CN108135976A - 靶向il-23a和b细胞激活因子(baff)的化合物和其用途 - Google Patents
靶向il-23a和b细胞激活因子(baff)的化合物和其用途 Download PDFInfo
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Abstract
本公开涉及对IL23A和BAFF具有特异性的化合物、包含所述化合物的组合物、以及其使用方法。还公开了与所述化合物和组合物相关的核酸、细胞以及产生方法。
Description
相关申请
本申请依照美国法典第35篇第119条要求2015年7月23日提交的美国临时申请序列号62/196,170;2015年8月4日提交的美国临时申请序列号62/201,067;以及2016年6月27日提交的美国临时申请序列号62/355,302的申请日的权益,这些美国临时申请的名称都为COMPOUND TARGETING IL-23A AND B-CELL ACTIVATING FACTOR(BAFF)AND USES THEREOF,所有这些美国临时申请的全部内容以引用的方式并入本文。
背景
炎症涉及抵抗感染所需的先天免疫应答和适应性免疫应答。然而,当炎症变得不受控制时,自身免疫性或自身炎症性疾病、神经退行性疾病、甚至癌症都可能会产生。已知促炎性细胞因子,如IL1、BAFF、TNF-α、IL6、IL12、IL17、IL18、以及IL23参与炎症和激活免疫细胞的特定途径。然而,还不清楚抑制这些细胞因子中的一种或多种是否或如何可以引起对自身免疫性或自身炎症性疾病的治疗。
白细胞介素23(IL23)是由两个亚基p40和p19组成的异二聚细胞因子。p19亚基也被称为IL-23A。虽然p19亚基是IL23独有的,但是p40亚基是与细胞因子IL12共有的。IL23正成为驱动造成局部组织炎症和损伤的IL17、IL22以及其他细胞因子产生的致病性Th17、γδT以及先天淋巴样细胞(ILC)的关键调节因子。IL23促进基质金属蛋白酶MMP9上调,增加血管生成,减少CD8+T细胞浸润,并且已经牵涉到癌性肿瘤的产生。此外,联同IL6和TGFβ1一起,IL23刺激初始CD4+T细胞分化成Th17细胞。进而,Th17细胞产生IL17,IL17是一种促炎性细胞因子,它增强T细胞启动并且刺激促炎性细胞因子,如IL1、IL6、TNF-α、NOS-2的产生,并且还诱导趋化因子的表达,从而导致炎症和疾病发病。IL23经由细胞表面受体发挥它的作用,所述细胞表面受体由与独特的IL23R亚基形成配偶体的IL12受体的IL12β1亚基构成。IL23R的表达限于特定的免疫细胞群体并且主要存在于T细胞(αβ和γδTCR+)和NK细胞的子组上。
在小鼠中,遗传切除IL23p19基因引起IL23功能的选择性丧失,伴有严重受损的T依赖性免疫应答,包括抗原特异性免疫球蛋白的产生减少和迟发型超敏反应受损(Ghilardi N等人,(2004)J.Immunol.172(5):2827-33)。IL23p40或IL23p19、或者IL23受体的任一个亚基(IL23R和IL12β1)有缺陷的敲除小鼠在多发性硬化、关节炎以及炎症性肠病的动物模型中产生不太严重的症状。已经在EAE中使用对IL23p19具有特异性的抗体获得了相似的结果并且T细胞介导的结肠炎模型进一步证实了IL23在这些疾病情形中的作用(Chen Y.等人(2006)J.Clin.Invet.116(5):1317-26;Elson CO.等人(2007)Gastroenterology 132(7):2359-70)。这突出了IL23在慢性炎症中的重要性(Langowski等人(2006)Nature 442(7101):461-5;Kikly K等人,(2006)Curr.Opin.Immunol.18(6):670-5)。此外,IL23产生升高已经被认为是炎症性关节炎和炎症性自身免疫性疾病的主要因素(Adamopoulos等人(2011)J.Immunol.187:593-594;以及Langris等人(2005)J.Exp.Med.201:233-240)。IL23、它的下游细胞因子IL22、以及骨形成之间的联系已经在其中IL23过表达的小鼠模型系统中公开(Sherlock等人(2012)Nat.Med.18:1069-76)。
B细胞激活因子(BAFF)是属于肿瘤坏死因子(TNF)配体超家族的一种细胞因子并且用作受体BAFF-R(BR3)、TACI(跨膜激活因子和钙调节因子和亲环蛋白配体相互作用因子)以及BCMA(B细胞成熟抗原)的配体。BAFF与它的受体之间的相互作用触发对于B细胞的形成和维持来说必要的信号,这进而响应于外来物质的侵袭合成免疫球蛋白。在患者中适当水平的BAFF有助于维持正常的免疫力水平,而不足的水平可能会引起免疫缺陷并且过高的水平可能会引起异常高的抗体产生。当患者表现出自身免疫时,它产生针对它自己的身体的组织或器官的抗体。包括红斑狼疮和类风湿性关节炎在内的自身免疫性疾病由体内过高水平的BAFF所引起。因此,重要的是调节BAFF的产生以治疗患有这些疾病的患者。
BAFF可以三种形式存在:膜结合形式(mbBAFF)、可溶性三聚体BAFF形式(sBAFF)以及由60个BAFF单体组成的多聚体形式(BAFF 60mer)。各种形式的BAFF在正常和疾病生理学中的相对重要性没有被完全了解。如所述,BAFF与三种受体,即BAFFR(BR3)、TACI以及BCMA结合。增殖诱导配体(APRIL)是TNF受体配体家族的相关成员,它已经被证实以高亲和力与TACI和BCMA结合。与高亲和力APRIL:BCMA相互作用相反,BAFF:BCMA相互作用具有低亲和力(1μM-2μM)并且不被认为在体内起重要作用(Bossen和Schneider,2006)。
可溶性BAFF在患有系统性红斑狼疮(SLE)的个体中以及在发炎的靶器官,如肾中以高水平表达。可溶性BAFF用作B细胞稳态和存活的关键因子(Kalled等人,2005;Mackay等人,2003;Smith和Cancro,2003;Patke等人,2004)。BAFF依赖性B细胞的自身抗体形成引起肾小球IC沉积,最初是在肾小球基底膜(GBM)、肾小球系膜以及近端肾小管上皮细胞(PTEC)内的间质组织处。这些IC沉积会造成补体固定和中性粒细胞激活,从而导致局部肾损伤。受损的肾细胞(MC、PTEC、肾成纤维细胞、内皮细胞)产生的炎症介质(例如IL6、IL8、MCP-1)通过增加免疫细胞浸润(例如B细胞、T细胞、树突状细胞、中性粒细胞以及巨噬细胞)而促进了炎症循环。
抗BAFF单克隆抗体贝利单抗(belimumab)已经显示出减少自身抗体形成的能力并且已经为患有系统性红斑狼疮(SLE)的患者提供了显著的益处。然而,贝利单抗在SLE患者中的功效最多是中等的,并且有很大的改进空间(Furie等人,2011)。因此,仍需要对于治疗和预防自身免疫性或炎症性疾病具有提高的功效的新组合物。此外,对更有效的治疗的鉴定应当允许施用降低的剂量以及更低的与治疗相关的成本。
发明内容
本文提供了对BAFF和IL23A具有特异性的化合物、包含这样的化合物的组合物、以及其使用方法和制备方法。
本公开的方面涉及一种化合物,所述化合物包含第一多肽和第二多肽,其中:
(A)所述第一多肽包含:
(i)对第一靶蛋白具有特异性的第一免疫球蛋白的轻链可变结构域(VL1);
(ii)对第二靶蛋白具有特异性的第二免疫球蛋白的重链可变结构域(VH2);以及
(iii)铰链区、重链恒定区2(CH2)以及重链恒定区3(CH3);并且
(B)所述第二多肽包含:
(i)所述对所述第二靶蛋白具有特异性的第二免疫球蛋白的轻链可变结构域(VL2);
(ii)所述对所述第一靶蛋白具有特异性的第一免疫球蛋白的重链可变结构域(VH1);
其中:
a)所述VL1和所述VH1缔合以形成结合所述第一靶蛋白的结合位点;
b)所述VL2和所述VH2缔合以形成结合所述第二靶蛋白的结合位点;
c)所述重链恒定区2(CH2)包含位置252处的酪氨酸、位置254处的苏氨酸以及位置256处的谷氨酸,所述位置是根据如Kabat中的EU索引编号的;以及
