720
Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser Leu Gln Thr Pro
225 230 235 240
tgg act ttt ggc cag ggg acc aag ctg gag atc aaa cgt gcg gcc gca 768
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Ala Ala Ala
245 250 255
<210>170
<211>256
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-026
<400>170
Ala Met Ala Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys
1 5 10 15
Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Asn Phe
20 25 30
Pro Tyr Ser Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu
35 40 45
Glu Trp Met Gly Ile Ile Phe Pro Gly Asp Ser Asp Thr Arg Tyr Ser
50 55 60
Pro Pro Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Asn Ser Lys Ser
65 70 75 80
Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met
85 90 95
Tyr Tyr Cys Ala Arg Thr Ser Asn Trp Asn Tyr Leu Asp Arg Phe Asp
100 105 110
Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly
115 120 125
Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Val Val Met
130 135 140
Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser
145 150 155 160
Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly His Asp
165 170 175
Tyr Leu Asp Trp Tyr Val Gln Lys Pro Gly Gln Ser Pro Gln Pro Leu
180 185 190
Ile Tyr Leu Gly Ser Asp Arg Ala Ser Gly Val Pro Asp Arg Phe Ser
195 200 205
Gly Ser Gly Ser Gly Thr His Phe Thr Leu Asn Ile Ser Arg Val Glu
210 215 220
Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser Leu Gln Thr Pro
225 230 235 240
Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Ala Ala Ala
245 250 255
<210>171
<211>747
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-031
<220>
<221>CDS
<222>(1)..(747)
<223>
<400>171
gcc atg gcc gag gtg cag ctg gtg gag tct ggg gga ggc gtg gtc cag 48
Ala Met Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
1 5 10 15
cct ggg agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc 96
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agt agc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg 144
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gca gtt ata tca tat gat gga agt aat aaa tac tat gca 192
Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
50 55 60
gac tcc gtg aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
acg ctg tat ctg caa atg aac agc ctg aga gct gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aaa ggg tcc gtc ctc ggt gat gct ttt gat atc tgg 336
Tyr Tyr Cys Ala Lys Gly Ser Val Leu Gly Asp Ala Phe Asp Ile Trp
100 105 110
ggc caa ggg aca atg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc 384
Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
gga acc ggc agc ggc act ggc ggg tcg acg gac atc cag atg acc cag 432
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Met Thr Gln
130 135 140
tct cca tct ttc gtg tct gca tct gta gga gac aga gtc acc atc act 480
Ser Pro Ser Phe Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
tgt cgg gcg agt cag ggt att agc agt tgg tta gcc tgg tat cag cag 528
Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln
165 170 175
aaa cca ggg aaa gcc cct aag ctc ctg atc tat gct gca tcc agt ttg 576
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
180 185 190
caa agt ggg gtc cca tca agg ttc agc ggc agt gga tct ggg aca gat 624
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
ttc act ctc acc atc agc agc ctg cag cct gaa gat ttt gca act tac 672
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
tat tgt caa cag gct aac agt ttc cca ctc act ttc ggc gga ggg acc 720
Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
aag gtg gag atc aaa cga gcg gcc gca 747
Lys Val Glu Ile Lys Arg Ala Ala Ala
245
<210>172
<211>249
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-031
<400>172
Ala Met Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
1 5 10 15
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Gly Ser Val Leu Gly Asp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Met Thr Gln
130 135 140
Ser Pro Ser Phe Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
180 185 190
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Val Glu Ile Lys Arg Ala Ala Ala
245
<210>173
<211>747
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-038
<220>
<221>CDS
<222>(1)..(747)
<223>
<400>173
gcc atg gcc cag gtg cag ctg gtg caa tct ggg gga ggc gtg gtc cag 48
Ala Met Ala Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln
1 5 10 15
cct ggg agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc 96
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agt agc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg 144
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gca gtt ata tca tat gat gga agt agt aaa tat tat gca 192
Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Ser Ser Lys Tyr Tyr Ala
50 55 60
gac tcc gtg aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
acg ctg tat ctg caa atg aac agc ctg aga gct gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aaa ggg tcc gtc ctc ggt gat gct ttt gat atc tgg 336
Tyr Tyr Cys Ala Lys Gly Ser Val Leu Gly Asp Ala Phe Asp Ile Trp
100 105 110
ggc caa ggg aca atg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc 384
Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
gga acc ggc agc ggc act ggc ggg tcg acg gac atc cag ttg act cag 432
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu Thr Gln
130 135 140
tct cca tct tcc gtg tct gca tct gta gga gac aga gtc acc atc act 480
Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
tgt cgg gcg agt cag ggt att agc ggc tgg tta gcc tgg tat cag cag 528
Cys Arg Ala Ser Gln Gly Ile Ser Gly Trp Leu Ala Trp Tyr Gln Gln
165 170 175
aaa cca gag aaa gcc cct aag ctc ctg atc tat gcg gca tcc agt ttg 576
Lys Pro Glu Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
180 185 190
caa cgt ggg gtc cca tca agg ttc agc ggc agt gga tct ggg aca gat 624
Gln Arg Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
ttc act ctc acc atc agc agc ctg cag cct gaa gat ttt gca act tac 672
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
tat tgt caa cag gct aac agt ttc ccc ccc acc ttc ggc caa ggg aca 720
Tyr Cys Gln Gln Ala Asn Ser Phe Pro Pro Thr Phe Gly Gln Gly Thr
225 230 235 240
cga ctg gag att aaa cgt gcg gcc gca 747
Arg Leu Glu Ile Lys Arg Ala Ala Ala
245
<210>174
<211>249
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-038
<400>174
Ala Met Ala Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln
1 5 10 15
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Ser Ser Lys Tyr Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Gly Ser Val Leu Gly Asp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu Thr Gln
130 135 140
Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Arg Ala Ser Gln Gly Ile Ser Gly Trp Leu Ala Trp Tyr Gln Gln
165 170 175
Lys Pro Glu Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
180 185 190
Gln Arg Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
Tyr Cys Gln Gln Ala Asn Ser Phe Pro Pro Thr Phe Gly Gln Gly Thr
225 230 235 240
Arg Leu Glu Ile Lys Arg Ala Ala Ala
245
<210>175
<211>747
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-040
<220>
<221>CDS
<222>(1)..(747)
<223>
<400>175
gcc atg gcc cag gtg cag ctg gtg cag tct ggg gga ggc gtg gtc cag 48
Ala Met Ala Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln
1 5 10 15
cct ggg agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc 96
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
ggt agc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg 144
Gly Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gca act ata ttc tat gat gga agt tat aaa gac tat gca 192
Glu Trp Val Ala Thr Ile Phe Tyr Asp Gly Ser Tyr Lys Asp Tyr Ala
50 55 60
gac tcc gtg aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
acg ctg tat ctg caa atg aac agc ctg aga gct gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aaa ggc agt aag gta ggc gac ttt gac tac tgg ggc 336
Tyr Tyr Cys Ala Lys Gly Ser Lys Val Gly Asp Phe Asp Tyr Trp Gly
100 105 110
cag gga acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga 384
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
acc ggc agc ggc act ggc ggg tcg acg cag cct gtg ctg act cag ccc 432
Thr Gly Ser Gly Thr Gly Gly Ser Thr Gln Pro Val Leu Thr Gln Pro
130 135 140
ccc tcg gtg tca gtg gcc cca gga cag acg gcc agg att tcc tgt ggg 480
Pro Ser Val Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Ser Cys Gly
145 150 155 160
gga gac aac att gga act aat act gtg cag tgg tac cag cag aag cca 528
Gly Asp Asn Ile Gly Thr Asn Thr Val Gln Trp Tyr Gln Gln Lys Pro
165 170 175
ggc cag gcc cct gtc ctg gtc gtc tat gat gat agc gac cgg ccc tca 576
Gly Gln Ala Pro Val Leu Val Val Tyr Asp Asp Ser Asp Arg Pro Ser
180 185 190
ggg atc cct gag cga ttc tct ggc tcc aac tct ggg gac acg gcc acc 624
Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asp Thr Ala Thr
195 200 205
ctg acc atc agc agg gtc gag gcc ggg gat gag gcc gat tat tac tgt 672
Leu Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys
210 215 220
cag gtg tgg gat gac agt agt gat ctg gtg gta ttc ggc gga ggg acc 720
Gln Val Trp Asp Asp Ser Ser Asp Leu Val Val Phe Gly Gly Gly Thr
225 230 235 240
aag gtc acc gtc cta ggt gcg gcc gca 747
Lys Val Thr Val Leu Gly Ala Ala Ala
245
<210>176
<211>249
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-040
<400>176
Ala Met Ala Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln
1 5 10 15
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Gly Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Thr Ile Phe Tyr Asp Gly Ser Tyr Lys Asp Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Gly Ser Lys Val Gly Asp Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
Thr Gly Ser Gly Thr Gly Gly Ser Thr Gln Pro Val Leu Thr Gln Pro
130 135 140
Pro Ser Val Ser Val Ala Pro Gly Gln Thr Ala Arg Ile Ser Cys Gly
145 150 155 160
Gly Asp Asn Ile Gly Thr Asn Thr Val Gln Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Val Leu Val Val Tyr Asp Asp Ser Asp Arg Pro Ser
180 185 190
Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asp Thr Ala Thr
195 200 205
Leu Thr Ile Ser Arg yal Glu Ala Gly Asp Glu Ala Asp Tyr Tyr Cys
210 215 220
Gln Val Trp Asp Asp Ser Ser Asp Leu Val Val Phe Gly Gly Gly Thr
225 230 235 240
Lys Val Thr Val Leu Gly Ala Ala Ala
245
<210>177
<211>774
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-060
<220>
<221>CDS
<222>(1)..(774)
<223>
<400>177
gcc atg gcc cag gtg cag ctg gtg gag tct ggc cca gga ctg gtg aag 48
Ala Met Ala Gln Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys
1 5 10 15
gct tcg gag acc ctg tcc ctc act tgc acg gtc tct gat ggc tcc atc 96
Ala Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Ile
20 25 30
agt agt ttc tac tgg agc tgg atc cgg cag ccc ccc ggg aag gga ctg 144
Ser Ser Phe Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu
35 40 45
gag tgg gtt ggg gaa atc cag gac act ggg agg acc aat tac aac ccc 192
Glu Trp Val Gly Glu Ile Gln Asp Thr Gly Arg Thr Asn Tyr Asn Pro
50 55 60
tcc ctc aag agt cga gtc act ata tca cta gac acg tcc aag aac cag 240
Ser Leu Lys Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln
65 70 75 80
ttc tcc ctg acg ttg agc tct gtg acc gct gcg gac acg gcc gtg tat 288
Phe Ser Leu Thr Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr
85 90 95
tac tgc gcg aga gag aag gag aaa tac tct gat aga agc ggt tat tcg 336
Tyr Cys Ala Arg Glu Lys Glu Lys Tyr Ser Asp Arg Ser Gly Tyr Ser
100 105 110
tac tac tac tat tac atg gac gtc tgg ggc aaa ggg acc acg gtc acc 384
Tyr Tyr Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr
115 120 125
gtc tcg agc ggt acg ggc ggt tca ggc gga acc ggc agc ggc act ggc 432
Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr Gly Ser Gly Thr Gly
130 135 140
ggg tcg acg gac atc cag atg acc cag tct cca tcc tcc ctg tct gca 480
Gly Ser Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
145 150 155 160
tct gta gga gac aga gtc acc atc act tgc cgg gca agt cag ggc att 528
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile
165 170 175
agc acc tat tta aat tgg tat cag cag aaa cca ggg aaa gcc cct aac 576
Ser Thr Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn
180 185 190
ctc ctg atc tac ggt gca tct aat ttg caa agt ggg gtc cca tca agg 624
Leu Leu Ile Tyr Gly Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg
195 200 205
ttc agt ggc agt gaa tct ggg aca gat ttc act ctc acc atc agc agt 672
Phe Ser Gly Ser Glu Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
210 215 220
cta caa cct gaa gat ttt gca act tac tac tgt cag cag agt ttc act 720
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Phe Thr
225 230 235 240
acc cct cgc acg ttc ggc caa ggg acc aag ctg gag atc aaa cgt gcg 768
Thr Pro Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Ala
245 250 255
gcc gca 774
Ala Ala
<210>178
<211>258
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-060
<400>178
Ala Met Ala Gln Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys
1 5 10 15
Ala Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Ile
20 25 30
Ser Ser Phe Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Gly Glu Ile Gln Asp Thr Gly Arg Thr Asn Tyr Asn Pro
50 55 60
Ser Leu Lys Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln
65 70 75 80
Phe Ser Leu Thr Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Glu Lys Glu Lys Tyr Ser Asp Arg Ser Gly Tyr Ser
100 105 110
Tyr Tyr Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr
115 120 125
Val Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr Gly Ser Gly Thr Gly
130 135 140
Gly Ser Thr Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
145 150 155 160
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile
165 170 175
Ser Thr Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn
180 185 190
Leu Leu Ile Tyr Gly Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg
195 200 205
Phe Ser Gly Ser Glu Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
210 215 220
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Phe Thr
225 230 235 240
Thr Pro Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Ala
245 250 255
Ala Ala
<210>179
<211>759
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-073
<220>
<221>CDS