d)所述第一靶蛋白是BAFF并且所述第二靶蛋白是IL-23A,或所述第一靶蛋白是IL-23A并且所述第二靶蛋白是BAFF,
并且其中:
(i)所述VL1包含SEQ ID NO:2,所述VH1包含SEQ ID NO:1,所述VL2包含SEQ IDNO:4并且所述VH2包含SEQ ID NO:3;或
(ii)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:2并且所述VH2包含SEQ ID NO:1;或
(iii)所述VL1包含SEQ ID NO:85,所述VH1包含SEQ ID NO:84,所述VL2包含SEQID NO:4并且所述VH2包含SEQ ID NO:4;或
(iv)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:85并且所述VH2包含SEQ ID NO:84;或
(v)所述VL1包含SEQ ID NO:87,所述VH1包含SEQ ID NO:86,所述VL2包含SEQ IDNO:4并且所述VH2包含SEQ ID NO:3;或
(vi)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:87并且所述VH2包含SEQ ID NO:86;或
(vii)所述VL1包含SEQ ID NO:89,所述VH1包含SEQ ID NO:88,所述VL2包含SEQID NO:4并且所述VH2包含SEQ ID NO:3;或
(viii)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:89并且所述VH2包含SEQ ID NO:88;或
(ix)所述VL1包含SEQ ID NO:91,所述VH1包含SEQ ID NO:90,所述VL2包含SEQ IDNO:4并且所述VH2包含SEQ ID NO:3;或
(x)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:91并且所述VH2包含SEQ ID NO:90。
在一些实施方案中,所述第一多肽还在所述VL1与所述VH2之间包含第一接头并且所述第二多肽还在所述VL2与所述VH1之间包含第二接头。在一些实施方案中,所述第一接头或所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。在一些实施方案中,所述第一接头和所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。在一些实施方案中,所述第一多肽还在所述VH2或所述V L1与所述铰链区之间包含第三接头,并且所述第二多肽还在所述V H1(在它的C末端处)或所述VL2(在它的C末端处)之后包含第四接头。在一些实施方案中,所述第一多肽的所述第三接头包含氨基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK(SEQ ID NO:82),并且所述第二多肽的所述第四接头包含氨基酸序列GGCGGGK VAACKEKVAALKEKVAALKEKVAALKE(SEQ ID NO:83)。在其他实施方案中,所述第一多肽的所述第三接头包含氨基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE(SEQ ID NO:83),并且所述第二多肽的所述第四接头包含氨基酸序列GGCGGGEVAACEKE VAALEKEVAALEKEVAALEK(SEQ ID NO:82)。在一些实施方案中,所述第一多肽的所述第三接头包含氨基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK(SEQ ID NO:82)或氨基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE(SEQ ID NO:83)。在其他实施方案中,所述第二多肽的所述第四接头包含氨基酸序列GG CGGGEVAACEKEVAALEKEVAALEKEVAALEK(SEQ ID NO:82)或氨基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE(SEQ ID NO:83)。在一些实施方案中,所述第三接头包含氨基酸序列VEPKSC(SEQ ID NO:72)或氨基酸序列FNRGEC(SEQ ID NO:71)。在一些实施方案中,所述第四接头包含氨基酸序列FNRGEC(SEQ ID NO:71)或氨基酸序列VEPKSC(SEQ ID NO:72)。在一些实施方案中,所述第三接头包含氨基酸序列VEPKSC(SEQID NO:72)并且所述第四接头包含氨基酸序列FNRGEC(SEQ ID NO:71)。
在一些实施方案中,所述第一多肽还在所述VH2或所述VL1(取决于构型)与所述铰链区之间包含重链恒定区1结构域(CH1),并且所述第二多肽还在所述VH1或所述VL2(取决于构型)的C末端处包含轻链恒定区结构域(CL),其中所述CL和所述CH1经由二硫键缔合在一起以形成C1结构域。在一些实施方案中,所述第一接头(在所述VL1与所述VH2之间)或所述第二接头(在所述VL2与所述VH1之间)包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。在一些实施方案中,所述第一接头和所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。在一些实施方案中,所述第一多肽还在所述VH2或所述VL1(取决于构型)与所述CH1之间包含第三接头,并且所述第二多肽还在所述VH1或所述VL2(取决于构型)与所述CL之间包含第四接头。在一些实施方案中,所述第三接头或所述第四接头包含氨基酸序列LGGGSG(SEQ IDNO:70)。在一些实施方案中,所述第三接头和所述第四接头包含氨基酸序列LGGGSG(SEQ IDNO:70)。在一些实施方案中,所述第三接头和/或所述第四接头包含任选的半胱氨酸残基。在一些实施方案中,所述第三接头和/或所述第四接头包含氨基酸序列GGCGGG(SEQ ID NO:135)或LGGCGGGS(SEQ ID NO:136)。
在一些实施方案中,所述重链恒定区2(CH2)包含位置234处的丙氨酸和位置235处的丙氨酸,所述位置是根据如Kabat中的用于常规抗体的EU索引编号的。
在一些实施方案中,所述铰链区、所述重链恒定区2(CH2)或所述重链恒定区3(CH3)的氨基酸序列源自于IgG1或源自于IgG4。在一些实施方案中,所述铰链区包含氨基酸序列EPKSCDKTHTCPPCP(SEQ ID NO:76)。SEQ ID NO:76的铰链区存在于例如SEQ ID NO:5多肽中。在其他实施方案中,所述铰链区包含氨基酸序列LEPKSSDKTHTCPPCP(SEQ ID NO:130)。SEQ ID NO:130的铰链区存在于例如SEQ ID NO:9多肽中。在另外的其他实施方案中,所述铰链区包含氨基酸序列ESKYGPPCPPCP(SEQ ID NO:134)。SEQ ID NO:134的铰链区存在于例如SEQ ID NO:13多肽中。
在一些实施方案中,所述化合物包含两个所述第一多肽和两个所述第二多肽,其中所述两个第一多肽经由至少一个二硫键缔合在一起。在一些实施方案中,所述化合物包含两个所述第一多肽和两个所述第二多肽,其中所述两个第一多肽经由至少一个二硫键缔合在一起并且其中所述第一多肽中的每一个经由至少一个二硫键与一个所述第二多肽缔合。
在一些实施方案中,
(i)所述第一多肽包含SEQ ID NO:5的氨基酸序列并且所述第二多肽包含SEQ IDNO:6的氨基酸序列;或
(ii)所述第一多肽包含SEQ ID NO:7的氨基酸序列并且所述第二多肽包含SEQ IDNO:8的氨基酸序列;或
(iii)所述第一多肽包含SEQ ID NO:9的氨基酸序列并且所述第二多肽包含SEQID NO:10的氨基酸序列;或
(iv)所述第一多肽包含SEQ ID NO:11的氨基酸序列并且所述第二多肽包含SEQID NO:12的氨基酸序列;或
(v)所述第一多肽包含SEQ ID NO:13的氨基酸序列并且所述第二多肽包含SEQ IDNO:14的氨基酸序列;或
(vi)所述第一多肽包含SEQ ID NO:15的氨基酸序列并且所述第二多肽包含SEQID NO:16的氨基酸序列;或
(vii)所述第一多肽包含SEQ ID NO:17的氨基酸序列并且所述第二多肽包含SEQID NO:18的氨基酸序列;或
(viii)所述第一多肽包含SEQ ID NO:19的氨基酸序列并且所述第二多肽包含SEQID NO:20的氨基酸序列;或
(ix)所述第一多肽包含SEQ ID NO:21的氨基酸序列并且所述第二多肽包含SEQID NO:22的氨基酸序列;或
(x)所述第一多肽包含SEQ ID NO:23的氨基酸序列并且所述第二多肽包含SEQ IDNO:24的氨基酸序列;或
(xi)所述第一多肽包含SEQ ID NO:25的氨基酸序列并且所述第二多肽包含SEQID NO:26的氨基酸序列;或
(xii)所述第一多肽包含SEQ ID NO:27的氨基酸序列并且所述第二多肽包含SEQID NO:28的氨基酸序列;或
(xiii)所述第一多肽包含SEQ ID NO:29的氨基酸序列并且所述第二多肽包含SEQID NO:30的氨基酸序列;或
(xiv)所述第一多肽包含SEQ ID NO:31的氨基酸序列并且所述第二多肽包含SEQID NO:32的氨基酸序列;或
(xv)所述第一多肽包含SEQ ID NO:33的氨基酸序列并且所述第二多肽包含SEQID NO:34的氨基酸序列;或
(xvi)所述第一多肽包含SEQ ID NO:35的氨基酸序列并且所述第二多肽包含SEQID NO:36的氨基酸序列;或
(xvii)所述第一多肽包含SEQ ID NO:37的氨基酸序列并且所述第二多肽包含SEQID NO:38的氨基酸序列;或
(xviii)所述第一多肽包含SEQ ID NO:39的氨基酸序列并且所述第二多肽包含SEQ ID NO:40的氨基酸序列;或
(xix)所述第一多肽包含SEQ ID NO:41的氨基酸序列并且所述第二多肽包含SEQID NO:42的氨基酸序列;或
(xx)所述第一多肽包含SEQ ID NO:43的氨基酸序列并且所述第二多肽包含SEQID NO:44的氨基酸序列;或
(xxi)所述第一多肽包含SEQ ID NO:45的氨基酸序列并且所述第二多肽包含SEQID NO:46的氨基酸序列;或
(xxii)所述第一多肽包含SEQ ID NO:47的氨基酸序列并且所述第二多肽包含SEQID NO:48的氨基酸序列;或
(xxiii)所述第一多肽包含SEQ ID NO:49的氨基酸序列并且所述第二多肽包含SEQ ID NO:50的氨基酸序列;或
(xxiv)所述第一多肽包含SEQ ID NO:51的氨基酸序列并且所述第二多肽包含SEQID NO:52的氨基酸序列;或
(xxv)所述第一多肽包含SEQ ID NO:53的氨基酸序列并且所述第二多肽包含SEQID NO:54的氨基酸序列;或
(xxvi)所述第一多肽包含SEQ ID NO:55的氨基酸序列并且所述第二多肽包含SEQID NO:56的氨基酸序列;或
(xxvii)所述第一多肽包含SEQ ID NO:57的氨基酸序列并且所述第二多肽包含SEQ ID NO:58的氨基酸序列;或
(xxviii)所述第一多肽包含SEQ ID NO:59的氨基酸序列并且所述第二多肽包含SEQ ID NO:60的氨基酸序列;或
(xxix)所述第一多肽包含SEQ ID NO:61的氨基酸序列并且所述第二多肽包含SEQID NO:62的氨基酸序列;或
(xxx)所述第一多肽包含SEQ ID NO:63的氨基酸序列并且所述第二多肽包含SEQID NO:64的氨基酸序列;或
(xxxi)所述第一多肽包含SEQ ID NO:65的氨基酸序列并且所述第二多肽包含SEQID NO:66的氨基酸序列;或
(xxxii)所述第一多肽包含SEQ ID NO:67的氨基酸序列并且所述第二多肽包含SEQ ID NO:68的氨基酸序列。
在一些实施方案中,其中所述化合物包含两个所述第一多肽和两个所述第二多肽,其中所述两个第一多肽经由至少一个二硫键缔合在一起。
在一些实施方案中,所述化合物包含两个所述第一多肽和两个所述第二多肽,并且其中所述第一多肽中的一个的铰链、CH2以及CH3与所述第一多肽中的另一个的铰链、CH2以及CH3缔合以形成四价分子。在一些实施方案中,所述化合物包含两个所述第一多肽和两个所述第二多肽,其中所述第一多肽中的每一个包含CH1、铰链、CH2以及CH3并且所述第二多肽中的每一个包含CL,并且其中所述第一多肽中的一个的铰链、CH2以及CH3与所述第一多肽中的另一个的铰链、CH2以及CH3缔合并且每一个所述第一多肽的CH1与一个所述第二多肽的CL缔合以形成四价分子(例如实施例部分中所述的单体、单体抗体)(例如化合物E和化合物V)。在一些实施方案中,所述化合物包含两个所述第一多肽和两个所述第二多肽,其中所述第一多肽中的每一个包含第三接头、铰链、CH2以及CH3,并且所述第二多肽中的每一个包含第四接头,并且其中所述第一多肽中的一个的铰链、CH2以及CH3与所述第一多肽中的另一个的铰链、CH2以及CH3缔合并且每一个所述第一多肽的第三接头与一个所述第二多肽的第四接头缔合以形成四价分子(例如实施例部分中所述的单体、单体抗体)(例如化合物U和化合物T)。
本公开的其他方面涉及与第二化合物竞争结合IL-23A和结合BAFF的第一化合物,其中所述第一化合物包含第三多肽和第四多肽,其中:
(A)所述第三多肽包含:
(i)对第一靶蛋白具有特异性的第一免疫球蛋白的轻链可变结构域(VL1);
(ii)对第二靶蛋白具有特异性的第二免疫球蛋白的重链可变结构域(VH2);以及
(iii)铰链区、重链恒定区2(CH2)以及重链恒定区3(CH3);并且
(B)所述第四多肽包含:
(i)所述对所述第二靶蛋白具有特异性的第二免疫球蛋白的轻链可变结构域(VL2);
(ii)所述对所述第一靶蛋白具有特异性的第一免疫球蛋白的重链可变结构域(VH1);
并且其中
(i)所述VL1和所述VH1缔合以形成结合所述第一靶蛋白的结合位点;
(ii)所述VL2和所述VH2缔合以形成结合所述第二靶蛋白的结合位点;以及
(iii)所述第一靶蛋白是BAFF并且所述第二靶蛋白是IL-23A,或所述第一靶蛋白是IL-23A并且所述第二靶蛋白是BAFF,
并且其中所述第二化合物包含第一多肽和第二多肽,其中:
(i)所述第一多肽包含SEQ ID NO:5的氨基酸序列并且所述第二多肽包含SEQ IDNO:6的氨基酸序列;或
(ii)所述第一多肽包含SEQ ID NO:7的氨基酸序列并且所述第二多肽包含SEQ IDNO:8的氨基酸序列;或
(iii)所述第一多肽包含SEQ ID NO:9的氨基酸序列并且所述第二多肽包含SEQID NO:10的氨基酸序列;或
(iv)所述第一多肽包含SEQ ID NO:11的氨基酸序列并且所述第二多肽包含SEQID NO:12的氨基酸序列;或
(v)所述第一多肽包含SEQ ID NO:13的氨基酸序列并且所述第二多肽包含SEQ IDNO:14的氨基酸序列;或
(vi)所述第一多肽包含SEQ ID NO:15的氨基酸序列并且所述第二多肽包含SEQID NO:16的氨基酸序列;或
(vii)所述第一多肽包含SEQ ID NO:17的氨基酸序列并且所述第二多肽包含SEQID NO:18的氨基酸序列;或
(viii)所述第一多肽包含SEQ ID NO:19的氨基酸序列并且所述第二多肽包含SEQID NO:20的氨基酸序列;或
(ix)所述第一多肽包含SEQ ID NO:21的氨基酸序列并且所述第二多肽包含SEQID NO:22的氨基酸序列;或
(x)所述第一多肽包含SEQ ID NO:23的氨基酸序列并且所述第二多肽包含SEQ IDNO:24的氨基酸序列;或