<222>(1)..(759)
<223>
<400>179
gcc atg gcc cag gtg cag ctg gtg cag tct ggg gga ggc gtg gcc cag 48
Ala Met Ala Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Ala Gln
1 5 10 15
cct ggg agg tcc ctg aga ctc tcc tgt gca gcg tct gga ttc acc ttc 96
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agt agt tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg 144
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gca gat ata tca tat gat gga agt aat aaa tac tat gca 192
Glu Trp Val Ala Asp Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
50 55 60
gac tcc gtg aag ggc cga ttc acc att tcc aga gac aat tcc aag aac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
acg ctg tat ctg caa atg aac agc ctg aga gct gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aaa gat ggg ctg gat tta act gga acg att cag cca 336
Tyr Tyr Cys Ala Lys Asp Gly Leu Asp Leu Thr Gly Thr Ile Gln Pro
100 105 110
ttt ggc tac tgg ggc cag ggc acc ctg gtc acc gtc tcg agc ggt acg 384
Phe Gly Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr
115 120 125
ggc ggt tca ggc gga acc ggc agc ggc act ggc ggg tcg acg gac atc 432
Gly Gly Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile
130 135 140
cag ttg acc cag tcg cca tcc ttc ctg tct gca tct gta gga gac aga 480
Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly Asp Arg
145 150 155 160
gtc acc atc act tgc cgg gcc agt cac agt att agt agc tgg ttg gcc 528
Val Thr Ile Thr Cys Arg Ala Ser His Ser Ile Ser Ser Trp Leu Ala
165 170 175
tgg tat cag cag aaa cca ggg aaa gcc cct aag ctc ctg atc tat aag 576
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys
180 185 190
gca tct agt tta gaa agt ggg gtc cca tca agg ttc agc ggc agt gga 624
Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
tct ggg aca gat ttc act ctc acc atc agc agc ctg cag cct gaa gat 672
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
ttt gca act tat tac tgt cta caa gat tac aat tac cct cgg acg ttc 720
Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Asn Tyr Pro Arg Thr Phe
225 230 235 240
ggc caa ggg acc aag ctg gag atc aaa cgt gcg gcc gca 759
Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Ala Ala Ala
245 250
<210>180
<211>253
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-073
<400>180
Ala Met Ala Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Ala Gln
1 5 10 15
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Asp Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Asp Gly Leu Asp Leu Thr Gly Thr Ile Gln Pro
100 105 110
Phe Gly Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr
115 120 125
Gly Gly Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile
130 135 140
Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser His Ser Ile Ser Ser Trp Leu Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys
180 185 190
Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Asn Tyr Pro Arg Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Ala Ala Ala
245 250
<210>181
<211>753
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-097
<220>
<221>CDS
<222>(1)..(753)
<223>
<400>181
gcc atg gcc gaa gtg cag ctg gtg cag tct ggg gga cac ttg gta cag 48
Ala Met Ala Glu Val Gln Leu Val Gln Ser Gly Gly His Leu Val Gln
1 5 10 15
cct ggg ggg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttt 96
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agc agc tat gcc atg agc tgg gtc cgc cag gct cca ggg aag ggg ctg 144
Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtc tca ctt att att ggt agc ggt cgt agc aca tac tac gca 192
Glu Trp Val Ser Leu Ile Ile Gly Ser Gly Arg Ser Thr Tyr Tyr Ala
50 55 60
gac tcc gtg aag ggc cgg ttc acc atc tcc aga gac aat tcc aag aac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
acg ctg tat ctg caa atg aac agc ctg aga gcc gag gac acg gcc gta 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aaa acc gcg agt aat ctt gga agg ggg ggt atg gac 336
Tyr Tyr Cys Ala Lys Thr Ala Ser Asn Leu Gly Arg Gly Gly Met Asp
100 105 110
gtc tgg ggc caa ggg acc acg gtc acc gtc tcg agc ggt acg ggc ggt 384
Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly
115 120 125
tca ggc gga acc ggc agc ggc act ggc ggg tcg acg gac att cag ttg 432
Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu
130 135 140
acc cag tct cca tcc tcc ctg tct gca tct gtg gga gac aga gtc act 480
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
atc act tgc cgg gcc agt cag ggc att agc agt cat tta gcc tgg tat 528
Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser His Leu Ala Trp Tyr
165 170 175
cag caa aaa cca ggg aaa gcc cct aag ctc ctg atc tat gct gca tcc 576
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser
180 185 190
agt ttg caa agt ggg gtc cca tca agg ttc agc ggc agt gga tct ggg 624
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
aca gaa ttc act ctc acc atc agc agc ctg cag cct gaa gat ttt gca 672
Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
act tat tac tgt caa cag ttt aat agt tac ccg atc acc ttc ggc caa 720
Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Ile Thr Phe Gly Gln
225 230 235 240
ggg aca cga ctg gag att aaa cgt gcg gcc gca 753
Gly Thr Arg Leu Glu Ile Lys Arg Ala Ala Ala
245 250
<210>182
<211>251
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-097
<400>182
Ala Met Ala Glu Val Gln Leu Val Gln Ser Gly Gly His Leu Val Gln
1 5 10 15
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ser Leu Ile Ile Gly Ser Gly Arg Ser Thr Tyr Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Thr Ala Ser Asn Leu Gly Arg Gly Gly Met Asp
100 105 110
Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Thr Gly Gly
115 120 125
Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu
130 135 140
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser His Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Ile Thr Phe Gly Gln
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys Arg Ala Ala Ala
245 250
<210>183
<211>747
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-098
<220>
<221>CDS
<222>(1)..(747)
<223>
<400>183
gcc atg gcc gaa gtg cag ctg gtg cag tct ggg gga ggc gcg gtc cag 48
Ala Met Ala Glu Val Gln Leu Val Gln Ser Gly Gly Gly Ala Val Gln
l 5 10 15
cct ggg agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc 96
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agt agc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg 144
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gct gtt ata tta tat gat gga agt gat aaa ttc tat gca 192
Glu Trp Val Ala Val Ile Leu Tyr Asp Gly Ser Asp Lys Phe Tyr Ala
50 55 60
gac tcc gtg aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
acg ctg tat ctg cag atg aac agc ctg aga gct gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aaa gta gca gtg gct ggt acg cac ttt gac tac tgg 336
Tyr Tyr Cys Ala Lys Val Ala Val Ala Gly Thr His Phe Asp Tyr Trp
100 105 110
ggc cag gga acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc 384
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
gga acc ggc agc ggc act ggc ggg tcg acg gac atc cag atg acc cag 432
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Met Thr Gln
130 135 140
tct cca tcc tcc ctg tct gca tct gta gga gac aga gtc acc atc act 480
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
tgc cgg gca agt cag ggc att aga aat gat tta ggc tgg tat cag cag 528
Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln Gln
165 170 175
aaa cca ggg aaa gcc cct aag ctc ctg atc tat gct gca tcc agt ttg 576
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
180 185 190
caa agt ggg gtc cca tca agg ttc agc ggc agt gga tct ggg aca gat 624
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
ttc act ctc acc atc agc agc ctg cag cct gaa gat ttt gca act tat 672
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
tac tgt caa cag ctt aat agt tac cct ccc act ttc ggc gga ggg acc 720
Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Pro Thr Phe Gly Gly Gly Thr
225 230 235 240
aag gtg gaa atc aaa cgt gcg gcc gca 747
Lys Val Glu Ile Lys Arg Ala Ala Ala
245
<210>184
<211>249
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-098
<400>I84
Ala Met Ala Glu Val Gln Leu Val Gln Ser Gly Gly Gly Ala Val Gln
1 5 10 15
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Val Ile Leu Tyr Asp Gly Ser Asp Lys Phe Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Val Ala Val Ala Gly Thr His Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Met Thr Gln
130 135 140
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
180 185 190
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Pro Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Val Glu Ile Lys Arg Ala Ala Ala
245
<210>185
<211>747
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-103
<220>
<221>CDS
<222>(1)..(747)
<223>
<400>185
gcc atg gcc cag gtg cag ctg cag gag tcg ggg gga ggc gtg gtc cag 48
Ala Met Ala Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln
1 5 10 15
cct ggg agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc 96
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agt agc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg 144
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gca gtt ata tta tat gat gga agt gat aaa tac tat gca 192
Glu Trp Val Ala Val Ile Leu Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala
50 55 60
gac tcc gtg aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
acg ctg tat ctg caa atg aac agc ctg aga gct gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aaa gtc gct gtg gct ggg gaa agc ttt gac tcc tgg 336
Tyr Tyr Cys Ala Lys Val Ala Val Ala Gly Glu Ser Phe Asp Ser Trp
100 105 110
ggc cgg ggc acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc 384
Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
gga acc ggc agc ggc act ggc ggg tcg acg gac atc cag ttg acc cag 432
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu Thr Gln
130 135 140
tct cca tct tcc gtg tct gca tct gta gga gac aga gtc acc atc act 480
Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
tgt cgg gcg agt cag ggt att agc agc tgg tta gcc tgg tat cag cag 528
Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln
165 170 175
aag cca ggg aaa gcc cct agg tcc ctg atc tat gat gca tcc agt ttg 576
Lys Pro Gly Lys Ala Pro Arg Ser Leu Ile Tyr Asp Ala Ser Ser Leu
180 185 190
caa agt ggg gtc cca tca agg ttc agc ggc agt gga tct ggg aca gac 624
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
ttt act ctc acc atc agc agc ctg cag cct gaa gat ttt gca act tac 672
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
tat tgt caa cag gct gac agt ttc ccg atc acc ttc ggc caa ggg aca 720
Tyr Cys Gln Gln Ala Asp Ser Phe Pro Ile Thr Phe Gly Gln Gly Thr
225 230 235 240
cga ctg gag att aaa cgt gcg gcc gca 747
Arg Leu Glu Ile Lys Arg Ala Ala Ala
245
<210>186
<211>249
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-103
<400>186
Ala Met Ala Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln
1 5 10 15
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Val Ile Leu Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Val Ala Val Ala Gly Glu Ser Phe Asp Ser Trp
100 105 110
Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu Thr Gln
130 135 140
Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ala Pro Arg Ser Leu Ile Tyr Asp Ala Ser Ser Leu
180 185 190
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
Tyr Cys Gln Gln Ala Asp Ser Phe Pro Ile Thr Phe Gly Gln Gly Thr
225 230 235 240
Arg Leu Glu Ile Lys Arg Ala Ala Ala
245
<210>187
<211>759
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-104
<220>
<221>CDS
<222>(1)..(759)
<223>
<400>187
gcc atg gcc cag gtg cag ctg cag gag tcg ggg gga ggc gtg gtc cag 48
Ala Met Ala Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln
1 5 10 15
cct ggg agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc 96
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agt agc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg 144
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gca act ata tca tat gat gga aat gtt aaa gac tat gca 192
Glu Trp Val Ala Thr Ile Ser Tyr Asp Gly Asn Val Lys Asp Tyr Ala
50 55 60
gac tcc gtg aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
acg ctg tat ctg caa atg aac agc ctg aga act gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aaa ata gtg gtg gtg acc gcc ctc gat gct ttt gat 336
Tyr Tyr Cys Ala Lys Ile Val Val Val Thr Ala Leu Asp Ala Phe Asp
100 105 110
atc tgg ggc caa ggg aca atg gtc acc gtc tcg agc ggt acg ggc ggt 384
Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly
115 120 125
tca ggc gga acc ggc agc ggc act ggc ggg tcg acg gac atc cag ttg 432
Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu
130 135 140
acc cag tct cct tcc acc ctg tct gca tct gta gga gac aga gtc acc 480
Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
atc act tgc cgg gcc agt cag att ctt ggt cac tgg ttg ccc ttg tcc 528
Ile Thr Cys Arg Ala Ser Gln Ile Leu Gly His Trp Leu Pro Leu Ser
165 170 175
tgg tat cag cag aaa cca ggt aaa gcc cct aaa ctc ctg atc tct aag 576
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Ser Lys
180 185 190
gcg tct agt tta gaa agt gga gtc cca cca agg ttc agc ggc agt gga 624
Ala Ser Ser Leu Glu Ser Gly Val Pro Pro Arg Phe Ser Gly Ser Gly
195 200 205
tct ggg tca gat ttc act ctc acc atc agc agc ctg cag ccc gat gat 672
Ser Gly Ser Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp
210 215 220
ttt gca act tat tac tgc ctc caa tat cat gag tac ccg ctc acc ttc 720
Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr His Glu Tyr Pro Leu Thr Phe
225 230 235 240
ggc gga ggg acc aag ctg gag atc aaa cgt gcg gcc gca 759
Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Ala Ala
245 250
<210>188
<211>253
<212>pRT
<213>Artificial sequence
<220>
<223>SC04-104
<400>188
Ala Met Ala Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln
1 5 10 15
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Thr Ile Ser Tyr Asp Gly Asn Val Lys Asp Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Ile Val Val Val Thr Ala Leu Asp Ala Phe Asp
100 105 110
Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly
115 120 125
Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu
130 135 140
Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Ile Leu Gly His Trp Leu Pro Leu Ser
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Ser Lys
180 185 190
Ala Ser Ser Leu Glu Ser Gly Val Pro Pro Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Ser Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr His Glu Tyr Pro Leu Thr Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Ala Ala
245 250
<210>189
<211>750
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-108
<220>
<221>CDS
<222>(1)..(750)
<223>
<400>189
gcc atg gcc gaa gtg cag ctg gtg cag tct ggg gga ggc ttg gta cag 48
Ala Met Ala Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln
1 5 10 15
cct ggg ggg tcc ctg aga ctc tcc tgt gca gcg tct gga ttc acc ttc 96
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agt agc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg 144
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gca gtt ata tta tat gat gga agt gat aag ttc tat gca 192
Glu Trp Val Ala Val Ile Leu Tyr Asp Gly Ser Asp Lys Phe Tyr Ala
50 55 60
gac tcc gtg aag ggc cga ttc acc atc tcc aga gac aat tcc aag gac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp
65 70 75 80
acg ctg tat ctg caa atg aac agc ctg aga gct gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aaa ttt atg ata gta gca gat gat gct ttt gat atc 336
Tyr Tyr Cys Ala Lys Phe Met Ile Val Ala Asp Asp Ala Phe Asp Ile
100 105 110
tgg ggc caa ggg aca atg gtc acc gtc tcg agc ggt acg ggc ggt tca 384
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser
115 120 125
ggc gga acc ggc agc ggc act ggc ggg tcg acg gac atc cag ttg acc 432
Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu Thr
130 135 140
cag tct cca tcc tca ctg tct gca tct gta gga gac aga gtc acc atc 480
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
act tgt cgg gcg agt cag ggc att agc agt cat tta gtc tgg tat cag 528
Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser His Leu Val Trp Tyr Gln
165 170 175
cag aaa cca ggg aaa gcc cct aag tcc ctg atc tat gct gca tcc agt 576
Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser
180 185 190
ttg caa agt ggg gtc cca tca agg ttc agc ggc agt gaa tct gcg aca 624
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Glu Ser Ala Thr
195 2O0 205
gat ttc act ctc acc atc agc agc ctg cag cct gaa gat ttt gca act 672
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
210 215 220
tat tac tgc caa cag tat tac agt tac cct atc acc ttc ggc caa ggg 720
Tyr Tyr Cys Gln Gln Tyr Tyr Ser Tyr Pro Ile Thr Phe Gly Gln Gly
225 230 235 240
aca cga ctg gag att aaa cgt gcg gcc gca 750
Thr Arg Leu Glu Ile Lys Arg Ala Ala Ala
245 250
<210>190
<211>250
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-108
<400>190
Ala Met Ala Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln
1 5 10 15
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Val Ile Leu Tyr Asp Gly Ser Asp Lys Phe Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Phe Met Ile Val Ala Asp Asp Ala Phe Asp Ile
100 105 110
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser
115 120 125
Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser His Leu Val Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser
180 185 190
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Glu Ser Ala Thr
195 200 205
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
210 215 220
Tyr Tyr Cys Gln Gln Tyr Tyr Ser Tyr Pro Ile Thr Phe Gly Gln Gly
225 230 235 240
Thr Arg Leu Glu Ile Lys Arg Ala Ala Ala
245 250
<210>191
<211>744
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-120
<220>
<221>CDS
<222>(1)..(744)
<223>
<400>191
gcc atg gcc gag gtg cag ctg gtg cag tct ggg gga ggc ttg gta cag 48
Ala Met Ala Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln
1 5 10 15
cct ggc agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc 96
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agt acc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg 144
Ser Thr Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gca act ata tca tat gat gga agt att aaa gac tat gca 192
Glu Trp Val Ala Thr Ile Ser Tyr Asp Gly Ser Ile Lys Asp Tyr Ala
50 55 60
gac tcc gag aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac 240
Asp Ser Glu Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
acg ctg tat ctg caa atg aac agc ctg aga gct gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aaa ggg ggg aag act gga gag ttt gac tac tgg ggc 336
Tyr Tyr Cys Ala Lys Gly Gly Lys Thr Gly Glu Phe Asp Tyr Trp Gly
100 105 110
cag gga acc ctg gtc acc gtc tcg agc ggt acg gge ggt tca ggc gga 384
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
acc ggc agc ggc act ggc ggg tcg acg gac atc cag ttg acc cag tct 432
Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu Thr Gln Ser
130 135 140
cct tcc acc ctg tct gca tct gta gga gac aga gtc acc atc act tgc 480
Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
145 150 155 160
cgg gcc agt cag ggc att aac agt tat tta gcc tgg tat cag caa gaa 528
Arg Ala Ser Gln Gly Ile Asn Ser Tyr Leu Ala Trp Tyr Gln Gln Glu
165 170 175
cca ggg aaa gcc cct aaa ctc ctg atc tat gct gca tcc act ttg caa 576
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln
180 185 190
agt ggg gtc cca tca agg ttc agc ggc agt gga tct ggg aca gaa ttc 624
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe
195 200 205
act ctc aca atc agc agc ctg cag cct gaa gat ttt gca act tat tac 672
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
210 215 220
tgt caa cag ctt aat agt tac ccc ttc act ttc ggc cct ggg acc aaa 720
Cys Gln Gln Leu Asn Ser Tyr Pro Phe Thr Phe Gly Pro Gly Thr Lys
225 230 235 240
gtg gat atc aaa cgt gcg gcc gca 744
Val Asp Ile Lys Arg Ala Ala Ala
245
<210>192
<211>248
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-120
<400>192
Ala Met Ala Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln
1 5 10 15
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Thr Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Thr Ile Ser Tyr Asp Gly Ser Ile Lys Asp Tyr Ala
50 55 60
Asp Ser Glu Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Gly Gly Lys Thr Gly Glu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu Thr Gln Ser
130 135 140
Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
145 150 155 160
Arg Ala Ser Gln Gly Ile Asn Ser Tyr Leu Ala Trp Tyr Gln Gln Glu
165 170 175
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln
180 185 190
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
210 215 220
Cys Gln Gln Leu Asn Ser Tyr Pro Phe Thr Phe Gly Pro Gly Thr Lys
225 230 235 240
Val Asp Ile Lys Arg Ala Ala Ala
245
<210>193
<211>747
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-125
<220>
<221>CDS
<222>(1)..(747)
<223>
<400>193
gcc atg gcc cag gtg cag ctg gtg gag tct ggg gga ggc gtg gtc cag 48
Ala Met Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
1 5 10 15
cct ggg agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc 96
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agt agc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg 144
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gca gtt ata tca tat gat gga agt gat aaa tac tat gca 192
Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala
50 55 60
gac tcc gtg aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
acg ctc tat ctg caa atg aac agc ttg aga gct gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aag ata gca aca gct ggt acc ggg ttt gac tac tgg 336
Tyr Tyr Cys Ala Lys Ile Ala Thr Ala Gly Thr Gly Phe Asp Tyr Trp
100 105 110
ggc cag gga acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc 384
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
gga acc ggc agc ggc act ggc ggg tcg acg gac atc cag atg acc cag 432
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Met Thr Gln
130 135 140
tct cca tct tcc gtg tct gca tct gta gga gac aga gtc acc atc act 480
Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
tgt cgg gcg agt cag ggc att agc agt tat tta gcc tgg tat cag caa 528
Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln
165 170 175
aaa cca ggg aaa gcc cct aag ctc ctg atc tat gat gcc tcc agt ttg 576
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu
180 185 190
gaa agt ggg gtc cca tca agg ttc agc ggc agt gga tct ggg aca gaa 624
Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu
195 200 205
ttc act ctc acc atc agc agc ctg cag cct gat gat ttt gca act tat 672
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr
210 215 220
tac tgt caa caa ctt aac agt tac cca ctc act ttc ggc gga ggg acc 720
Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
aag gtg gag atc aaa cgt gcg gcc gca 747
Lys Val Glu Ile Lys Arg Ala Ala Ala
245
<210>194
<211>249
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-125
<400>194
Ala Met Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
1 5 10 15
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Ile Ala Thr Ala Gly Thr Gly Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Met Thr Gln
130 135 140
Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu
180 185 190
Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu
195 200 205
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr
210 215 220
Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Val Glu Ile Lys Arg Ala Ala Ala
245
<210>195
<211>756
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-126
<220>
<221>CDS
<222>(1)..(756)
<223>
<400>195
gcc atg gcc cag gtc acc ttg aag gag tct ggt ccc acg ctg gtg aac 48
Ala Met Ala Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Asn
1 5 10 15
ccc aca cag acc ctc acg ttg acc tgc acc ttc tct ggg ttc tcg ctc 96
Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu
20 25 30
agc act ggt gga gtg ggt gtg ggc tgg ttc cgt cag ccc cca ggg aag 144
Ser Thr Gly Gly Val Gly Val Gly Trp Phe Arg Gln Pro Pro Gly Lys
35 40 45
gcc ctg gag tgg ctt gca cgc att gat tgg gat gat gat aaa tac tac 192
Ala Leu Glu Trp Leu Ala Arg Ile Asp Trp Asp Asp Asp Lys Tyr Tyr
50 55 60
agc aca tct ctg aag acc agg ctc acc atc tcc aag gac acc tcc aaa 240
Ser Thr Ser Leu Lys Thr Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys
65 70 75 80
atc cag gtg gtc ctt aca atg acc aac atg gac cct gtg gac aca gcc 288
Ile Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala
85 90 95
acg tat tac tgt gca cgg atg ggt ttc act gga acc tac ttt gac tac 336
Thr Tyr Tyr Cys Ala Arg Met Gly Phe Thr Gly Thr Tyr Phe Asp Tyr
100 105 110
tgg ggc cag ggc acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca 384
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser
115 120 125
ggc gga acc ggc agc ggc act ggc ggg tcg acg cag tct gtg ctg act 432
Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Gln Ser Val Leu Thr
130 135 140
cag cca ccc tca gtg tca gtg gcc cca gga aag acg gcc agg att acc 480
Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys Thr Ala Arg Ile Thr
145 150 155 160
tgt ggg gga aac aac att gga agt aaa agt gtg cac tgg tac cag cag 528
Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val His Trp Tyr Gln Gln
165 170 175
aag cca ggc cag gcc cct gtg ctg gtc atc tat tat gat agc gac cgg 576
Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Tyr Asp Ser Asp Arg
180 185 190
ccc tca ggg atc cct gag cga ttc tct ggc tcc aac tct ggg aac acg 624
Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr
195 200 205
gcc acc ctg acc atc agc agg gtc gaa gcc ggg gat gag gct gac tat 672
Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp Tyr
210 215 220
tac tgt cag gtg tgg gat agt agt agt gat cat ccc tat gtc ttc gga 720
Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His Pro Tyr Val Phe Gly
225 230 235 240
act ggg acc aag ctg acc gtc cta ggt gcg gcc gca 756
Thr Gly Thr Lys Leu Thr Val Leu Gly Ala Ala Ala
245 250
<210>196
<211>252
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-126
<400>196
Ala Met Ala Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Asn
1 5 10 15
Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu
20 25 30
Ser Thr Gly Gly Val Gly Val Gly Trp Phe Arg Gln Pro Pro Gly Lys
35 40 45
Ala Leu Glu Trp Leu Ala Arg Ile Asp Trp Asp Asp Asp Lys Tyr Tyr
50 55 60
Ser Thr Ser Leu Lys Thr Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys
65 70 75 80
Ile Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala
85 90 95
Thr Tyr Tyr Cys Ala Arg Met Gly Phe Thr Gly Thr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser
115 120 125
Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Gln Ser Val Leu Thr
130 135 140
Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys Thr Ala Arg Ile Thr
145 150 155 160
Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val His Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Tyr Asp Ser Asp Arg
180 185 190
Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr
195 200 205
Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala Asp Tyr
210 215 220
Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His Pro Tyr Val Phe Gly
225 230 235 240
Thr Gly Thr Lys Leu Thr Val Leu Gly Ala Ala Ala
245 250
<210>197
<211>747
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-140
<220>
<221>CDS
<222>(1)..(747)
<223>
<400>197
gcc atg gcc cag atg cag ctg gtg cag tct ggg gga ggc gtg gtc cag 48
Ala Met Ala Gln Met Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln
1 5 10 15
cct ggg agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc 96
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agt agc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg 144
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gca gtt ata tta tat gat gga agt aat aaa tac tat gca 192
Glu Trp Val Ala Val Ile Leu Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
50 55 60
gac tcc gtg aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
gcg ttg tat ctg caa atg aac agc ctg aga gct gag gac acg gct gtg 288
Ala Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aag gtg acc aac ccc gga gat gct ttt gat atc tgg 336
Tyr Tyr Cys Ala Lys Val Thr Asn Pro Gly Asp Ala Phe Asp Ile Trp
100 105 110
ggc caa ggg acc atg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc 384
Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
gga acc ggc agc ggc act ggc ggg tcg acg gac atc cag atg acc cag 432
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Met Thr Gln
130 135 140
tct cca tcc tcc ctg tct gca tct gtc gga gac aga gtc acc atc act 480
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
tgc cgg gca agt cag ggc att agc agt gct tta gcc tgg tat cag cag 528
Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala Leu Ala Trp Tyr Gln Gln
165 170 175
aaa cca ggg aaa gct cct aag ctc ctg atc tat gat gcc tcc agt ttg 576
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu
180 185 190
gaa agt ggg gtc cca tca agg ttc agc ggc agt gga tct ggg aca gat 624
Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
ttc act ctc acc atc agc agc ctg cag cct gaa gat ttt gca act tat 672
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
tac tgt caa cag ttt aat agt tac ccg ctc act ttc ggc gga ggg acc 720
Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
aag gtg gaa atc aaa cgt gcg gcc gca 747
Lys Val Glu Ile Lys Arg Ala Ala Ala
245
<210>198
<211>249
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-140
<400>198
Ala Met Ala Gln Met Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln
1 5 10 15
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Val Ile Leu Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Ala Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Val Thr Asn Pro Gly Asp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Met Thr Gln
130 135 140
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala Leu Ala Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Ser Leu
180 185 190
Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Val Glu Ile Lys Arg Ala Ala Ala
245
<210>199
<211>744
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-144
<220>
<221>CDS
<222>(1)..(744)
<223>
<400>199
gcc atg gcc cag gtg cag ctg cag gag ttg ggg gga ggc gtg gtc cag 48
Ala Met Ala Gln Val Gln Leu Gln Glu Leu Gly Gly Gly Val Val Gln
1 5 10 15
cct ggg agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc 96
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
ggt agc tat ggc atg cac tgg gtc cgc cag gct ccg ggc aag ggg ctg 144
Gly Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gca act ata tca tat gat gga agt att aaa gac tat gca 192
Glu Trp Val Ala Thr Ile Ser Tyr Asp Gly Ser Ile Lys Asp Tyr Ala
50 55 60
gac tcc gag aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac 240
Asp Ser Glu Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
aca ctg tat ctg caa atg aac agc ctg aga gct gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aaa ggg ggg aag act gga gag ttt gac tac tgg ggc 336
Tyr Tyr Cys Ala Lys Gly Gly Lys Thr Gly Glu Phe Asp Tyr Trp Gly
100 105 110
cag gga acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga 384
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
acc ggc agc ggc act ggc ggg tcg acg gac atc cag ttg acg cag tct 432
Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu Thr Gln Ser
130 135 140
cca tcc tcc ctg tct gca tct gta gga gac aga gtc acc atc act tgc 480
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
145 150 155 160
cgg gcc agt cag ggc att agc agt tat tta gcc tgg tat cag caa aaa 528
Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys
165 170 175
cca ggg aaa ggc cct aag ctc ctg atc tat gct gca tcc act tta caa 576
Pro Gly Lys Gly Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln
180 185 190
agt ggg gtc cca tca agg ttc agc ggc agt gga tct ggg aca gac ttc 624
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
agt ctc acc atc agt agc ctg cag cct gaa gat tta gca act tat tac 672
Ser Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Leu Ala Thr Tyr Tyr
210 215 220
tgc caa cag tat gat agt tac cct ctc act ttc ggc gga ggg acc aag 720
Cys Gln Gln Tyr Asp Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
gtg gaa atc aaa cgt gcg gcc gca 744
Val Glu Ile Lys Arg Ala Ala Ala
245
<210>200
<211>248
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-144
<400>200
Ala Met Ala Gln Val Gln Leu Gln Glu Leu Gly Gly Gly Val Val Gln
1 5 10 15
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Gly Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Thr Ile Ser Tyr Asp Gly Ser Ile Lys Asp Tyr Ala
50 55 60
Asp Ser Glu Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Gly Gly Lys Thr Gly Glu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu Thr Gln Ser
130 135 140
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
145 150 155 160
Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Lys Gly Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln
180 185 190
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Ser Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Leu Ala Thr Tyr Tyr
210 215 220
Cys Gln Gln Tyr Asp Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Val Glu Ile Lys Arg Ala Ala Ala
245
<210>201
<211>744
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-146
<220>
<221>CDS
<222>(1)..(744)
<223>
<400>201
gcc atg gcc gaa gtg cag ctg gtg cag tct ggg gga ggc gtg gtc cag 48
Ala Met Ala Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln
1 5 10 15
cct ggg agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc 96
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agt agc tat ggc atg cac tgg gtc cgc cag gct ccg ggc aag ggg ctg 144
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gca act ata tca tat gat gga agt att aaa gac tat gca 192
Glu Trp Val Ala Thr Ile Ser Tyr Asp Gly Ser Ile Lys Asp Tyr Ala
50 55 60
gac tcc gag gag ggc cga ttc acc atc tcc aga gac aat tcc aag aac 240
Asp Ser Glu Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
aca ctg tat ctg caa atg aac agc ctg aga gct gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aaa ggg ggg aag act gga gag ttt gac tac tgg ggc 336
Tyr Tyr Cys Ala Lys Gly Gly Lys Thr Gly Glu Phe Asp Tyr Trp Gly
100 105 110
cag ggc acc ctg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc gga 384
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
acc ggc agc ggc act ggc ggg tcg acg gat gtt gtg atg act cag tct 432
Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Val Val Met Thr Gln Ser
130 135 140
cca gcc acc ctg tct gtg tct cca ggg gaa agc gcc aca ctc ttc tgc 480
Pro Ala Thr Leu Ser Val Ser Pro Gly Glu Ser Ala Thr Leu Phe Cys
145 150 155 160
agg gcc agt gag agt gtt tat agc aac ttg gcc tgg tat cag cac aaa 528
Arg Ala Ser Glu Ser Val Tyr Ser Asn Leu Ala Trp Tyr Gln His Lys
165 170 175
cct ggc cgg gct ccc agg ctc ctc atc tat ggt gca tcc acc agg gcc 576
Pro Gly Arg Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Ala
180 185 190
act ggt atc cca gcc agg ttc gat ggc act ggg tct ggg aca gac ttc 624
Thr Gly Ile Pro Ala Arg Phe Asp Gly Thr Gly Ser Gly Thr Asp Phe
195 200 205
aca ctc acc atc agc agc ctg cag tct gaa gat ttt gca gtt tat tac 672
Thr Leu Thr Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr
210 215 220
tgt cag caa tat aat gac tgg ccg atc acc ttc ggc caa ggg aca cga 720
Cys Gln Gln Tyr Asn Asp Trp Pro Ile Thr Phe Gly Gln Gly Thr Arg
225 230 235 240
ctg gag att aaa cgt gcg gcc gca 744
Leu Glu Ile Lys Arg Ala Ala Ala
245
<210>202
<211>248
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-146
<400>202
Ala Met Ala Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln
1 5 10 15
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Thr Ile Ser Tyr Asp Gly Ser Ile Lys Asp Tyr Ala
50 55 60
Asp Ser Glu Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Gly Gly Lys Thr Gly Glu Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly Gly
115 120 125
Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Val Val Met Thr Gln Ser
130 135 140
Pro Ala Thr Leu Ser Val Ser Pro Gly Glu Ser Ala Thr Leu Phe Cys
145 150 155 160
Arg Ala Ser Glu Ser Val Tyr Ser Asn Leu Ala Trp Tyr Gln His Lys
165 170 175
Pro Gly Arg Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Ala
180 185 190
Thr Gly Ile Pro Ala Arg Phe Asp Gly Thr Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr
210 215 220
Cys Gln Gln Tyr Asn Asp Trp Pro Ile Thr Phe Gly Gln Gly Thr Arg
225 230 235 240
Leu Glu Ile Lys Arg Ala Ala Ala
245
<210>203
<211>747
<212>DNA
<213>Artificial sequence
<220>
<223>SC04-164
<220>
<221>CDS
<222>(1)..(747)
<223>
<400>203
gcc atg gcc gag gtg cag ctg gtg gag tct ggg gga ggc gtg gtc cag 48
Ala Met Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
1 5 10 15
cct ggg agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc 96
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
agt agc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg 144
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
gag tgg gtg gca gtt ata tca tat gat gga agc agt aaa tac tac gca 192
Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Ser Ser Lys Tyr Tyr Ala
50 55 60
gac tcc gtg aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac 240
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
acg ctg tat ctg caa atg aac agc ctg aga gct gag gac acg gct gtg 288
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
tat tac tgt gcg aaa ggg tcc gtc ctc ggt gat gct ttt gat atc tgg 336
Tyr Tyr Cys Ala Lys Gly Ser Val Leu Gly Asp Ala Phe Asp Ile Trp
100 105 110
ggc caa ggg aca atg gtc acc gtc tcg agc ggt acg ggc ggt tca ggc 384
Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
gga acc ggc agc ggc act ggc ggg tcg acg gac atc cag ttg acc cag 432
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu Thr Gln
130 135 140
tct cca tct tct gtg tct gca tct gta gga gac aga gtc acc atc act 480
Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
tgt cgg gcg agt cag ggt att agc agc tgg tta gcc tgg tat cag cag 528
Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln
165 170 175
aaa cca ggg aaa gcc cct aag ctc ctg atc tat gct gca tcc agt ttg 576
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
180 185 190
caa agt ggg gtc cca tca agg ttc agc ggc agt gga tct ggg aca gat 624
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
ttc act ctc act atc agc agc ctg cag cct gaa gat ttt gca act tac 672
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
tat tgt caa cag gct aac agt ttc ccg ctc act ttc ggc gga ggg acc 720
Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
aaa gtg gat atc aaa cgt gcg gcc gca 747
Lys Val Asp Ile Lys Arg Ala Ala Ala
245
<210>204
<211>249
<212>PRT
<213>Artificial sequence
<220>
<223>SC04-164
<400>204
Ala Met Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
1 5 10 15
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
20 25 30
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
35 40 45
Glu Trp Val Ala Val Ile Ser Tyr Asp Gly Ser Ser Lys Tyr Tyr Ala
50 55 60
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
65 70 75 80
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Lys Gly Ser Val Leu Gly Asp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Thr Gly Gly Ser Gly
115 120 125
Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Asp Ile Gln Leu Thr Gln
130 135 140
Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
180 185 190
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
Lys Val Asp Ile Lys Arg Ala Ala Ala
245
<210>205
<211>786
<212>DNA
<213>Artificial sequence
<220>
<223>S057
<220>
<221>CDS
<222>(1)..(786)
<223>
<400>205
gcc atg gcc cag gtg cag ctg gtg cag agc gga gcc gag gtg aag aag 48
Ala Met Ala Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
1 5 10 15
ccc ggc agc agc gtg aag gtg agc tgc aag gcc agc ggc ggc acc ttc 96
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe
20 25 30
aac agg tac acc gtg aac tgg gtg aga cag gcc cca ggc cag ggc ctg 144
Asn Arg Tyr Thr Val Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
35 40 45
gag tgg atg ggc ggc atc atc cct atc ttc ggc acc gcc aac tac gcc 192
Glu Trp Met Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala
50 55 60
cag aga ttc cag ggc agg ctc acc atc acc gcc gac gag agc acc agc 240
Gln Arg Phe Gln Gly Arg Leu Thr Ile Thr Ala Asp Glu Ser Thr Ser
65 70 75 80
acc gcc tac atg gag ctg agc agc ctg aga agc gat gac acc gcc gtg 288
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val
85 90 95
tac ttc tgc gcc agg gag aac ctg gat aac agc ggc acc tac tac tac 336
Tyr Phe Cys Ala Arg Glu Asn Leu Asp Asn Ser Gly Thr Tyr Tyr Tyr
100 105 110
ttc agc ggc tgg ttc gac ccc tgg ggc cag ggc acc ctg gtg acc gtc 384
Phe Ser Gly Trp Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val
115 120 125
tcg agc ggt acg ggc ggt tca ggc gga acc ggc agc ggc act ggc ggg 432
Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly
130 135 140
tcg acg cag agc gcc ctc acc cag ccc aga agc gtg agc ggc agc cct 480
Ser Thr Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro
145 150 155 160
ggc cag agc gtg acc atc agc tgc acc ggc acc agc agc gac atc ggc 528
Gly Gln Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly
165 170 175
ggc tac aac ttc gtg agc tgg tat cag cag cac ccc ggc aag gcc cct 576
Gly Tyr Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
180 185 190
aag ctc atg atc tac gac gcc acc aag aga ccc agc ggc gtg ccc gac 624
Lys Leu Met Ile Tyr Asp Ala Thr Lys Arg Pro Ser Gly Val Pro Asp
195 200 205
aga ttc agc ggc agc aag agc ggc aac acc gcc agc ctc acc atc agc 672
Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser
210 215 220
gga ctg cag gcc gag gac gag gcc gac tac tac tgc tgc agc tac gcc 720
Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala
225 230 235 240
ggc gac tac acc cct ggc gtg gtg ttc ggc gga ggc acc aag ctt acc 768
Gly Asp Tyr Thr Pro Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr
245 250 255
gtg cta ggt gcg gcc gca 786
Val Leu Gly Ala Ala Ala
260
<210>206
<211>262
<212>PRT
<213>Artificial sequence
<220>
<223>S057
<400>206
Ala Met Ala Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
1 5 10 15
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe
20 25 30
Asn Arg Tyr Thr Val Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
35 40 45
Glu Trp Met Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala
50 55 60
Gln Arg Phe Gln Gly Arg Leu Thr Ile Thr Ala Asp Glu Ser Thr Ser
65 70 75 80