(xi)所述第一多肽包含SEQ ID NO:25的氨基酸序列并且所述第二多肽包含SEQID NO:26的氨基酸序列;或
(xii)所述第一多肽包含SEQ ID NO:27的氨基酸序列并且所述第二多肽包含SEQID NO:28的氨基酸序列;或
(xiii)所述第一多肽包含SEQ ID NO:29的氨基酸序列并且所述第二多肽包含SEQID NO:30的氨基酸序列;或
(xiv)所述第一多肽包含SEQ ID NO:31的氨基酸序列并且所述第二多肽包含SEQID NO:32的氨基酸序列;或
(xv)所述第一多肽包含SEQ ID NO:33的氨基酸序列并且所述第二多肽包含SEQID NO:34的氨基酸序列;或
(xvi)所述第一多肽包含SEQ ID NO:35的氨基酸序列并且所述第二多肽包含SEQID NO:36的氨基酸序列;或
(xvii)所述第一多肽包含SEQ ID NO:37的氨基酸序列并且所述第二多肽包含SEQID NO:38的氨基酸序列;或
(xviii)所述第一多肽包含SEQ ID NO:39的氨基酸序列并且所述第二多肽包含SEQ ID NO:40的氨基酸序列;或
(xix)所述第一多肽包含SEQ ID NO:41的氨基酸序列并且所述第二多肽包含SEQID NO:42的氨基酸序列;或
(xx)所述第一多肽包含SEQ ID NO:43的氨基酸序列并且所述第二多肽包含SEQID NO:44的氨基酸序列;或
(xxi)所述第一多肽包含SEQ ID NO:45的氨基酸序列并且所述第二多肽包含SEQID NO:46的氨基酸序列;或
(xxii)所述第一多肽包含SEQ ID NO:47的氨基酸序列并且所述第二多肽包含SEQID NO:48的氨基酸序列;或
(xxiii)所述第一多肽包含SEQ ID NO:49的氨基酸序列并且所述第二多肽包含SEQ ID NO:50的氨基酸序列;或
(xxiv)所述第一多肽包含SEQ ID NO:51的氨基酸序列并且所述第二多肽包含SEQID NO:52的氨基酸序列;或
(xxv)所述第一多肽包含SEQ ID NO:53的氨基酸序列并且所述第二多肽包含SEQID NO:54的氨基酸序列;或
(xxvi)所述第一多肽包含SEQ ID NO:55的氨基酸序列并且所述第二多肽包含SEQID NO:56的氨基酸序列;或
(xxvii)所述第一多肽包含SEQ ID NO:57的氨基酸序列并且所述第二多肽包含SEQ ID NO:58的氨基酸序列;或
(xxviii)所述第一多肽包含SEQ ID NO:59的氨基酸序列并且所述第二多肽包含SEQ ID NO:60的氨基酸序列;或
(xxix)所述第一多肽包含SEQ ID NO:61的氨基酸序列并且所述第二多肽包含SEQID NO:62的氨基酸序列;或
(xxx)所述第一多肽包含SEQ ID NO:63的氨基酸序列并且所述第二多肽包含SEQID NO:64的氨基酸序列;或
(xxxi)所述第一多肽包含SEQ ID NO:65的氨基酸序列并且所述第二多肽包含SEQID NO:66的氨基酸序列;或
(xxxii)所述第一多肽包含SEQ ID NO:67的氨基酸序列并且所述第二多肽包含SEQ ID NO:68的氨基酸序列。
本公开的其他方面涉及一种化合物,所述化合物包含两个第一多肽和两个第二多肽;
其中所述两个第一多肽经由至少一个二硫键缔合在一起并且其中所述第一多肽中的每一个经由至少一个二硫键与一个所述第二多肽缔合;
其中所述第一多肽中的每一个包含:
(i)对第一靶蛋白具有特异性的第一免疫球蛋白的轻链可变结构域(VL1);
(ii)对第二靶蛋白具有特异性的第二免疫球蛋白的重链可变结构域(VH2);
(iii)重链恒定区1(CH1)、铰链区、重链恒定区2(CH2)以及重链恒定区3(CH3);并且
其中所述第二多肽中的每一个包含:
(i)所述对所述第二靶蛋白具有特异性的第二免疫球蛋白的轻链可变结构域(VL2);
(ii)所述对所述第一靶蛋白具有特异性的第一免疫球蛋白的重链可变结构域(VH1);
(iii)轻链恒定区结构域(CL);
其中所述第一多肽中的一个的铰链、CH2以及CH3与所述第一多肽中的另一个的铰链、CH2以及CH3缔合并且每一个所述第一多肽的CH1与所述每一个第二多肽的CL缔合以形成四价分子;
其中
a)所述VL1和所述VH1缔合以形成结合所述第一靶蛋白的结合位点;
b)所述VL2和所述VH2缔合以形成结合所述第二靶蛋白的结合位点;
c)所述重链恒定区2(CH2)包含位置252处的酪氨酸、位置254处的苏氨酸以及位置256处的谷氨酸,所述位置是根据如Kabat中的EU索引编号的;以及
d)所述第一靶蛋白是BAFF并且所述第二靶蛋白是IL-23A,或所述第一靶蛋白是IL-23A并且所述第二靶蛋白是BAFF,
并且其中:
(i)所述VL1包含SEQ ID NO:2,所述VH1包含SEQ ID NO:1,所述VL2包含SEQ IDNO:4并且所述VH2包含SEQ ID NO:3;或
(ii)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:2并且所述VH2包含SEQ ID NO:1;或
(iii)所述VL1包含SEQ ID NO:85,所述VH1包含SEQ ID NO:84,所述VL2包含SEQID NO:4并且所述VH2包含SEQ ID NO:4;或
(iv)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:85并且所述VH2包含SEQ ID NO:84;或
(v)所述VL1包含SEQ ID NO:87,所述VH1包含SEQ ID NO:86,所述VL 2包含SEQ IDNO:4并且所述VH2包含SEQ ID NO:3;或
(vi)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:87并且所述VH2包含SEQ ID NO:86;或
(vii)所述VL1包含SEQ ID NO:89,所述VH1包含SEQ ID NO:88,所述VL2包含SEQID NO:4并且所述VH2包含SEQ ID NO:3;或
(viii)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:89并且所述VH2包含SEQ ID NO:88;或
(ix)所述VL1包含SEQ ID NO:91,所述VH1包含SEQ ID NO:90,所述VL2包含SEQ IDNO:4并且所述VH2包含SEQ ID NO:3;或
(x)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:91并且所述VH2包含SEQ ID NO:90。
在与上述方面有关的一些实施方案中,所述第一多肽中的每一个还在所述VL1与所述VH2之间包含第一接头,并且所述第二多肽中的每一个还在所述VL2与所述VH1之间包含第二接头。在一些实施方案中,所述第一接头或所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。在一些实施方案中,所述第一接头和所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。在一些实施方案中,所述第一多肽中的每一个还在所述VH2(或所述VL1)与所述CH1之间包含第三接头,并且所述第二多肽中的每一个还在所述VH1(或所述VL2)与所述CL之间包含第四接头。在一些实施方案中,所述第三接头或所述第四接头包含氨基酸序列LGGGSG(SEQ ID NO:70)。在一些实施方案中,所述第三接头和所述第四接头包含氨基酸序列LGGGSG(SEQ ID NO:70)。在一些实施方案中,所述第三接头和/或所述第四接头包含任选的半胱氨酸残基。在一些实施方案中,所述第三接头和/或所述第四接头包含氨基酸序列GGCGGG(SEQ ID NO:135)或LGGCGGGS(SEQ ID NO:136)。在一些实施方案中,所述重链恒定区2(CH2)包含位置234处的丙氨酸和位置235处的丙氨酸,所述位置是根据如Kabat中的EU索引编号的。在一些实施方案中,所述铰链区、所述重链恒定区2(CH2)或所述重链恒定区3(CH3)的氨基酸序列源自于IgG1或源自于IgG4。在一些实施方案中,所述铰链区包含氨基酸序列EPKSCDKTHTCPPCP(SEQ ID NO:76)、氨基酸序列LEPKSSDKTHTCPPCP(SEQID NO:130)或氨基酸序列ESKYGPPCPPCP(SEQ ID NO:134)。
在一些实施方案中,
(i)所述第一多肽中的每一个包含SEQ ID NO:5的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:6的氨基酸序列;或
(ii)所述第一多肽中的每一个包含SEQ ID NO:7的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:8的氨基酸序列;或
(iii)所述第一多肽中的每一个包含SEQ ID NO:13的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:14的氨基酸序列;或
(iv)所述第一多肽中的每一个包含SEQ ID NO:15的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:16的氨基酸序列;或
(v)所述第一多肽中的每一个包含SEQ ID NO:21的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:22的氨基酸序列;或
(vi)所述第一多肽中的每一个包含SEQ ID NO:25的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:26的氨基酸序列;或
(vii)所述第一多肽中的每一个包含SEQ ID NO:29的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:30的氨基酸序列;或
(viii)所述第一多肽中的每一个包含SEQ ID NO:33的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:34的氨基酸序列;或
(ix)所述第一多肽中的每一个包含SEQ ID NO:37的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:38的氨基酸序列;或
(x)所述第一多肽中的每一个包含SEQ ID NO:41的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:42的氨基酸序列;或
(xi)所述第一多肽中的每一个包含SEQ ID NO:45的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:46的氨基酸序列;或
(xii)所述第一多肽中的每一个包含SEQ ID NO:49的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:50的氨基酸序列;或
(xiii)所述第一多肽中的每一个包含SEQ ID NO:53的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:54的氨基酸序列;或
(xiv)所述第一多肽中的每一个包含SEQ ID NO:55的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:56的氨基酸序列;或
(xv)所述第一多肽中的每一个包含SEQ ID NO:57的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:58的氨基酸序列;或
(xvi)所述第一多肽中的每一个包含SEQ ID NO:59的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:60的氨基酸序列;或
(xvii)所述第一多肽中的每一个包含SEQ ID NO:61的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:62的氨基酸序列;或
(xviii)所述第一多肽中的每一个包含SEQ ID NO:63的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:64的氨基酸序列;或
(xix)所述第一多肽中的每一个包含SEQ ID NO:65的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:66的氨基酸序列;或
(xx)所述第一多肽中的每一个包含SEQ ID NO:67的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:68的氨基酸序列。
本公开的其他方面涉及一种化合物,所述化合物包含两个第一多肽和两个第二多肽;其中所述两个第一多肽经由至少一个二硫键缔合在一起并且其中所述第一多肽中的每一个经由至少一个二硫键与一个所述第二多肽缔合;并且其中(i)所述第一多肽中的每一个包含SEQ ID NO:5的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:6的氨基酸序列;或
(ii)所述第一多肽中的每一个包含SEQ ID NO:7的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:8的氨基酸序列;或
(iii)所述第一多肽中的每一个包含SEQ ID NO:13的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:14的氨基酸序列;或
(iv)所述第一多肽中的每一个包含SEQ ID NO:15的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:16的氨基酸序列;或
(v)所述第一多肽中的每一个包含SEQ ID NO:21的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:22的氨基酸序列;或
(vi)所述第一多肽中的每一个包含SEQ ID NO:25的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:26的氨基酸序列;或
(vii)所述第一多肽中的每一个包含SEQ ID NO:29的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:30的氨基酸序列;或
(viii)所述第一多肽中的每一个包含SEQ ID NO:33的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:34的氨基酸序列;或
(ix)所述第一多肽中的每一个包含SEQ ID NO:37的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:38的氨基酸序列;或
(x)所述第一多肽中的每一个包含SEQ ID NO:41的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:42的氨基酸序列;或
(xi)所述第一多肽中的每一个包含SEQ ID NO:45的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:46的氨基酸序列;或
(xii)所述第一多肽中的每一个包含SEQ ID NO:49的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:50的氨基酸序列;或
(xiii)所述第一多肽中的每一个包含SEQ ID NO:53的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:54的氨基酸序列;或