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val
85 90 95
Tyr Phe Cys Ala Arg Glu Asn Leu Asp Asn Ser Gly Thr Tyr Tyr Tyr
100 105 110
Phe Ser Gly Trp Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val
115 120 125
Ser Ser Gly Thr Gly Gly Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly
130 135 140
Ser Thr Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro
145 150 155 160
Gly Gln Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly
165 170 175
Gly Tyr Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
180 185 190
Lys Leu Met Ile Tyr Asp Ala Thr Lys Arg Pro Ser Gly Val Pro Asp
195 200 205
Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser
210 215 220
Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala
225 230 235 240
Gly Asp Tyr Thr Pro Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr
245 250 255
Val Leu Gly Ala Ala Ala
260
<210>207
<211>524
<212>PRT
<213>Rabies virus
<220>
<221>MISC_FEATURE
<223>G protein of rabies virus ERA strain
<400>207
Met Val Pro Gln Ala Leu Leu Phe Val Pro Leu Leu Val Phe Pro Leu
1 5 10 15
Cys Phe Gly Lys Phe Pro Ile Tyr Thr Ile Leu Asp Lys Leu Gly Pro
20 25 30
Trp Ser Pro Ile Asp Ile His His Leu Ser Cys Pro Asn Asn Leu Val
35 40 45
Val Glu Asp Glu Gly Cys Thr Asn Leu Ser Gly Phe Ser Tyr Met Glu
50 55 60
Leu Lys Val Gly Tyr Ile Leu Ala Ile Lys Met Asn Gly Phe Thr Cys
65 70 75 80
Thr Gly Val Val Thr Glu Ala Glu Asn Tyr Thr Asn Phe Val Gly Tyr
85 90 95
Val Thr Thr Thr Phe Lys Arg Lys His Phe Arg Pro Thr Pro Asp Ala
100 105 110
Cys Arg Ala Ala Tyr Asn Trp Lys Met Ala Gly Asp Pro Arg Tyr Glu
115 120 125
Glu Ser Leu His Asn Pro Tyr Pro Asp Tyr Arg Trp Leu Arg Thr Val
130 135 140
Lys Thr Thr Lys Glu Ser Leu Val Ile Ile Ser Pro Ser Val Ala Asp
145 150 155 160
Leu Asp Pro Tyr Asp Arg Ser Leu His Ser Arg Val Phe Pro Ser Gly
165 170 175
Lys Cys Ser Gly Val Ala Val Ser Ser Thr Tyr Cys Ser Thr Asn His
180 185 190
Asp Tyr Thr Ile Trp Met Pro Glu Asn Pro Arg Leu Gly Met Ser Cys
195 200 205
Asp Ile Phe Thr Asn Ser Arg Gly Lys Arg Ala Ser Lys Gly Ser Glu
210 215 220
Thr Cys Gly Phe Val Asp Glu Arg Gly Leu Tyr Lys Ser Leu Lys Gly
225 230 235 240
Ala Cys Lys Leu Lys Leu Cys Gly Val Leu Gly Leu Arg Leu Met Asp
245 250 255
Gly Thr Trp Val Ala Met Gln Thr Ser Asn Glu Thr Lys Trp Cys Pro
260 265 270
Pro Asp Gln Leu Val Asn Leu His Asp Phe Arg Ser Asp Glu Ile Glu
275 280 285
His Leu Val Val Glu Glu Leu Val Arg Lys Arg Glu Glu Cys Leu Asp
290 295 300
Ala Leu Glu Ser Ile Met Thr Thr Lys Ser Val Ser Phe Arg Arg Leu
305 310 315 320
Ser His Leu Arg Lys Leu Val Pro Gly Phe Gly Lys Ala Tyr Thr Ile
325 330 335
Phe Asn Lys Thr Leu Met Glu Ala Asp Ala His Tyr Lys Ser Val Arg
340 345 350
Thr Trp Asn Glu Ile Leu Pro Ser Lys Gly Cys Leu Arg Val Gly Gly
355 360 365
Arg Cys His Pro His Val Asn Gly Val Phe Phe Asn Gly Ile Ile Leu
370 375 380
Gly Pro Asp Gly Asn Val Leu Ile Pro Glu Met Gln Ser Ser Leu Leu
385 390 395 400
Gln Gln His Met Glu Leu Leu Glu Ser Ser Val Ile Pro Leu Val His
405 410 415
Pro Leu Ala Asp Pro Ser Thr Val Phe Lys Asp Gly Asp Glu Ala Glu
420 425 430
Asp Phe Val Glu Val His Leu Pro Asp Val His Asn Gln Val Ser Gly
435 440 445
Val Asp Leu Gly Leu Pro Asn Trp Gly Lys Tyr Val Leu Leu Ser Ala
450 455 460
Gly Ala Leu Thr Ala Leu Met Leu Ile Ile Phe Leu Met Thr Cys Cys
465 470 475 480
Arg Arg Val Asn Arg Ser Glu Pro Thr Gln His Asn Leu Arg Gly Thr
485 490 495
Gly Arg Glu Val Ser Val Thr Pro Gln Ser Gly Lys Ile Ile Ser Ser
500 505 510
Trp Glu Ser His Lys Ser Gly Gly Glu Thr Arg Leu
515 520
<210>208
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda1A
<400>208
cagtctgtgc tgactcagcc acc 23
<210>209
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda1B
<400>209
cagtctgtgy tgacgcagcc gcc 23
<210>210
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda1C
<400>210
cagtctgtcg tgacgcagcc gcc 23
<210>211
<211>21
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda2
<400>211
cartctgccc tgactcagcc t 21
<210>212
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda3A
<400>212
tcctatgwgc tgactcagcc acc 23
<210>213
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda3B
<400>213
tcttctgagc tgactcagga ccc 23
<210>214
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda4
<400>214
cacgttatac tgactcaacc gcc 23
<210>215
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda5
<400>215
caggctgtgc tgactcagcc gtc 23
<210>216
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda6
<400>216
aattttatgc tgactcagcc cca 23
<210>217
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda7/8
<400>217
cagrctgtgg tgacycagga gcc 23
<210>218
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda9
<400>218
cwgcctgtgc tgactcagcc mcc 23
<210>219
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVkappa1B
<400>219
gacatccagw tgacccagtc tcc 23
<210>220
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVkappa2
<400>220
gatgttgtga tgactcagtc tcc 23
<210>221
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVkappa3
<400>221
gaaattgtgw tgacrcagtc tcc 23
<210>222
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVkappa4
<400>222
gatattgtga tgacccacac tcc 23
<210>223
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVkappa5
<400>223
gaaacgacac tcacgcagtc tcc 23
<210>224
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVkappa6
<400>224
gaaattgtgc tgactcagtc tcc 23
<210>225
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVkappalB-SalI
<400>225
tgagcacaca ggtcgacgga catccagwtg acccagtctc c 41
<210>226
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVkappa2-SalI
<400>226
tgagcacaca ggtcgacgga tgttgtgatg actcagtctc c 41
<210>227
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVkappa3B-SalI
<400>227
tgagcacaca ggtcgacgga aattgtgwtg acrcagtctc c 41
<210>228
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVkappa4B-SalI
<400>228
tgagcacaca ggtcgacgga tattgtgatg acccacactc c 41
<210>229
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVkappa5-SalI
<400>229
tgagcacaca ggtcgacgga aacgacactc acgcagtctc c 41
<210>230
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVkappa6-SalI
<400>230
tgagcacaca ggtcgacgga aattgtgctg actcagtctc c 41
<210>231
<211>48
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuJkappal-NotI
<400>231
gagtcattct cgacttgcgg ccgcacgttt gatttccacc ttggtccc 48
<210>232
<211>48
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuJkappa2-NotI
<400>232
gagtcattct cgacttgcgg ccgcacgttt gatctccagc ttggtccc 48
<210>233
<211>48
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuJkappa3-NotI
<400>233
gagtcattct cgacttgcgg ccgcacgttt gatatccact ttggtccc 48
<210>234
<211>48
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuJkappa4-NotI
<400>234
gagtcattct cgacttgcgg ccgcacgttt gatctccacc ttggtccc 48
<210>235
<211>48
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuJkappa5-NotI
<400>235
gagtcattct cgacttgcgg ccgcacgttt aatctccagt cgtgtccc 48
<210>236
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda1A-SalI
<400>236
tgagcacaca ggtcgacgca gtctgtgctg actcagccac c 41
<210>237
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda1B-SalI
<400>237
tgagcacaca ggtcgacgca gtctgtgytg acgcagccgc c 41
<210>238
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda1C-SalI
<400>238
tgagcacaca ggtcgacgca gtctgtcgtg acgcagccgc c 41
<210>239
<211>39
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda2-SalI
<400>239
tgagcacaca ggtcgacgca rtctgccctg actcagcct 39
<210>240
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda3A-SalI
<400>240
tgagcacaca ggtcgacgtc ctatgwgctg actcagccac c 41
<210>241
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda3B-SalI
<400>241
tgagcacaca ggtcgacgtc ttctgagctg actcaggacc c 41
<210>242
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda4-SalI
<400>242
tgagcacaca ggtcgacgca cgttatactg actcaaccgc c 41
<210>243
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda5-SalI
<400>243
tgagcacaca ggtcgacgca ggctgtgctg actcagccgt c 41
<210>244
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda6-SalI
<400>244
tgagcacaca ggtcgacgaa ttttatgctg actcagcccc a 41
<210>245
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda7/8-SalI
<400>245
tgagcacaca ggtcgacgca grctgtggtg acycaggagc c 41
<210>246
<211>41
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVlambda9-SalI
<400>246
tgagcacaca ggtcgacgcw gcctgtgctg actcagccmc c 41
<210>247
<211>48
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuJlambdal-NotI
<400>247
gagtcattct cgacttgcgg ccgcacctag gacggtgacc ttggtccc 48
<210>248
<211>48
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuJlambda2/3-NotI
<400>248
gagtcattct cgacttgcgg ccgcacctag gacggtcagc ttggtccc 48
<210>249
<211>48
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuJlambda4/5-NotI
<400>249
gagtcattct cgacttgcgg ccgcacytaa aacggtgagc tgggtccc 48
<210>250
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH1B/7A
<400>250
cagrtgcagc tggtgcartc tgg 23
<210>251
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH1C
<400>251
saggtccagc tggtrcagtc tgg 23
<210>252
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH2B
<400>252
saggtgcagc tggtggagtc tgg 23
<210>253
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH3B
<400>253
saggtgcagc tggtggagtc tgg 23
<210>254
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH3C
<400>254
gaggtgcagc tggtggagwc ygg 23
<210>255
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH4B
<400>255
caggtgcagc tacagcagtg ggg 23
<210>256
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH4C
<400>256
cagstgcagc tgcaggagtc sgg 23
<210>257
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH5B
<400>257
gargtgcagc tggtgcagtc tgg 23
<210>258
<211>23
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH6A
<400>258
caggtacagc tgcagcagtc agg 23
<210>259
<211>56
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH1B/7A-SfiI
<400>259
gtcctcgcaa ctgcggccca gccggccatg gcccagrtgc agctggtgca rtctgg 56
<210>260
<211>56
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH1C-SfiI
<400>260
gtcctcgcaa ctgcggccca gccggccatg gccsaggtcc agctggtrca gtctgg 56
<210>261
<211>56
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH2B-SfiI
<400>261
gtcctcgcaa ctgcggccca gccggccatg gcccagrtca ccttgaagga gtctgg 56
<210>262
<211>56
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH3B-SfiI
<400>262
gtcctcgcaa ctgcggccca gccggccatg gccsaggtgc agctggtgga gtctgg 56
<210>263
<211>56
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH3C-SfiI
<400>263
gtcctcgcaa ctgcggccca gccggccatg gccgaggtgc agctggtgga gwcygg 56
<210>264
<211>56
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH4B-SfiI
<400>264
gtcctcgcaa ctgcggccca gccggccatg gcccaggtgc agctacagca gtgggg 56
<210>265
<211>56
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH4C-SfiI
<400>265
gtcctcgcaa ctgcggccca gccggccatg gcccagstgc agctgcagga gtcsgg 56
<210>266
<211>56
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH5B-SfiI
<400>266
gtcctcgcaa ctgcggccca gccggccatg gccgargtgc agctggtgca gtctgg 56
<210>267
<211>56
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuVH6A-SfiI
<400>267
gtcctcgcaa ctgcggccca gccggccatg gcccaggtac agctgcagca gtcagg 56
<210>268
<211>36
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuJH1/2-XhoI
<400>268
gagtcattct cgactcgaga cggtgaccag ggtgcc 36
<210>269
<211>36
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuJH3-XhoI
<400>269
gagtcattct cgactcgaga cggtgaccat tgtccc 36
<210>270
<211>36
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuJH4/5-XhoI
<400>270
gagtcattct cgactcgaga cggtgaccag ggttcc 36
<210>271
<211>36
<212>DNA
<213>Artificial sequence
<220>
<223>Primer HuJH6-XhoI
<400>271
gagtcattct cgactcgaga cggtgaccgt ggtccc 36
<210>272
<211>381
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain variable region of CR57
<400>272
caggtgcagc tggtgcagag cggagccgag gtgaagaagc ccggcagcag cgtgaaggtg 60
agctgcaagg ccagcggcgg caccttcaac aggtacaccg tgaactgggt gagacaggcc 120
ccaggccagg gcctggagtg gatgggcggc atcatcccta tcttcggcac cgccaactac 180
gcccagagat tccagggcag gctcaccatc accgccgacg agagcaccag caccgcctac 240
atggagctga gcagcctgag aagcgatgac accgccgtgt acttctgcgc cagggagaac 300
ctggataaca gcggcaccta ctactacttc agcggctggt tcgacccctg gggccagggc 360
accctggtga ccgtgagctc a 381
<210>273
<211>127
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain variable region of CR57
<400>273
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Asn Arg Tyr
20 25 30
Thr Val Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Arg Phe
50 55 60
Gln Gly Arg Leu Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Glu Asn Leu Asp Asn Ser Gly Thr Tyr Tyr Tyr Phe Ser Gly
100 105 110
Trp Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210>274
<211>336
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain variable region of CR57
<400>274
cagagcgccc tcacccagcc cagaagcgtg agcggcagcc ctggccagag cgtgaccatc 60
agctgcaccg gcaccagcag cgacatcggc ggctacaact tcgtgagctg gtatcagcag 120
caccccggca aggcccctaa gctcatgatc tacgacgcca ccaagagacc cagcggcgtg 180
cccgacagat tcagcggcag caagagcggc aacaccgcca gcctcaccat cagcggactg 240
caggccgagg acgaggccga ctactactgc tgcagctacg ccggcgacta cacccctggc 300
gtggtgttcg gcggaggcac caagcttacc gtccta 336
<210>275
<211>112
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain variable region of CR57
<400>275
Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Gly Tyr
20 25 30
Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Ala Thr Lys Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Asp
85 90 95
Tyr Thr Pro Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210>276
<211>12
<212>PRT
<213>Artificial sequence
<220>
<223>CDR3 of CRJB
<400>276
Arg Gln His Ile Ser Ser Phe Pro Trp Phe Asp Ser
1 5 10
<210>277
<211>6778
<212>DNA
<213>Artificial sequence
<220>
<223>Vector pSyu-CO3-HCgammal
<400>277
gacggatcgg gagatctccc gatcccctat ggtgcactct cagtacaatc tgctctgatg 60
ccgcatagtt aagccagtat ctgctccctg cttgtgtgtt ggaggtcgct gagtagtgcg 120
cgagcaaaat ttaagctaca acaaggcaag gcttgaccga caattgcatg aagaatctgc 180
ttagggttag gcgttttgcg ctgcttcgct aggtggtcaa tattggccat tagccatatt 240