(xiv)所述第一多肽中的每一个包含SEQ ID NO:55的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:56的氨基酸序列;或
(xv)所述第一多肽中的每一个包含SEQ ID NO:57的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:58的氨基酸序列;或
(xvi)所述第一多肽中的每一个包含SEQ ID NO:59的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:60的氨基酸序列;或
(xvii)所述第一多肽中的每一个包含SEQ ID NO:61的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:62的氨基酸序列;或
(xviii)所述第一多肽中的每一个包含SEQ ID NO:63的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:64的氨基酸序列;或
(xix)所述第一多肽中的每一个包含SEQ ID NO:65的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:66的氨基酸序列;或
(xx)所述第一多肽中的每一个包含SEQ ID NO:67的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:68的氨基酸序列。
本公开的其他方面涉及一种化合物,所述化合物包含两个第一多肽和两个第二多肽;
其中所述两个第一多肽经由至少一个二硫键缔合在一起并且其中所述第一多肽中的每一个经由至少一个二硫键与一个所述第二多肽缔合;
其中所述第一多肽中的每一个包含:
(iv)对第一靶蛋白具有特异性的第一免疫球蛋白的轻链可变结构域(VL1);
(v)对第二靶蛋白具有特异性的第二免疫球蛋白的重链可变结构域(VH2);
(vi)铰链区、重链恒定区2(CH2)以及重链恒定区3(CH3);并且
其中所述第二多肽中的每一个包含:
(i)所述对所述第二靶蛋白具有特异性的第二免疫球蛋白的轻链可变结构域(VL2);以及
(ii)所述对所述第一靶蛋白具有特异性的第一免疫球蛋白的重链可变结构域(VH1);
其中所述第一多肽中的一个的铰链、CH2以及CH3与所述第一多肽中的另一个的铰链、CH2以及CH3缔合;并且
其中
e)所述VL1和所述VH1缔合以形成结合所述第一靶蛋白的结合位点;
f)所述VL2和所述VH2缔合以形成结合所述第二靶蛋白的结合位点;
g)所述重链恒定区2(CH2)包含位置252处的酪氨酸、位置254处的苏氨酸以及位置256处的谷氨酸,所述位置是根据如Kabat中的EU索引编号的;以及
h)所述第一靶蛋白是BAFF并且所述第二靶蛋白是IL-23A,或所述第一靶蛋白是IL-23A并且所述第二靶蛋白是BAFF,
并且其中:
(i)所述VL1包含SEQ ID NO:2,所述VH1包含SEQ ID NO:1,所述VL2包含SEQ IDNO:4并且所述VH2包含SEQ ID NO:3;或
(ii)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:2并且所述VH2包含SEQ ID NO:1;或
(iii)所述VL1包含SEQ ID NO:85,所述VH1包含SEQ ID NO:84,所述VL2包含SEQID NO:4并且所述VH2包含SEQ ID NO:4;或
(iv)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:85并且所述VH2包含SEQ ID NO:84;或
(v)所述VL1包含SEQ ID NO:87,所述VH1包含SEQ ID NO:86,所述VL2包含SEQ IDNO:4并且所述VH2包含SEQ ID NO:3;或
(vi)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:87并且所述VH2包含SEQ ID NO:86;或
(vii)所述VL1包含SEQ ID NO:89,所述VH1包含SEQ ID NO:88,所述VL2包含SEQID NO:4并且所述VH2包含SEQ ID NO:3;或
(viii)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:89并且所述VH2包含SEQ ID NO:88;或
(ix)所述VL1包含SEQ ID NO:91,所述VH1包含SEQ ID NO:90,所述VL2包含SEQ IDNO:4并且所述VH2包含SEQ ID NO:3;或
(x)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:91并且所述VH2包含SEQ ID NO:90。
在与上述方面有关的一些实施方案中,所述第一多肽中的每一个还在所述VL1与所述VH2之间包含第一接头,并且所述第二多肽中的每一个还在所述VL2与所述VH1之间包含第二接头。在一些实施方案中,所述第一接头或所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。在一些实施方案中,所述第一接头和所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。在一些实施方案中,所述第一多肽中的每一个还在所述VH2或所述VL1与所述铰链区之间包含第三接头,并且所述第二多肽中的每一个还在所述VH1或所述VL2的C末端处包含第四接头。在一些实施方案中,所述第一多肽的所述第三接头包含氨基酸序列GGCGGGEVAACEKEVAAL EKEVAALEKEVAALEK(SEQ ID NO:82),并且所述第二多肽的所述第四接头包含氨基酸序列GGCGGGKVAACKEKVAALKEKVAALKE KVAALKE(SEQ ID NO:83)。在其他实施方案中,所述第一多肽的所述第三接头包含氨基酸序列GGCGGGKVAACKEKVAALKEKVAAL KEKVAALKE(SEQ ID NO:83),并且所述第二多肽的所述第四接头包含氨基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALE K(SEQ ID NO:82)。在一些实施方案中,所述第一多肽的所述第三接头包含氨基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAAL EK(SEQ ID NO:82)或氨基酸序列GGCGGGKVAACKEKVAALKEK VAALKEKVAALKE(SEQ ID NO:83)。在其他实施方案中,所述第二多肽的所述第四接头包含氨基酸序列GGCGGGEVAACEKEVAALEK EVAALEKEVAALEK(SEQ ID NO:82)或氨基酸序列GGCGGGKVAA CKEKVAALKEKVAALKEKVAALKE(SEQ ID NO:83)。在一些实施方案中,所述第三接头包含氨基酸序列VEPKSC(SEQ ID NO:72)或氨基酸序列FNRGEC(SEQ IDNO:71)。在一些实施方案中,所述第四接头包含氨基酸序列FNRGEC(SEQ ID NO:71)或氨基酸序列VEP KSC(SEQ ID NO:72)。在一些实施方案中,所述第三接头包含氨基酸序列VEPKSC(SEQ ID NO:72)并且所述第四接头包含氨基酸序列FNRGEC(SEQ ID NO:71)。在一些实施方案中,所述重链恒定区2(C H2)包含位置234处的丙氨酸和位置235处的丙氨酸,所述位置是根据如Kabat中的EU索引编号的。在一些实施方案中,所述铰链区、所述重链恒定区2(CH2)或所述重链恒定区3(CH3)的氨基酸序列源自于IgG1或源自于IgG4。在一些实施方案中,所述铰链区包含氨基酸序列EPKSCDKTHTCPPCP(SEQ ID NO:76)、氨基酸序列LEPKSSDKTHTCPPCP(SEQ ID NO:130)或氨基酸序列ESKYGPPCPPCP(SEQ ID NO:134)。在一些实施方案中,(i)所述第一多肽中的每一个包含SEQ ID NO:9的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:10的氨基酸序列;或