attcattggt tatatagcat aaatcaatat tggctattgg ccattgcata cgttgtatcc 300
atatcataat atgtacattt atattggctc atgtccaaca ttaccgccat gttgacattg 360
attattgact agttattaat agtaatcaat tacggggtca ttagttcata gcccatatat 420
ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc ccaacgaccc 480
ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag ggactttcca 540
ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac atcaagtgta 600
tcatatgcca agtacgcccc ctattgacgt caatgacggt aaatggcccg cctggcatta 660
tgcccagtac atgaccttat gggactttcc tacttggcag tacatctacg tattagtcat 720
cgctattacc atggtgatgc ggttttggca gtacatcaat gggcgtggat agcggtttga 780
ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt tttggcacca 840
aaatcaacgg gactttccaa aatgtcgtaa caactccgcc ccattgacgc aaatgggcgg 900
taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc gtcagatcgc 960
ctggagacgc catccacgct gttttgacct ccatagaaga caccgggacc gatccagcct 1020
ccgcggccgg gaacggtgca ttggaagctg gcctggatgg cctgactctc ttaggtagcc 1080
ttgcagaagt tggtcgtgag gcactgggca ggtaagtatc aaggttacaa gacaggttta 1140
aggagatcaa tagaaactgg gcttgtcgag acagagaaga ctcttgcgtt tctgataggc 1200
acctattggt cttactgaca tccactttgc ctttctctcc acaggtgtcc actcccagtt 1260
caattacagc tcgccaccat ggcctgcccc ggcttcctgt gggccctggt gatcagcacc 1320
tgcctggaat tcagcatgag cagcgctagc accaagggcc ccagcgtgtt ccccctggcc 1380
cccagcagca agagcaccag cggcggcaca gccgccctgg gctgcctggt gaaggactac 1440
ttccccgagc ccgtgaccgt gagctggaac agcggcgcct tgaccagcgg cgtgcacacc 1500
ttccccgccg tgctgcagag cagcggcctg tacagcctga gcagcgtggt gaccgtgccc 1560
agcagcagcc tgggcaccca gacctacatc tgcaacgtga accacaagcc cagcaacacc 1620
aaggtggaca aacgcgtgga gcccaagagc tgcgacaaga cccacacctg ccccccctgc 1680
cctgcccccg agctgctggg cggaccctcc gtgttcctgt tcccccccaa gcccaaggac 1740
accctcatga tcagccggac ccccgaggtg acctgcgtgg tggtggacgt gagccacgag 1800
gaccccgagg tgaagttcaa ctggtacgtg gacggcgtgg aggtgcacaa cgccaagacc 1860
aagccccggg aggagcagta caacagcacc taccgggtgg tgagcgtgct caccgtgctg 1920
caccaggact ggctgaacgg caaggagtac aagtgcaagg tgagcaacaa ggccctgcct 1980
gcccccatcg agaagaccat cagcaaggcc aagggccagc cccgggagcc ccaggtgtac 2040
accctgcccc ccagccggga ggagatgacc aagaaccagg tgtccctcac ctgtctggtg 2100
aagggcttct accccagcga catcgccgtg gagtgggaga gcaacggcca gcccgagaac 2160
aactacaaga ccaccccccc tgtgctggac agcgacggca gcttcttcct gtacagcaag 2220
ctcaccgtgg acaagagccg gtggcagcag ggcaacgtgt tcagctgcag cgtgatgcac 2280
gaggccctgc acaaccacta cacccagaag agcctgagcc tgagccccgg caagtgataa 2340
tctagagggc ccgtttaaac ccgctgatca gcctcgactg tgccttctag ttgccagcca 2400
tctgttgttt gcccctcccc cgtgccttcc ttgaccctgg aaggtgccac tcccactgtc 2460
ctttcctaat aaaatgagga aattgcatcg cattgtctga gtaggtgtca ttctattctg 2520
gggggtgggg tggggcagga cagcaagggg gaggattggg aagacaatag caggcatgct 2580
ggggatgcgg tgggctctat ggcttctgag gcggaaagaa ccagctgggg ctctaggggg 2640
tatccccacg cgccctgtag cggcgcatta agcgcggcgg gtgtggtggt tacgcgcagc 2700
gtgaccgcta cacttgccag cgccctagcg cccgctcctt tcgctttctt cccttccttt 2760
ctcgccacgt tcgccggctt tccccgtcaa gctctaaatc gggggctccc tttagggttc 2820
cgatttagtg ctttacggca cctcgacccc aaaaaacttg attagggtga tggttcacgt 2880
agtgggccat cgccctgata gacggttttt cgccctttga cgttggagtc cacgttcttt 2940
aatagtggac tcttgttcca aactggaaca acactcaacc ctatctcggt ctattctttt 3000
gatttataag ggattttgcc gatttcggcc tattggttaa aaaatgagct gatttaacaa 3060
aaatttaacg cgaattaatt ctgtggaatg tgtgtcagtt agggtgtgga aagtccccag 3120
gctccccagc aggcagaagt atgcaaagca tgcatctcaa ttagtcagca accaggtgtg 3180
gaaagtcccc aggctcccca gcaggcagaa gtatgcaaag catgcatctc aattagtcag 3240
caaccatagt cccgccccta actccgccca tcccgcccct aactccgccc agttccgccc 3300
attctccgcc ccatggctga ctaatttttt ttatttatgc agaggccgag gccgcctctg 3360
cctctgagct attccagaag tagtgaggag gcttttttgg aggcctaggc ttttgcaaaa 3420
agctcccggg agcttgtata tccattttcg gatctgatca agagacagga tgaggatcgt 3480
ttcgcatgat tgaacaagat ggattgcacg caggttctcc ggccgcttgg gtggagaggc 3540
tattcggcta tgactgggca caacagacaa tcggctgctc tgatgccgcc gtgttccggc 3600
tgtcagcgca ggggcgcccg gttctttttg tcaagaccga cctgtccggt gccctgaatg 3660
aactgcagga cgaggcagcg cggctatcgt ggctggccac gacgggcgtt ccttgcgcag 3720
ctgtgctcga cgttgtcact gaagcgggaa gggactggct gctattgggc gaagtgccgg 3780
ggcaggatct cctgtcatct caccttgctc ctgccgagaa agtatccatc atggctgatg 3840
caatgcggcg gctgcatacg cttgatccgg ctacctgccc attcgaccac caagcgaaac 3900
atcgcatcga gcgagcacgt actcggatgg aagccggtct tgtcgatcag gatgatctgg 3960
acgaagagca tcaggggctc gcgccagccg aactgttcgc caggctcaag gcgcgcatgc 4020
ccgacggcga ggatctcgtc gtgacccatg gcgatgcctg cttgccgaat atcatggtgg 4080
aaaatggccg cttttctgga ttcatcgact gtggccggct gggtgtggcg gatcgctatc 4140
aggacatagc gttggctacc cgtgatattg ctgaagagct tggcggcgaa tgggctgacc 4200
gcttcctcgt gctttacggt atcgccgctc ccgattcgca gcgcatcgcc ttctatcgcc 4260
ttcttgacga gttcttctga gcgggactct ggggttcgaa atgaccgacc aagcgacgcc 4320
caacctgcca tcacgagatt tcgattccac cgccgccttc tatgaaaggt tgggcttcgg 4380
aatcgttttc cgggacgccg gctggatgat cctccagcgc ggggatctca tgctggagtt 4440
cttcgcccac cccaacttgt ttattgcagc ttataatggt tacaaataaa gcaatagcat 4500
cacaaatttc acaaataaag catttttttc actgcattct agttgtggtt tgtccaaact 4560
catcaatgta tcttatcatg tctgtatacc gtcgacctct agctagagct tggcgtaatc 4620
atggtcatag ctgtttcctg tgtgaaattg ttatccgctc acaattccac acaacatacg 4680
agccggaagc ataaagtgta aagcctgggg tgcctaatga gtgagctaac tcacattaat 4740
tgcgttgcgc tcactgcccg ctttccagtc gggaaacctg tcgtgccagc tgcattaatg 4800
aatcggccaa cgcgcgggga gaggcggttt gcgtattggg cgctcttccg cttcctcgct 4860
cactgactcg ctgcgctcgg tcgttcggct gcggcgagcg gtatcagctc actcaaaggc 4920
ggtaatacgg ttatccacag aatcagggga taacgcagga aagaacatgt gagcaaaagg 4980
ccagcaaaag gccaggaacc gtaaaaaggc cgcgttgctg gcgtttttcc ataggctccg 5040
cccccctgac gagcatcaca aaaatcgacg ctcaagtcag aggtggcgaa acccgacagg 5100
actataaaga taccaggcgt ttccccctgg aagctccctc gtgcgctctc ctgttccgac 5160
cctgccgctt accggatacc tgtccgcctt tctcccttcg ggaagcgtgg cgctttctca 5220
tagctcacgc tgtaggtatc tcagttcggt gtaggtcgtt cgctccaagc tgggctgtgt 5280
gcacgaaccc cccgttcagc ccgaccgctg cgccttatcc ggtaactatc gtcttgagtc 5340
caacccggta agacacgact tatcgccact ggcagcagcc actggtaaca ggattagcag 5400
agcgaggtat gtaggcggtg ctacagagtt cttgaagtgg tggcctaact acggctacac 5460
tagaagaaca gtatttggta tctgcgctct gctgaagcca gttaccttcg gaaaaagagt 5520
tggtagctct tgatccggca aacaaaccac cgctggtagc ggtttttttg tttgcaagca 5580
gcagattacg cgcagaaaaa aaggatctca agaagatcct ttgatctttt ctacggggtc 5640
tgacgctcag tggaacgaaa actcacgtta agggattttg gtcatgagat tatcaaaaag 5700
gatcttcacc tagatccttt taaattaaaa atgaagtttt aaatcaatct aaagtatata 5760
tgagtaaact tggtctgaca gttaccaatg cttaatcagt gaggcaccta tctcagcgat 5820
ctgtctattt cgttcatcca tagttgcctg actccccgtc gtgtagataa ctacgatacg 5880
ggagggctta ccatctggcc ccagtgctgc aatgataccg cgagacccac gctcaccggc 5940
tccagattta tcagcaataa accagccagc cggaagggcc gagcgcagaa gtggtcctgc 6000
aactttatcc gcctccatcc agtctattaa ttgttgccgg gaagctagag taagtagttc 6060
gccagttaat agtttgcgca acgttgttgc cattgctaca ggcatcgtgg tgtcacgctc 6120
gtcgtttggt atggcttcat tcagctccgg ttcccaacga tcaaggcgag ttacatgatc 6180
ccccatgttg tgcaaaaaag cggttagctc cttcggtcct ccgatcgttg tcagaagtaa 6240
gttggccgca gtgttatcac tcatggttat ggcagcactg cataattctc ttactgtcat 6300
gccatccgta agatgctttt ctgtgactgg tgagtactca accaagtcat tctgagaata 6360
gtgtatgcgg cgaccgagtt gctcttgccc ggcgtcaata cgggataata ccgcgccaca 6420
tagcagaact ttaaaagtgc tcatcattgg aaaacgttct tcggggcgaa aactctcaag 6480
gatcttaccg ctgttgagat ccagttcgat gtaacccact cgtgcaccca actgatcttc 6540
agcatctttt actttcacca gcgtttctgg gtgagcaaaa acaggaaggc aaaatgccgc 6600
aaaaaaggga ataagggcga cacggaaatg ttgaatactc atactcttcc tttttcaata 6660
ttattgaagc atttatcagg gttattgtct catgagcgga tacatatttg aatgtattta 6720
gaaaaataaa caaatagggg ttccgcgcac atttccccga aaagtgccac ctgacgtc 6778
<210>278
<211>6283
<212>DNA
<213>Artificial sequence
<220>
<223>Vector pSyn-CO4-Clambda
<400>278
gacggatcgg gagatctccc gatcccctat ggtgcactct cagtacaatc tgctctgatg 60
ccgcatagtt aagccagtat ctgctccctg cttgtgtgtt ggaggtcgct gagtagtgcg 120
cgagcaaaat ttaagctaca acaaggcaag gcttgaccga caattgttaa ttaacatgaa 180
gaatctgctt agggttaggc gttttgcgct gcttcgctag gtggtcaata ttggccatta 240
gccatattat tcattggtta tatagcataa atcaatattg gctattggcc attgcatacg 300
ttgtatccat atcataatat gtacatttat attggctcat gtccaacatt accgccatgt 360
tgacattgat tattgactag ttattaatag taatcaatta cggggtcatt agttcatagc 420
ccatatatgg agttccgcgt tacataactt acggtaaatg gcccgcctgg ctgaccgccc 480
aacgaccccc gcccattgac gtcaataatg acgtatgttc ccatagtaac gccaataggg 540
actttccatt gacgtcaatg ggtggagtat ttacggtaaa ctgcccactt ggcagtacat 600
caagtgtatc atatgccaag tacgccccct attgacgtca atgacggtaa atggcccgcc 660
tggcattatg cccagtacat gaccttatgg gactttccta cttggcagta catctacgta 720
ttagtcatcg ctattaccat ggtgatgcgg ttttggcagt acatcaatgg gcgtggatag 780
cggtttgact cacggggatt tccaagtctc caccccattg acgtcaatgg gagtttgttt 840
tggcaccaaa atcaacggga ctttccaaaa tgtcgtaaca actccgcccc attgacgcaa 900
atgggcggta ggcgtgtacg gtgggaggtc tatataagca gagctcgttt agtgaaccgt 960
cagatcgcct ggagacgcca tccacgctgt tttgacctcc atagaagaca ccgggaccga 1020
tccagcctcc gcggccggga acggtgcatt ggaatcgatg actctcttag gtagccttgc 1080
agaagttggt cgtgaggcac tgggcaggta agtatcaagg ttacaagaca ggtttaagga 1140
gatcaataga aactgggctt gtcgagacag agaagactct tgcgtttctg ataggcacct 1200
attggtctta ctgacatcca ctttgccttt ctctccacag gtgtccactc ccagttcaat 1260
tacagctcgc caccatggcc tgccccggct tcctgtgggc cctggtgatc agcacctgcc 1320
tcgagatccc cggaccgcgg ccgcaagctt accgtgctgg gccagcccaa ggccgctccc 1380
agcgtgaccc tgttcccccc ctcctccgag gagctgcagg ccaacaaggc caccctggtg 1440
tgcctcatca gcgacttcta ccctggcgcc gtgaccgtgg cctggaaggc cgacagcagc 1500
cccgtgaagg ccggcgtgga gaccaccacc cccagcaagc agagcaacaa caagtacgcc 1560
gccagcagct acctgagcct cacccccgag cagtggaaga gccaccggag ctacagctgc 1620
caggtgaccc acgagggcag caccgtggag aagaccgtgg cccccaccga gtgcagctaa 1680
tagacttaag tttaaaccgc tgatcagcct cgactgtgcc ttctagttgc cagccatctg 1740
ttgtttgccc ctcccccgtg ccttccttga ccctggaagg tgccactccc actgtccttt 1800
cctaataaaa tgaggaaatt gcatcgcatt gtctgagtag gtgtcattct attctggggg 1860
gtggggtggg gcaggacagc aagggggagg attgggaaga caatagcagg catgctgggg 1920
atgcggtggg ctctatggct tctgaggcgg aaagaaccag ctggggctct agggggtatc 1980
cccacgcgcc ctgtagcggc gcattaagcg cggcgggtgt ggtggttacg cgcagcgtga 2040
ccgctacact tgccagcgcc ctagcgcccg ctcctttcgc tttcttccct tcctttctcg 2100
ccacgttcgc cggctttccc cgtcaagctc taaatcgggg gctcccttta gggttccgat 2160
ttagtgcttt acggcacctc gaccccaaaa aacttgatta gggtgatggt tcacgtagtg 2220
ggccatcgcc ctgatagacg gtttttcgcc ctttgacgtt ggagtccacg ttctttaata 2280
gtggactctt gttccaaact ggaacaacac tcaaccctat ctcggtctat tcttttgatt 2340
tataagggat tttggccatt tcggcctatt ggttaaaaaa tgagctgatt taacaaaaat 2400
ttaacgcgaa ttaattctgt ggaatgtgtg tcagttaggg tgtggaaagt ccccaggctc 2460
cccagcaggc agaagtatgc aaagcatgca tctcaattag tcagcaacca ggtgtggaaa 2520
gtccccaggc tccccagcag gcagaagtat gcaaagcatg catctcaatt agtcagcaac 2580
catagtcccg cccctaactc cgcccatccc gcccctaact ccgcccagtt ccgcccattc 2640
tccgccccat ggctgactaa ttttttttat ttatgcagag gccgaggccg cctctgcctc 2700
tgagctattc cagaagtagt gaggaggctt ttttggaggc ctaggctttt gcaaaaagct 2760
cccgggagct tgtatatcca ttttcggatc tgatcagcac gtgatgaaaa agcctgaact 2820
caccgcgacg tctgtcgaga agtttctgat cgaaaagttc gacagcgtct ccgacctgat 2880
gcagctctcg gagggcgaag aatctcgtgc tttcagcttc gatgtaggag ggcgtggata 2940
tgtcctgcgg gtaaatagct gcgccgatgg tttctacaaa gatcgttatg tttatcggca 3000
ctttgcatcg gccgcgctcc cgattccgga agtgcttgac attggggaat tcagcgagag 3060
cctgacctat tgcatctccc gccgtgcaca gggtgtcacg ttgcaagacc tgcctgaaac 3120
cgaactgccc gctgttctgc agccggtcgc ggaggccatg gatgcgatcg ctgcggccga 3180
tcttagccag acgagcgggt tcggcccatt cggaccgcaa ggaatcggtc aatacactac 3240
atggcgtgat ttcatatgcg cgattgctga tccccatgtg tatcactggc aaactgtgat 3300
ggacgacacc gtcagtgcgt ccgtcgcgca ggctctcgat gagctgatgc tttgggccga 3360
ggactgcccc gaagtccggc acctcgtgca cgcggatttc ggctccaaca atgtcctgac 3420
ggacaatggc cgcataacag cggtcattga ctggagcgag gcgatgttcg gggattccca 3480
atacgaggtc gccaacatct tcttctggag gccgtggttg gcttgtatgg agcagcagac 3540
gcgctacttc gagcggaggc atccggagct tgcaggatcg ccgcggctcc gggcgtatat 3600
gctccgcatt ggtcttgacc aactctatca gagcttggtt gacggcaatt tcgatgatgc 3660
agcttgggcg cagggtcgat gcgacgcaat cgtccgatcc ggagccggga ctgtcgggcg 3720
tacacaaatc gcccgcagaa gcgcggccgt ctggaccgat ggctgtgtag aagtactcgc 3780
cgatagtgga aaccgacgcc ccagcactcg tccgagggca aaggaatagc acgtgctacg 3840
agatttcgat tccaccgccg ccttctatga aaggttgggc ttcggaatcg ttttccggga 3900
cgccggctgg atgatcctcc agcgcgggga tctcatgctg gagttcttcg cccaccccaa 3960
cttgtttatt gcagcttata atggttacaa ataaagcaat agcatcacaa atttcacaaa 4020
taaagcattt ttttcactgc attctagttg tggtttgtcc aaactcatca atgtatctta 4080
tcatgtctgt ataccgtcga cctctagcta gagcttggcg taatcatggt catagctgtt 4140
tcctgtgtga aattgttatc cgctcacaat tccacacaac atacgagccg gaagcataaa 4200
gtgtaaagcc tggggtgcct aatgagtgag ctaactcaca ttaattgcgt tgcgctcact 4260
gcccgctttc cagtcgggaa acctgtcgtg ccagctgcat taatgaatcg gccaacgcgc 4320
ggggagaggc ggtttgcgta ttgggcgctc ttccgcttcc tcgctcactg actcgctgcg 4380
ctcggtcgtt cggctgcggc gagcggtatc agctcactca aaggcggtaa tacggttatc 4440
cacagaatca ggggataacg caggaaagaa catgtgagca aaaggccagc aaaaggccag 4500
gaaccgtaaa aaggccgcgt tgctggcgtt tttccatagg ctccgccccc ctgacgagca 4560
tcacaaaaat cgacgctcaa gtcagaggtg gcgaaacccg acaggactat aaagatacca 4620
ggcgtttccc cctggaagct ccctcgtgcg ctctcctgtt ccgaccctgc cgcttaccgg 4680
atacctgtcc gcctttctcc cttcgggaag cgtggcgctt tctcatagct cacgctgtag 4740
gtatctcagt tcggtgtagg tcgttcgctc caagctgggc tgtgtgcacg aaccccccgt 4800
tcagcccgac cgctgcgcct tatccggtaa ctatcgtctt gagtccaacc cggtaagaca 4860
cgacttatcg ccactggcag cagccactgg taacaggatt agcagagcga ggtatgtagg 4920
cggtgctaca gagttcttga agtggtggcc taactacggc tacactagaa gaacagtatt 4980
tggtatctgc gctctgctga agccagttac cttcggaaaa agagttggta gctcttgatc 5040
cggcaaacaa accaccgctg gtagcggttt ttttgtttgc aagcagcaga ttacgcgcag 5100
aaaaaaagga tctcaagaag atcctttgat cttttctacg gggtctgacg ctcagtggaa 5160