(ii)所述第一多肽中的每一个包含SEQ ID NO:11的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:12的氨基酸序列;或
(iii)所述第一多肽中的每一个包含SEQ ID NO:17的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:18的氨基酸序列;或
(iv)所述第一多肽中的每一个包含SEQ ID NO:19的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:20的氨基酸序列;或
(v)所述第一多肽中的每一个包含SEQ ID NO:23的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:24的氨基酸序列;或
(vi)所述第一多肽中的每一个包含SEQ ID NO:27的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:28的氨基酸序列;或
(vii)所述第一多肽中的每一个包含SEQ ID NO:31的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:32的氨基酸序列;或
(viii)所述第一多肽中的每一个包含SEQ ID NO:35的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:36的氨基酸序列;或
(ix)所述第一多肽中的每一个包含SEQ ID NO:39的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:40的氨基酸序列;或
(x)所述第一多肽中的每一个包含SEQ ID NO:43的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:44的氨基酸序列;或
(xi)所述第一多肽中的每一个包含SEQ ID NO:47的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:48的氨基酸序列;或
(xii)所述第一多肽中的每一个包含SEQ ID NO:51的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:52的氨基酸序列。
本公开的另外的其他方面涉及一种药物组合物,所述药物组合物包含本文所述的化合物,如上文所述的化合物。
本公开的其他方面涉及一种治疗自身免疫性或炎症性疾病的方法,所述方法包括向受试者施用本文所述的化合物,如上文所述的化合物、或包含所述化合物的药物组合物。
本公开的另外的其他方面涉及用于药物的本文所述的化合物,如上文所述的化合物。在一些实施方案中,所述用途是治疗自身免疫性或炎症性疾病。
本公开的其他方面涉及一种用于药物的药物组合物,所述药物组合物包含本文所述的化合物,如上文所述的化合物。在一些实施方案中,所述用途是治疗自身免疫性或炎症性疾病。
本公开的另外的其他方面涉及一种核酸,所述核酸包含编码本文所述的多肽,如上文所述的多肽的核苷酸序列。本公开的其他方面涉及一种载体,所述载体包含所述核酸。在一些实施方案中,所述载体包含与所述核酸可操作地连接的启动子。本公开的其他方面涉及一种细胞,所述细胞包含所述核酸或所述载体。
本公开的其他方面涉及一种制备如本文所述的化合物或多肽,如上文所述的多肽的方法,所述方法包括获得本文所述的细胞,如上文所述的细胞;以及使如本文所述的核酸在所述细胞中表达。在一些实施方案中,所述方法还包括分离和纯化所述多肽或化合物。
本公开的一个或多个实施方案的细节阐述于以下说明中。本公开的其他特征或优势将从以下附图和几个实施方案的详细说明以及所附权利要求书中显而易见。
附图简述
以下附图形成本说明书的一部分并且被包括以进一步说明本公开的某些方面,这些方面可以通过参考这些附图中的一个或多个,结合本文所呈现的具体实施方案的详细说明来更好地理解。
图1A是对BAFF和IL23A具有特异性的示例性化合物的示意图。第一多肽链含有CH3结构域、CH2结构域、VH2(VHII)结构域以及VL1(VLI)结构域。第二多肽链含有VH1(VHI)结构域和VL2(VLII)结构域。VL1和VH1对第一靶蛋白(BAFF或IL23A)具有特异性并且VL2和VH2对第二靶蛋白(IL23A或BAFF)具有特异性。上图单独地示出了每一条多肽链。下图示出了四价化合物(例如实施例部分中所述的单体、单体抗体),所述四价化合物是经由一个第一多肽的CH2结构域和CH3结构域与另一个第一多肽的CH2结构域和CH3结构域缔合而形成的。第一靶蛋白和第二靶蛋白的结合结构域分别是经由VH1和VL1缔合以及经由VH2和VL2缔合而形成的。
图1B是对BAFF和IL23A具有特异性的另一种示例性化合物的示意图。第一多肽链含有CH3结构域、CH2结构域、CH1结构域、VH2(VHII)结构域以及VL1(VLI)结构域。第二多肽链含有CL结构域、VH1(VHI)结构域以及VL2(VLII)结构域。VL1和VH1对第一靶蛋白(BAFF或IL23A)具有特异性并且VL2和VH2对第二靶蛋白(IL23A或BAFF)具有特异性。上图单独地示出了每一条多肽链。下图示出了四价化合物(例如实施例部分中所述的单体、单体抗体),所述四价化合物是经由一个第一多肽的CH2结构域和CH3结构域与另一个第一多肽的CH2结构域和CH3结构域缔合而形成的。第一靶蛋白和第二靶蛋白的结合结构域分别是经由VH1和VL1缔合以及经由VH2和VL2缔合而形成的。所述化合物进一步经由CL结构域与CH1结构域之间的相互作用而缔合。
图2是示出了如实施例10中所述,在雄性食蟹猴中在单次1mg/kg静脉内剂量之后化合物A(实心正方形)、化合物B(空心正方形)、化合物C(实心三角形)以及化合物D(空心三角形)的血清浓度(平均值±SD)的图表。
图3示出了如实施例11中所述,在每两周一次施用100mg皮下剂量之后,化合物B的预测人血清浓度-时间曲线。虚线表示目标C最小(30nM)。
图4示出了如实施例14中所述,化合物B的单体百分比相对于浓度的图表总结。
图5示出了相比于抗BAFF,化合物B在体内维持功能效能。用等摩尔的抗BAFF或化合物B对小鼠进行给药并且用人BAFF微环攻击以诱导B细胞扩增。在第14天,收集脾脏并且通过流式细胞术分析小鼠B220+B细胞作为对BAFF的功能性阻断的量度。
图6示出了相比于抗IL23,化合物B在体内维持功能效能。在IL23诱导细胞因子测定中评价化合物B。用等摩尔的抗IL23或化合物B对小鼠进行给药并且用人IL23攻击两次以诱发耳部炎症。在最后的注射之后二十四小时,收集耳朵并且分析小鼠IL17A和小鼠IL22作为对IL23的功能性阻断的量度。
具体实施方式
本文描述了结合BAFF和IL-23A(也被称为IL23p19或IL23A)这两者的化合物。迄今为止,还没有获得批准的靶向BAFF和IL23A这两者的化合物。存在有限的研究使用生物治疗方法同时中和两种/更多种关键的炎症介质并且这些研究未能显示出对于类风湿性关节炎(RA)所测量的临床结果的改善。此外,这样的组合可能增加副作用,如感染风险(参见例如,Genovese,M.C.,Cohen,S.,Moreland,L.,Lium,D.,Robbins,S.等人,(2004).Arth.Rheum.50,1412-9;Genovese,M.C.,Cohen,S.,Moreland,L.,Lium,D.,Robbins,S.等人,(2004).Arth.Rheum.50,1412-9;以及Weinblatt,M.,Schiff,M.,Goldman,A.Kremer,J.,Luggen,M.等人,(2007).Ann.Rheum.Dis.66,228-34)。此外,这样的双特异性化合物已经由于与溶解度(例如聚集)和稳定性(例如不佳的药物代谢动力学)相关的问题而难以设计。