cgaaaactca cgttaaggga ttttggtcat gagattatca aaaaggatct tcacctagat 5220
ccttttaaat taaaaatgaa gttttaaatc aatctaaagt atatatgagt aaacttggtc 5280
tgacagttac caatgcttaa tcagtgaggc acctatctca gcgatctgtc tatttcgttc 5340
atccatagtt gcctgactcc ccgtcgtgta gataactacg atacgggagg gcttaccatc 5400
tggccccagt gctgcaatga taccgcgaga cccacgctca ccggctccag atttatcagc 5460
aataaaccag ccagccggaa gggccgagcg cagaagtggt cctgcaactt tatccgcctc 5520
catccagtct attaattgtt gccgggaagc tagagtaagt agttcgccag ttaatagttt 5580
gcgcaacgtt gttgccattg ctacaggcat cgtggtgtca cgctcgtcgt ttggtatggc 5640
ttcattcagc tccggttccc aacgatcaag gcgagttaca tgatccccca tgttgtgcaa 5700
aaaagcggtt agctccttcg gtcctccgat cgttgtcaga agtaagttgg ccgcagtgtt 5760
atcactcatg gttatggcag cactgcataa ttctcttact gtcatgccat ccgtaagatg 5820
cttttctgtg actggtgagt actcaaccaa gtcattctga gaatagtgta tgcggcgacc 5880
gagttgctct tgcccggcgt caatacggga taataccgcg ccacatagca gaactttaaa 5940
agtgctcatc attggaaaac gttcttcggg gcgaaaactc tcaaggatct taccgctgtt 6000
gagatccagt tcgatgtaac ccactcgtgc acccaactga tcttcagcat cttttacttt 6060
caccagcgtt tctgggtgag caaaaacagg aaggcaaaat gccgcaaaaa agggaataag 6120
ggcgacacgg aaatgttgaa tactcatact cttccttttt caatattatt gaagcattta 6180
tcagggttat tgtctcatga gcggatacat atttgaatgt atttagaaaa ataaacaaat 6240
aggggttccg cgcacatttc cccgaaaagt gccacctgac gtc 6283
<210>279
<211>6267
<212>DNA
<213>Artificial sequence
<220>
<223>Vector pSyn-C05-Ckappa
<400>279
gacggatcgg gagatctccc gatcccctat ggtgcactct cagtacaatc tgctctgatg 60
ccgcatagtt aagccagtat ctgctccctg cttgtgtgtt ggaggtcgct gagtagtgcg 120
cgagcaaaat ttaagctaca acaaggcaag gcttgaccga caattgttaa ttaacatgaa 180
gaatctgctt agggttaggc gttttgcgct gcttcgctag gtggtcaata ttggccatta 240
gccatattat tcattggtta tatagcataa atcaatattg gctattggcc attgcatacg 300
ttgtatccat atcataatat gtacatttat attggctcat gtccaacatt accgccatgt 360
tgacattgat tattgactag ttattaatag taatcaatta cggggtcatt agttcatagc 420
ccatatatgg agttccgcgt tacataactt acggtaaatg gcccgcctgg ctgaccgccc 480
aacgaccccc gcccattgac gtcaataatg acgtatgttc ccatagtaac gccaataggg 540
actttccatt gacgtcaatg ggtggagtat ttacggtaaa ctgcccactt ggcagtacat 600
caagtgtatc atatgccaag tacgccccct attgacgtca atgacggtaa atggcccgcc 660
tggcattatg cccagtacat gaccttatgg gactttccta cttggcagta catctacgta 720
ttagtcatcg ctattaccat ggtgatgcgg ttttggcagt acatcaatgg gcgtggatag 780
cggtttgact cacggggatt tccaagtctc caccccattg acgtcaatgg gagtttgttt 840
tggcaccaaa atcaacggga ctttccaaaa tgtcgtaaca actccgcccc attgacgcaa 900
atgggcggta ggcgtgtacg gtgggaggtc tatataagca gagctcgttt agtgaaccgt 960
cagatcgcct ggagacgcca tccacgctgt tttgacctcc atagaagaca ccgggaccga 1020
tccagcctcc gcggccggga acggtgcatt ggaatcgatg actctcttag gtagccttgc 1080
agaagttggt cgtgaggcac tgggcaggta agtatcaagg ttacaagaca ggtttaagga 1140
gatcaataga aactgggctt gtcgagacag agaagactct tgcgtttctg ataggcacct 1200
attggtctta ctgacatcca ctttgccttt ctctccacag gtgtccactc ccagttcaat 1260
tacagctcgc caccatggcc tgccccggct tcctgtgggc cctggtgatc agcacctgcc 1320
tcgagttcag cggccctaag cggaccgtgg ccgctcccag cgtgttcatc ttccccccct 1380
ccgacgagca gctgaagagc ggcaccgcca gcgtggtgtg cctgctgaac aacttctacc 1440
cccgggaggc caaggtgcag tggaaggtgg acaacgccct gcagagcggc aacagccagg 1500
agagcgtgac cgagcaggac agcaaggact ccacctacag cctgagcagc accctcaccc 1560
tgagcaaggc cgactacgag aagcacaagg tgtacgcctg cgaggtgacc caccagggcc 1620
tgagcagccc cgtgaccaag agcttcaacc ggggcgagtg ttaatagact taagtttaaa 1680
ccgctgatca gcctcgactg tgccttctag ttgccagcca tctgttgttt gcccctcccc 1740
cgtgccttcc ttgaccctgg aaggtgccac tcccactgtc ctttcctaat aaaatgagga 1800
aattgcatcg cattgtctga gtaggtgtca ttctattctg gggggtgggg tggggcagga 1860
cagcaagggg gaggattggg aagacaatag caggcatgct ggggatgcgg tgggctctat 1920
ggcttctgag gcggaaagaa ccagctgggg ctctaggggg tatccccacg cgccctgtag 1980
cggcgcatta agcgcggcgg gtgtggtggt tacgcgcagc gtgaccgcta cacttgccag 2040
cgccctagcg cccgctcctt tcgctttctt cccttccttt ctcgccacgt tcgccggctt 2100
tccccgtcaa gctctaaatc gggggctccc tttagggttc cgatttagtg ctttacggca 2160
cctcgacccc aaaaaacttg attagggtga tggttcacgt agtgggccat cgccctgata 2220
gacggttttt cgccctttga cgttggagtc cacgttcttt aatagtggac tcttgttcca 2280
aactggaaca acactcaacc ctatctcggt ctattctttt gatttataag ggattttggc 2340
catttcggcc tattggttaa aaaatgagct gatttaacaa aaatttaacg cgaattaatt 2400
ctgtggaatg tgtgtcagtt agggtgtgga aagtccccag gctccccagc aggcagaagt 2460
atgcaaagca tgcatctcaa ttagtcagca accaggtgtg gaaagtcccc aggctcccca 2520
gcaggcagaa gtatgcaaag catgcatctc aattagtcag caaccatagt cccgccccta 2580
actccgccca tcccgcccct aactccgccc agttccgccc attctccgcc ccatggctga 2640
ctaatttttt ttatttatgc agaggccgag gccgcctctg cctctgagct attccagaag 2700
tagtgaggag gcttttttgg aggcctaggc ttttgcaaaa agctcccggg agcttgtata 2760
tccattttcg gatctgatca gcacgtgatg aaaaagcctg aactcaccgc gacgtctgtc 2820
gagaagtttc tgatcgaaaa gttcgacagc gtctccgacc tgatgcagct ctcggagggc 2880
gaagaatctc gtgctttcag cttcgatgta ggagggcgtg gatatgtcct gcgggtaaat 2940
agctgcgccg atggtttcta caaagatcgt tatgtttatc ggcactttgc atcggccgcg 3000
ctcccgattc cggaagtgct tgacattggg gaattcagcg agagcctgac ctattgcatc 3060
tcccgccgtg cacagggtgt cacgttgcaa gacctgcctg aaaccgaact gcccgctgtt 3120
ctgcagccgg tcgcggaggc catggatgcg atcgctgcgg ccgatcttag ccagacgagc 3180
gggttcggcc cattcggacc acaaggaatc ggtcaataca ctacatggcg tgatttcata 3240
tgcgcgattg ctgatcccca tgtgtatcac tggcaaactg tgatggacga caccgtcagt 3300
gcgtccgtcg cgcaggctct cgatgagctg atgctttggg ccgaggactg ccccgaagtc 3360
cggcacctcg tgcacgcgga tttcggctcc aacaatgtcc tgacggacaa tggccgcata 3420
acagcggtca ttgactggag cgaggcgatg ttcggggatt cccaatacga ggtcgccaac 3480
atcttcttct ggaggccgtg gttggcttgt atggagcagc agacgcgcta cttcgagcgg 3540
aggcatccgg agcttgcagg atcgccgcgg ctccgggcgt atatgctccg cattggtctt 3600
gaccaactct atcagagctt ggttgacggc aatttcgatg atgcagcttg ggcgcagggt 3660
cgatgcgacg caatcgtccg atccggagcc gggactgtcg ggcgtacaca aatcgcccgc 3720
agaagcgcgg ccgtctggac cgatggctgt gtagaagtac tcgccgatag tggaaaccga 3780
cgccccagca ctcgtccgag ggcaaaggaa tagcacgtgc tacgagattt cgattccacc 3840
gccgccttct atgaaaggtt gggcttcgga atcgttttcc gggacgccgg ctggatgatc 3900
ctccagcgcg gggatctcat gctggagttc ttcgcccacc ccaacttgtt tattgcagct 3960
tataatggtt acaaataaag caatagcatc acaaatttca caaataaagc atttttttca 4020
ctgcattcta gttgtggttt gtccaaactc atcaatgtat cttatcatgt ctgtataccg 4080
tcgacctcta gctagagctt ggcgtaatca tggtcatagc tgtttcctgt gtgaaattgt 4140
tatccgctca caattccaca caacatacga gccggaagca taaagtgtaa agcctggggt 4200
gcctaatgag tgagctaact cacattaatt gcgttgcgct cactgcccgc tttccagtcg 4260
ggaaacctgt cgtgccagct gcattaatga atcggccaac gcgcggggag aggcggtttg 4320
cgtattgggc gctcttccgc ttcctcgctc actgactcgc tgcgctcggt cgttcggctg 4380
cggcgagcgg tatcagctca ctcaaaggcg gtaatacggt tatccacaga atcaggggat 4440
aacgcaggaa agaacatgtg agcaaaaggc cagcaaaagg ccaggaaccg taaaaaggcc 4500
gcgttgctgg cgtttttcca taggctccgc ccccctgacg agcatcacaa aaatcgacgc 4560
tcaagtcaga ggtggcgaaa cccgacagga ctataaagat accaggcgtt tccccctgga 4620
agctccctcg tgcgctctcc tgttccgacc ctgccgctta ccggatacct gtccgccttt 4680
ctcccttcgg gaagcgtggc gctttctcat agctcacgct gtaggtatct cagttcggtg 4740
taggtcgttc gctccaagct gggctgtgtg cacgaacccc ccgttcagcc cgaccgctgc 4800
gccttatccg gtaactatcg tcttgagtcc aacccggtaa gacacgactt atcgccactg 4860
gcagcagcca ctggtaacag gattagcaga gcgaggtatg taggcggtgc tacagagttc 4920
ttgaagtggt ggcctaacta cggctacact agaagaacag tatttggtat ctgcgctctg 4980
ctgaagccag ttaccttcgg aaaaagagtt ggtagctctt gatccggcaa acaaaccacc 5040
gctggtagcg gtttttttgt ttgcaagcag cagattacgc gcagaaaaaa aggatctcaa 5100
gaagatcctt tgatcttttc tacggggtct gacgctcagt ggaacgaaaa ctcacgttaa 5160
gggattttgg tcatgagatt atcaaaaagg atcttcacct agatcctttt aaattaaaaa 5220
tgaagtttta aatcaatcta aagtatatat gagtaaactt ggtctgacag ttaccaatgc 5280
ttaatcagtg aggcacctat ctcagcgatc tgtctatttc gttcatccat agttgcctga 5340
ctccccgtcg tgtagataac tacgatacgg gagggcttac catctggccc cagtgctgca 5400
atgataccgc gagacccacg ctcaccggct ccagatttat cagcaataaa ccagccagcc 5460
ggaagggccg agcgcagaag tggtcctgca actttatccg cctccatcca gtctattaat 5520
tgttgccggg aagctagagt aagtagttcg ccagttaata gtttgcgcaa cgttgttgcc 5580
attgctacag gcatcgtggt gtcacgctcg tcgtttggta tggcttcatt cagctccggt 5640
tcccaacgat caaggcgagt tacatgatcc cccatgttgt gcaaaaaagc ggttagctcc 5700
ttcggtcctc cgatcgttgt cagaagtaag ttggccgcag tgttatcact catggttatg 5760
gcagcactgc ataattctct tactgtcatg ccatccgtaa gatgcttttc tgtgactggt 5820
gagtactcaa ccaagtcatt ctgagaatag tgtatgcggc gaccgagttg ctcttgcccg 5880
gcgtcaatac gggataatac cgcgccacat agcagaactt taaaagtgct catcattgga 5940
aaacgttctt cggggcgaaa actctcaagg atcttaccgc tgttgagatc cagttcgatg 6000
taacccactc gtgcacccaa ctgatcttca gcatctttta ctttcaccag cgtttctggg 6060
tgagcaaaaa caggaaggca aaatgccgca aaaaagggaa taagggcgac acggaaatgt 6120
tgaatactca tactcttcct ttttcaatat tattgaagca tttatcaggg ttattgtctc 6180
atgagcggat acatatttga atgtatttag aaaaataaac aaataggggt tccgcgcaca 6240
tttccccgaa aagtgccacc tgacgtc 6267
<210>280
<211>46
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5H-B
<400>280
acctgtcttg aattctccat ggccgaggtg cagctggtgg agtctg 46
<210>281
<211>47
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5H-C
<400>281
acctgtcttg aattctccat ggcccaggtg cagctggtgg agtctgg 47
<210>282
<211>49
<212>DNA
<213>Artificial seGuence
<220>
<223>Oligonucleotide 5H-C-long
<400>282
acctgtcttg aattctccat ggcccaggtg cagctggtgg agtctgggg 49
<210>283
<211>50
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5H-F
<400>283
acctgtcttg aattctccat ggcccaggtg cagctgcagg agtccggccc 50
<210>284
<211>47
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5H-H
<400>284
acctgtcttg aattctccat ggccgaggtg cagctggtgc agtctgg 47
<210>285
<211>47
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5H-I
<400>285
acctgtcttg aattctccat ggccgaggtg cagctgctgg agtctgg 47
<210>286
<211>47
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5H-M
<400>286
acctgtcttg aattctccat ggcccaggtg accttgaagg agtctgg 47
<210>287
<211>47
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide sy3H-A
<400>287
gcccttggtg ctagcgctgg agacggtcac cagggtgccc tggcccc 47
<210>288
<211>47
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide sy3H-C
<400>288
gcccttggtg ctagcgctgg agacggtcac ggtggtgccc tggcccc 47
<210>289
<211>54
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide sy3H-C-long
<400>289
gcccttggtg ctagcgctgg agacggtcac ggtggtgccc ttgccccaga cgtc 54
<210>290
<211>47
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide sy3H-D
<400>290
gcccttggtg ctagcgctgg acacggtcac catggtgccc tggcccc 47
<210>291
<211>47
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide sy3H-E
<400>291
gcccttggtg ctagcgctgg acacggtcac cagggtgccc cggcccc 47
<210>292
<211>44
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 3L-B
<400>292
ttttccttag cggccgcgac tcacctagga cggtcagctt ggtc 44
<210>293
<211>44
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5K-B
<400>293
acctgtctcg agttttccat ggctgacatc cagatgaccc agtc 44
<210>294
<211>55
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5K-C
<400>294
acctgtctcg agttttccat ggctgacatc cagatgaccc agtctccatc ctccc 55
<210>295
<211>47
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5K-G
<400>295
acctgtctcg agttttccat ggctgacatc gtgatgaccc agtctcc 47
<210>296
<211>47
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5K-K
<400>296
acctgtctcg agttttccat ggctgccatc cagatgaccc agtctcc 47
<210>297
<211>44
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5K-M
<400>297
acctgtctcg agttttccat ggctgacatc cagctgaccc agtc 44
<210>298
<211>44
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5K-N
<400>298
acctgtctcg agttttccat ggctgacatc cagatgactc agtc 44
<210>299
<211>44
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5K-O
<400>299
acctgtctcg agttttccat ggctgccatc cagctgaccc agtc 44
<210>300
<211>44
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5K-Q
<400>300
acctgtctcg agttttccat ggctgagatc gtgatgactc agtc 44
<210>301
<211>45
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5L-E
<400>301
acctgtctcg agttttccat ggcttcctac gtgctgactc agccg 45
<210>302
<211>44
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide 5L-F
<400>302
acctgtctcg agttttccat ggctcagtcc gtgctgactc agcc 44
<210>303
<211>44
<212>DNA
<213>Artificial sequence
<220>
<223>Oligoucleotide 5L-G
<400>303
acctgtctcg agttttccat ggcttcctac gtgctgactc agcc 44
<210>304
<211>42
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide sy3K-F
<400>304
gctgggggcg gccacggtcc gcttgatctc caccttggtc cc 42
<210>305
<211>42
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide sy3K-I
<400>305
gctgggggcg gccacggtcc gcttgatctc cagccgtgtc cc 42
<210>306
<211>42
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide sy3K-J
<400>306
gctgggggcg gccacggtcc gcttgatctc cagcttggtc cc 42
<210>307
<211>42
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide sy3K-K
<400>307
gctgggggcg gccacggtcc gcttgatgtc caccttggtc cc 42
<210>308
<211>43
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide sy3L-A
<400>308
ccagcacggt aagcttcagc acggtcacct tggtgccagt tcc 43
<210>309
<211>43
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide sy3L-C
<400>309
ccagcacggt aagcttcagc acggtcagct tggtgcctcc gcc 43
<210>310
<211>37
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide sy3L-D
<400>310
ccagcacggt aagcttcaac acggtcagct gggtccc 37
<210>311
<211>52
<212>DNA
<213>Artificial sequence
<220>
<223>Oligonucleotide sy5L-A
<400>311
acctgtctcg agttttccat ggcttcctcc gagctgaccc aggaccctgc tg 52
<210>312
<211>756
<212>DNA
<213>Artificial sequence
<220>
<223>scFv SOJB
<400>312
gccatggccc agatcaccct gaaggagacc ggccccaccc tggtgaagcc cacccagacc 60
ctcaccctca cctgcacctt cagcggcttc agcctgagca ccagcggcgt cggcgtgggc 120
tggatcagac agccccctgg caaggccctg gagtgggtga ccctcatcta ctgggacgac 180
gacaagagat acagccccag cctggagaac agggtgacca tccggaagga caccagcaag 240
aaccaggtgg ccctcaccat gaccaacatg gaccccctgg ataccggcac ctactactgc 300
gcccacaggc agcacatcag cagcttcccc tggttcgaca gctggggcca gggcacactg 360
gtgaccgtct cgagcggtac gggcggttca ggcggaaccg gcagcggcac tggcgggtcg 420
acgagctacg tgctcaccca gccccccagc gtgagcgtgg cccctggcaa gaccgccaga 480
atcaactgcg gcggcaacaa catcgagtac cggagcgtgc actggtatca gcagaagagc 540
ggccaggccc ccgtggccgt gatctacgac aacagcgaca gacctagcgg catccccgag 600
agattcagcg gcagcaagag cggcaacacc gccaccctca ccatcagcag agtggaggcc 660
ggcgacgagg ccgactacta ctgccaggtg tgggacatca gcagcgatgt ggtgttcggc 720
ggaggcacca agcttaccgt gctaggtgcg gccgca 756
<210>313
<211>252
<212>PRT
<213>Artificial sequence
<220>
<223>scFv SOJB
<400>313
Ala Met Ala Gln Ile Thr Leu Lys Glu Thr Gly Pro Thr Leu Val Lys
1 5 10 15
Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu
20 25 30
Ser Thr Ser Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys
35 40 45
Ala Leu Glu Trp Val Thr Leu Ile Tyr Trp Asp Asp Asp Lys Arg Tyr
50 55 60
Ser Pro Ser Leu Glu Asn Arg Val Thr Ile Arg Lys Asp Thr Ser Lys
65 70 75 80
Asn Gln Val Ala Leu Thr Met Thr Asn Met Asp Pro Leu Asp Thr Gly
85 90 95
Thr Tyr Tyr Cys Ala His Arg Gln His Ile Ser Ser Phe Pro Trp Phe
100 105 110
Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Thr Gly
115 120 125
Gly Ser Gly Gly Thr Gly Ser Gly Thr Gly Gly Ser Thr Ser Tyr Val
130 135 140
Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys Thr Ala Arg
145 150 155 160
Ile Asn Cys Gly Gly Asn Asn Ile Glu Tyr Arg Ser Val His Trp Tyr
165 170 175
Gln Gln Lys Ser Gly Gln Ala Pro Val Ala Val Ile Tyr Asp Asn Ser
180 185 190
Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Lys Ser Gly
195 200 205
Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly Asp Glu Ala
210 215 220
Asp Tyr Tyr Cys Gln Val Trp Asp Ile Ser Ser Asp Val Val Phe Gly
225 230 235 240
Gly Gly Thr Lys Leu Thr Val Leu Gly Ala Ala Ala
245 250
<210>314
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>314
Ser Leu Lys Gly Ala Cys Lys Leu Lys Leu Cys Gly Val Leu Gly
1 5 10 15
<210>315
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>315
Leu Lys Gly Ala Cys Lys Leu Lys Leu Cys Gly Val Leu Gly Leu
1 5 10 15
<210>316
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>316
Lys Gly Ala Cys Lys Leu Lys Leu Cys Gly Val Leu Gly Leu Arg
1 5 10 15
<210>317
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>317
Gly Ala Cys Lys Leu Lys Leu Cys Gly Val Leu Gly Leu Arg Leu
1 5 10 15
<210>318
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>318
Ala Cys Lys Leu Lys Leu Cys Gly Val Leu Gly Leu Arg Leu Met
1 5 10 15
<210>319
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>319
Cys Lys Leu Lys Leu Cys Gly Val Leu Gly Leu Arg Leu Met Asp
1 5 10 15
<210>320
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>320
Lys Leu Lys Leu Cys Gly Val Leu Gly Leu Arg Leu Met Asp Gly
1 5 10 15
<210>321
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>321
Leu Lys Leu Cys Gly Val Leu Gly Leu Arg Leu Met Asp Gly Thr
1 5 10 15
<210>322
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>322
Lys Leu Cys Gly Val Leu Gly Leu Arg Leu Met Asp Gly Thr Trp
1 5 10 15
<210>323
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>323
Gly Phe Gly Lys Ala Tyr Thr Ile Phe Asn Lys Thr Leu Met Glu
1 5 10 15
<210>324
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>324
Phe Gly Lys Ala Tyr Thr Ile Phe Asn Lys Thr Leu Met Glu Ala
1 5 10 15
<210>325
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>325
Gly Lys Ala Tyr Thr Ile Phe Asn Lys Thr Leu Met Glu Ala Asp
1 5 10 15
<210>326
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>326
Lys Ala Tyr Thr Ile Phe Asn Lys Thr Leu Met Glu Ala Asp Ala
1 5 10 15
<210>327
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>327
Ala Tyr Thr Ile Phe Asn Lys Thr Leu Met Glu Ala Asp Ala His
1 5 10 15
<210>328
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>328
Tyr Thr Ile Phe Asn Lys Thr Leu Met Glu Ala Asp Ala His Tyr
1 5 10 15
<210>329
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>329
Thr Ile Phe Asn Lys Thr Leu Met Glu Ala Asp Ala His Tyr Lys
1 5 10 15
<210>330
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>330
Ile Phe Asn Lys Thr Leu Met Glu Ala Asp Ala His Tyr Lys Ser
1 5 10 15
<210>331
<211>15
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>331
Phe Asn Lys Thr Leu Met Glu Ala Asp Ala His Tyr Lys Ser Val
1 5 10 15
<210>332
<211>23
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>332
Ser Leu Lys Gly Ala Cys Lys Leu Lys Leu Cys Gly Val Leu Gly Leu
1 5 10 15
Arg Leu Met Asp Gly Thr Trp
20
<210>333
<211>23
<212>PRT
<213>Artificial sequence
<220>
<223>Peptide
<400>333
Gly Phe Gly Lys Ala Tyr Thr Ile Phe Asn Lys Thr Leu Met Glu Ala
1 5 10 15
Asp Ala His Tyr Lys Ser Val
20
<210>334
<211>2083
<212>DNA
<213>Artificial sequence
<220>
<223>Heavy chain of CR04-098
<220>
<221>Intron
<222>(358)..(484)
<223>
<220>
<221>Intron
<222>(1663)..(1759)
<223>
<220>
<221>Intron
<222>(1215)..(1332)
<223>
<220>
<221>Intron
<222>(779)..(1169)
<223>
<400>334
caggtgcagc tggtggagtc tgggggaggc gcggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggctgtt atattatatg atggaagtga taaattctat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcagatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagtagca 300
gtggctggta cgcactttga ctactggggc cagggcaccc tggtgaccgt cagctcaggt 360
gagtgcggcc gcgagcccag acactggacg ctgaacctcg cggacagtta agaacccagg 420
ggcctctgcg ccctgggccc agctctgtcc cacaccgcgg tcacatggca ccacctctct 480
tgcagcctcc accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc 540
tgggggcaca gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt 600
gtcgtggaac tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc 660
ctcaggactc tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca 720
gacctacatc tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttgg 780
tgagaggcca gcacagggag ggagggtgtc tgctggaagc caggctcagc gctcctgcct 840
ggacgcatcc cggctatgca gtcccagtcc agggcagcaa ggcaggcccc gtctgcctct 900
tcacccggag gcctctgccc gccccactca tgctcaggga gagggtcttc tggctttttc 960
cccaggctct gggcaggcac aggctaggtg cccctaaccc aggccctgca cacaaagggg 1020
caggtgctgg gctcagacct gccaagagcc atatccggga ggaccctgcc cctgacctaa 1080
gcccacccca aaggccaaac tctccactcc ctcagctcgg acaccttctc tcctcccaga 1140
ttccagtaac tcccaatctt ctctctgcag agcccaaatc ttgtgacaaa actcacacat 1200
gcccaccgtg cccaggtaag ccagcccagg cctcgccctc cagctcaagg cgggacaggt 1260
gccctagagt agcctgcatc cagggacagg ccccagccgg gtgctgacac gtccacctcc 1320
atctcttcct cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 1380
cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 1440
agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 1500
gccaagacaa agccgcggga ggagcagtac aacagcacgt accgtgtggt cagcgtcctc 1560
accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 1620
gccctcccag cccccatcga gaaaaccatc tccaaagcca aaggtgggac ccgtggggtg 1680
cgagggccac atggacagag gccggctcgg cccaccctct gccctgagag tgaccgctgt 1740
accaacctct gtccctacag ggcagccccg agaaccacag gtgtacaccc tgcccccatc 1800
ccgggaggag atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc 1860
cagcgacatc gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac 1920
gcctcccgtg ctggactccg acggctcctt cttcctctat agcaagctca ccgtggacaa 1980
gagcaggtgg cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa 2040
ccactacacg cagaagagcc tctccctgtc tccgggtaaa tga 2083
<210>335
<211>449
<212>PRT
<213>Artificial sequence
<220>
<223>Heavy chain of CR04-098
<400>335
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ala Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Leu Tyr Asp Gly Ser Asp Lys Phe Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Ala Val Ala Gly Thr His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210>336
<211>847
<212>DNA
<213>Artificial sequence
<220>
<223>Light chain of CR04-098
<220>
<221>Intron
<222>(322)..(526)
<223>
<400>336
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaacag cttaatagtt accctcccac tttcggcgga 300
gggaccaagg tggagatcaa acgtaagtgc actttgcggc cgctaggaag aaactcaaaa 360
catcaagatt ttaaatacgc ttcttggtct ccttgctata attatctggg ataagcatgc 420
tgttttctgt ctgtccctaa catgccctgt gattatccgc aaacaacaca cccaagggca 480
gaactttgtt acttaaacac catcctgttt gcttctttcc tcaggaactg tggctgcacc 540
atctgtcttc atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt 600
gtgcctgctg aataacttct atcccagaga ggccaaagta cagtggaagg tggataacge 660
cctccaatcg ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta 720
cagcctcagc agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc 780
ctgcgaagtc acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga 840
gtgttag 847
<210>337
<211>213
<212>PRT
<213>Artificial sequence
<220>
<223>Light chain of CR04-098
<400>337
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
Claims (44)
1.一种具有狂犬病病毒中和活性的结合分子,其特征在于所述结合分子包含至少一个CDR3区域,该区域包含选自如下一组的氨基酸序列:SEQ ID NO:1、SEQ ID NO:2、,SEQ ID NO:3、,SEQ ID NO:4、,SEQ ID NO:5、,SEQ ID NO:6、,SEQ ID NO:7、,SEQ ID NO:8、,SEQ ID NO:9、,SEQ ID NO:10、,SEQ ID NO:11、,SEQ ID NO:12、,SEQ ID NO:13、,SEQ ID NO:14、,SEQ ID NO:15、,SEQ ID NO:16、,SEQ ID NO:17、,SEQ ID NO:18、,SEQ ID NO:19、,SEQ ID NO:20、,SEQ ID NO:21、,SEQ ID NO:22、,SEQ ID NO:23和SEQ IDNO:24。
2.权利要求1的结合分子,其特征在于所述该结合分子包含一种条可变重链,该可变重链包含选自如下一组的氨基酸序列:SEQ IDNO:26、,SEQ ID NO:27、,SEQ ID NO:28、,SEQ ID NO:29、,SEQID NO:30、,SEQ ID NO:31、,SEQ ID NO:32、,SEQ ID NO:33、,SEQ ID NO:34、,SEQ ID NO:35、,SEQ ID NO:36、,SEQ ID NO:37、,SEQ ID NO:38、,SEQ ID NO:39、,SEQ ID NO:40、,SEQ ID NO:41、,SEQ ID NO:42、,SEQ ID NO:43、,SEQ ID NO:44、,SEQ ID NO:45、,SEQ ID NO:46、,SEQ ID NO:47、,SEQ ID NO:48、,SEQ ID NO:49,及SEQ ID NO:335的第1-119位氨基酸。
3.权利要求1或2的结合分子的功能变体,其特征在于所述功能变体具有狂犬病病毒中和活性。
4.一种免疫缀合物,其包含权利要求1或2的结合分子或者权利要求3的功能变体的免疫缀合物,所述免疫缀合物进一步包含至少一种标记。
5.一种核酸分子,其编码权利要求1或2的结合分子或者权利要求3的功能变体的核酸分子。
6.一种载体,其包含权利要求5的至少一种核酸分子的载体。
7.一种宿主,其包含权利要求6的至少一种载体的宿主。
8.权利要求7的宿主,其中所述宿主是衍生自人体细胞的细胞。
9.一种产生权利要求1或2的结合分子或者权利要求3的功能变体的方法,其中所述方法包括如下步骤:
a)在有益于所述结合分子或者功能变体表达的条件下培养权利要求7或8的宿主,及任选地
b)回收表达的结合分子或者功能变体。
10.一种药物组合物,其包含权利要求1或2的结合分子的药物组合物,所述药物组合物进一步包含至少一种药物可接受的赋形剂。
11.权利要求10的药物组合物,其包含至少一种额外的结合分子,所述额外的结合分子包含至少一个种CDR3区域,该区域包含选自如下一组的氨基酸序列:SEQ ID NO:1、,SEQ ID NO:2、,SEQ IDNO:3、,SEQ ID NO:4,、SEQ ID NO:5,、SEQ ID NO:6,、SEQ ID NO:7,、SEQ ID NO:8,、SEQ ID NO:9,、SEQ ID NO:10,、SEQ ID NO:11,、SEQ ID NO:12,、SEQ ID NO:13,、SEQ ID NO:14,、SEQ ID NO:15,、SEQ ID NO:16,、SEQ ID NO:17,、SEQ ID NO:18,、SEQ ID NO:19,、SEQ ID NO:20,、SEQ ID NO:21,、SEQ ID NO:22,、SEQ ID NO:23,、SEQ ID NO:24和SEQ ID NO:25,其中所述结合分子能与狂犬病病毒的不同的非竞争表位反应。
12.权利要求11的药物组合物,其特征在于所述额外的结合分子包含一条种可变重链,该重链包含选自如下一组的氨基酸序列:SEQ ID NO:26,、SEQ ID NO:27,、SEQ ID NO:28,、SEQ ID NO:29,、SEQ ID NO:30,、SEQ ID NO:31,、SEQ ID NO:32,、SEQ ID NO:33,、SEQ ID NO:34,、SEQ ID NO:35,、SEQ ID NO:36,、SEQ ID NO:37,、SEQ ID NO:38,、SEQ ID NO:39,、SEQ ID NO:40,、SEQ ID NO:41,、SEQ ID NO:42,、SEQ ID NO:43,、SEQ ID NO:44,、SEQ ID NO:45,、SEQ ID NO:46,、SEQ ID NO:47,、SEQ ID NO:48,、SEQ ID NO:49,、SEQ ID NO:273,、及SEQ ID NO:335的第1-119位氨基酸。
13.一种包含至少两种中和狂犬病病毒的结合分子的药物组合物,其特征在于所述结合分子能与狂犬病病毒的不同的非竞争表位反应。
14.权利要求13的药物组合物,其特征在于第一种中和狂犬病病毒的结合分子能与位于狂犬病病毒G蛋白的抗原位点I的表位反应,第二种中和狂犬病病毒的结合分子能与位于狂犬病病毒G蛋白的抗原位点III的表位反应。
15.权利要求13的药物组合物,其特征在于第一种中和狂犬病病毒的结合分子包含至少一个种CDR3区域,该区域包含SEQ ID NO:25所示氨基酸序列,第二种中和狂犬病病毒的结合分子包含至少一个种CDR3区域,该区域包含选自SEQ ID NO:4、,SEQ ID NO:10,、SEQ ID NO:14,、SEQ ID NO:15,、SEQ ID NO:16和SEQ ID NO:22的氨基酸序列。
16.用作药物的权利要求1或2的结合分子、权利要求3的功能变体、权利要求4的免疫缀合物、或者权利要求10-15的药物组合物。
17.用于得自狂犬病毒属的疾病的诊断、预防、治疗或其组合的权利要求1或2的结合分子、权利要求3的功能变体、权利要求4的免疫缀合物或者权利要求10-15的药物组合物用于得自狂犬病毒的病变的诊断、预防、治疗或其组合。
18.权利要求1或2的结合分子、权利要求3的功能变体、权利要求4的免疫缀合物、或者权利要求10-15的药物组合物在制备用于诊断、预防、治疗或其组合用于得自狂犬病毒属的疾病变的药物中的应用。
19.一种试剂盒,其包含权利要求1或2的至少一种结合分子、权利要求3的至少一种功能变体、权利要求4的至少一种免疫缀合物、或者权利要求10-15的至少一种药物组合物或其组合。
20.一种鉴别特异性结合狂犬病病毒的结合分子或者编码特异性结合狂犬病病毒的结合分子的核酸分子的方法,其中所述方法包括如下步骤:
a)将可复制的遗传包装的表面上的结合分子集合与狂犬病病毒或其片段在有益于结合的条件下接触,
b)选择与狂犬病病毒或其片段结合的结合分子至少一次,和
c)分离并回收与狂犬病病毒或其片段结合的结合分子。
21.一种鉴别潜在性具有狂犬病病毒中和活性的结合分子或者编码潜在性具有狂犬病病毒中和活性的结合分子的核酸分子的方法,其中所述方法包括如下步骤:
a)将可复制的遗传包装的表面上的结合分子集合与狂犬病病毒或其片段在有益于结合的条件下接触,
b)从未结合的结合分子中分离和回收与狂犬病病毒或其片段结合的结合分子,
c)分离至少一种回收的结合分子,和
d)核实该分离的结合分子是否具有狂犬病病毒中和活性。
22.权利要求21的方法,其进一步包括分离并回收含有可变重链3-30种系基因的结合分子的步骤。
23.权利要求20-22任一项的方法,其中可复制遗传包装表面上的结合分子集合是从分离自细胞的RNA中制备的,所述细胞得自已经接种了狂犬病疫苗或者已经暴露于狂犬病病毒的对象的细胞的RNA中制备的。
24.权利要求20-23任一项的方法,其中可复制遗传包装表面上的结合分子集合是单链Fv文库。
25.权利要求23和24任一项的方法,其中所述对象是已经接种了狂犬病疫苗的人。
26.权利要求20-25任一项的方法,其特征在于所述可复制的遗传包装选自噬菌体颗粒、细菌、酵母、真菌、微生物孢子及核糖体。
27.可复制的遗传包装表面上的人结合分子集合,其特征在于所述集合是从分离自细胞的RNA中制备的,所述细胞得自已经接种了狂犬病疫苗或者已经暴露于狂犬病病毒的对象的细胞的RNA中制备的。
28.权利要求27的集合,其特征在于所述集合是单链Fv文库。
29.权利要求27或28的集合,其特征在于所述对象是已经接种可狂犬病疫苗的人。
30.一种鉴别潜在性具有对抗导致生物体发生疾病的感染因子潜在性具有因子的中和活性的结合分子或者编码潜在性具有对抗导致生物体发生疾病的感染因子潜在性具有因子的中和活性的结合分子的核酸分子的方法,其中所述方法包括如下步骤:
a)将可复制遗传包装表面上的结合分子集合与于至少一种细胞在有益于结合的条件下接触,所述细胞在其表面上表达导致生物体发生疾病的感染因子的蛋白质的细胞在有益于结合的条件下接触,
b)从不结合所述细胞的结合分子中分离和回收结合分子,该结合分子结合表达导致生物体发生疾病的感染因子的蛋白质的细胞的结合分子,
c)分离至少一种回收的结合分子,和
d)核实分离的结合分子是否具有对抗导致生物体发生疾病的感染因子的中和活性。
31.权利要求30的方法,其特征在于所述结合分子是人分子。
32.权利要求30或31的方法,其特征在于所述感染因子是病毒、细菌、酵母、真菌或者寄生物。
33.权利要求30-32任一项的方法,其特征在于所述蛋白质是通常在感染因子表面上表达的蛋白质。
34.权利要求30-33任一项的方法,其特征在于可复制遗传包装表面上的结合分子集合要减去在其表面上不表达导致生物体发生疾病的感染因子蛋白质的细胞。
35.具有狂犬病病毒中和活性的结合分子,其特征在于所述结合分子包含至少一个种重链CDR3区域,该区域包含SEQ ID NO:25所示氨基酸序列,所述结合分子具有至少2500IU/mg蛋白质的中和活性
36.权利要求35的结合分子,其特征在于所述结合分子包含一条种可变重链,该重链包含SEQ ID NO:273所示氨基酸序列。
37.权利要求35或36的结合分子,其特征在于所述结合分子包含一条种重链,该重链包含SEQ ID NO:123所示氨基酸序列。
38.一种核酸分子,其编码权利要求35-37任一项的结合分子的核酸分子。
39.权利要求38的核酸分子,其特征在于所述核酸分子包含SEQID NO:122所示核苷酸序列。
40.一种药物组合物,其包含至少两种结合分子的药物组合物,其特征在于所述结合分子具有差异小于1.5pI单位的等电点。
41.权利要求40的药物组合物,其特征在于所述结合分子是人单克隆抗体。
42.权利要求40或41的药物组合物,其特征在于两种结合分子均能中和感染因子。
43.权利要求40-42任一项的药物组合物,其特征在于两种结合分子均能中和狂犬病病毒。
44.权利要求1、2或者35-37的结合分子,其特征在于所述结合分子是人分子。
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102924571A (zh) * | 2012-10-29 | 2013-02-13 | 复旦大学 | 狂犬病毒糖蛋白与核蛋白的抗原表位多肽及其筛选、鉴定方法与应用 |
CN105814077A (zh) * | 2013-12-12 | 2016-07-27 | 赛特瑞恩股份有限公司 | 能够中和狂犬病毒的结合分子 |
CN105814077B (zh) * | 2013-12-12 | 2019-07-26 | 赛特瑞恩股份有限公司 | 能够中和狂犬病毒的结合分子 |
CN103954777A (zh) * | 2014-05-20 | 2014-07-30 | 北京凯思百奥科技发展有限公司 | 一种狂犬病病毒单克隆抗体及其应用 |
CN104761640A (zh) * | 2015-02-03 | 2015-07-08 | 中国食品药品检定研究院 | 具有中和活性的抗狂犬病病毒单克隆抗体的制备及应用 |
WO2020029860A1 (zh) * | 2018-08-09 | 2020-02-13 | 北京智仁美博生物科技有限公司 | 针对狂犬病病毒的双特异性抗体及其用途 |
US11773155B2 (en) | 2018-08-09 | 2023-10-03 | Beijing Wisdomab Biotechnology Co., Ltd | Bispecific antibody against rabies virus, and application thereof |
CN111171145A (zh) * | 2020-01-21 | 2020-05-19 | 兰州生物制品研究所有限责任公司 | 一种抗狂犬病病毒单克隆抗体、制备方法及用途 |
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