惊人的是,已经发现本文所述的结合BAFF和IL-23A的化合物中的一些与靶向IL-23A或BAFF的单独抗体相比具有相似的或改进的特性。还发现一些化合物具有合适的药物代谢动力学并且在合适的范围是可溶的以用于给药的目的。此外,在一些实施方案中,从单独治疗的副作用和更低剂量的观点来看,相对于多次单独剂量施用,单次施用存在优势。此外,在一些实施方案中,所述化合物的CMC特性显示一些化合物具有高熔融温度(Tm)和低的聚集。在一个方面,一种示例性化合物在高浓度下显示出特别低的聚集。本文所述的化合物被认为与标准抗体分子,例如IgG分子或抗原结合片段(例如Fab)相比,具有一种或多种有利的特性,例如副作用减少、施用的简易性和安全性增加、半衰期延长、结合亲和力增加、或抑制活性增加。
因此,本公开的方面涉及对BAFF和IL-23A这两者具有特异性的化合物以及这样的化合物的使用方法和制备方法。在一个方面,主题技术涉及具有提高的治疗和预防自身免疫性或炎症性疾病的功效的组合物,所述疾病如系统性红斑狼疮(SLE)、伴有肾脏牵涉/狼疮性肾炎(LN)的系统性红斑狼疮、ANCA相关血管炎(AAV)、原发性舍格伦综合征(primarySjogren's syndrome,pSS)、慢性移植物抗宿主病(cGVHD)、系统性硬化(SSc)、类风湿性关节炎(RA)、银屑病(Ps)、强直性脊柱炎(AS)、以及银屑病关节炎(PA)。BAFF/IL23A双重拮抗剂将抑制自身抗体/免疫复合物和IL23轴介导的终末器官损伤,并且与用于治疗SLE和LN的当前护理标准相比,可以实现更好的对临床反应的诱导和维持。与共同施用BAFF抗体和IL-23抗体以同时抑制这两个途径相比,BAFF/IL23A双重拮抗剂对于患者是更方便的,这可以使得依从性提高和疼痛减少。BAFF/IL23A双重拮抗剂应当允许施用降低的剂量以及更低的与治疗相关的成本。此外,BAFF/IL23A拮抗剂也可以有益于治疗涉及失调的B细胞/自身抗体和IL23介导的组织损伤的一群疾病,包括原发性舍格伦综合征(pSS)、慢性移植物抗宿主病(cGVHD)、系统性硬化(SSc)以及ANCA相关血管炎(AAV)。
很难设计将两种药理实体组合在一起并且维持每一种组分的功能效能,而同时具有适用于大规模制造的生物物理学特性的双重靶向治疗分子。双重靶向分子的开发已经受到与体外和体内稳定性相关的许多问题的阻碍,如低表达、聚集、有限的保存期、不佳的血清稳定性以及不佳的体内药物代谢动力学特性(Demarest SJ,Glaser SM.(2008).CurrOpin Drug Discov Devel.11,675-87)。
在此,我们公开了一种产生抑制BAFF和IL23这两者的功能的双重靶向分子的方法。主题技术的双重靶向分子具有有利的和惊人的特性,如高熔融温度(Tm)、在高浓度下低的聚集、以及允许每两周一次或不太频繁的皮下施用的预测人PK特性。
化合物
本公开的方面涉及一种对BAFF和IL23A这两者具有特异性的化合物。BAFF的示例性蛋白质序列和IL23A的示例性蛋白质序列示于下文中。
>sp|Q9Y275|B细胞激活因子(BAFF)-TN13B_人肿瘤坏死因子配体超家族成员13BOS=智人GN=TNFSF13B PE=1SV=1
MDDSTEREQSRLTSCLKKREEMKLKECVSILPRKESPSVRSSKDGKLLAATLLLALLSCCLTVVSFYQVAALQGDLASLRAELQGHHAEKLPAGAGAPKAGLEEAPAVTAGLKIFEPPAPGEGNSSQNSRNKRAVQGPEETVTQDCLQLIADSETPTIQKGSYTFVPWLLSFKRGSALEEKENKILVKETGYFFIYGQVLYTDKTYAMGHLIQRKKVHVFGDELSLVTLFRCIQNMPETLPNNSCYSAGIAKLEEGDELQLAIPRENAQISLDGDVTFFGALKLL(SEQ ID NO:80)
>NP_057668.1-IL23A[智人]
MLGSRAVMLLLLLPWTAQGRAVPGGSSPAWTQCQQLSQKLCTLAWSAHPLVGHMDLREEGDEETTNDVPHIQCGDGCDPQGLRDNSQFCLQRIHQGLIFYEKLLGSDIFTGEPSLLPDSPVGQLHASLLGLSQLLQPEGHHWETQQIPSLSPSQPWQRLLLRFKILRSLQAFVAVAARVFAHGAATLSP(氨基酸1-19是预测的信号序列)(SEQ ID NO:81)
在一些实施方案中,所述化合物包含第一多肽和第二多肽。在一些实施方案中,所述第一多肽包含(i)对第一靶蛋白具有特异性的第一免疫球蛋白的轻链可变结构域(VL1);(ii)对第二靶蛋白具有特异性的第二免疫球蛋白的重链可变结构域(VH2);以及(iii)铰链区、重链恒定区2(CH2)以及重链恒定区3(CH3)。在一些实施方案中,所述第一多肽还包含重链恒定区1(CH1)。在一些实施方案中,所述第二多肽包含:(i)对第二靶蛋白具有特异性的第二免疫球蛋白的轻链可变结构域(VL2);(ii)对第一靶蛋白具有特异性的第一免疫球蛋白的重链可变结构域(VH1)。在一些实施方案中,所述第二多肽还包含轻链恒定区(CL)。
应当了解的是,第一多肽的可变结构域/区和恒定结构域/区可以按照任何顺序,并且第二多肽的可变结构域/区和恒定结构域/区(如果有的话)可以按照任何顺序。从N末端到C末端,第一多肽和第二多肽上的结构域/区的多种示例性构型示于下文中。
第一多肽构型1:N-VL1-VH2-铰链-CH2-CH3-C
第一多肽构型2:N-VH2-VL1-铰链-CH2-CH3-C
第一多肽构型3:N-VL1-VH2-CH1-铰链-CH2-CH3-C
第一多肽构型4:N-VH2-VL1-CH1-铰链-CH2-CH3-C
第二多肽构型1:N-VL2-VH1-C
第二多肽构型2:N-VH1-VL2-C
第二多肽构型3:N-VL2-VH1-CL-C
第二多肽构型4:N-VH1-VL2-CL-C
所述化合物的示例性构型示于图1A和图1B中。
在一些实施方案中,第一多肽和第二多肽的可变区彼此缔合以形成第一靶蛋白的结合位点和第二靶蛋白的结合位点。在一些实施方案中,第一多肽的VL1和第二多肽的VH1缔合以形成结合第一靶蛋白的结合位点,并且第二多肽的VL2和第一多肽的VH2缔合以形成结合第二靶蛋白的结合位点。在一些实施方案中,所述第一靶蛋白是BAFF并且所述第二靶蛋白是IL23A。在其他实施方案中,所述第一靶蛋白是IL23A并且所述第二靶蛋白是BAFF。应当了解的是,术语“第一”和“第二”并不意图暗示任一种靶蛋白的重要性水平。
VL1、VH1、VL2、以及VH2中的每一个的序列的示例性组合提供于下表1中并且还提供于实施例1中的表2中。
表1:VL1、VH1、VL2、以及VH2的序列的示例性组合。
在一些实施方案中,所述化合物包含VL1序列,所述VL1序列包含第一轻链CDR1、CDR2、以及CDR3;以及VH1序列,所述VH1序列包含第一重链CDR1、CDR2、以及CDR3;VL2序列,所述VL2序列包含第二轻链CDR1、CDR2以及CDR3;以及VH2序列,所述VH2序列包含第二重链CDR1、CDR2、以及CDR3。在一些实施方案中,所述CDR是表1中所提供的一个或多个VL1序列、VH1序列、VL2序列、以及VH2序列的CDR。表1中所提供的VL1序列、VH1序列、VL2序列、以及VH2序列的示例性轻链CDR序列和重链CDR序列示于下文中:
SEQ ID NO:1 CDR:GGTFNNNAIN(SEQ ID NO:92)(CDR1)、GIIPMFGTAKYSQNFQG(SEQID NO:93)(CDR2)、SRDLLLFPHHALSP(SEQ ID NO:94)(CDR3)
SEQ ID NO:2 CDR:QGDSLRSYYAS(SEQ ID NO:95)(CDR1)、GKNNRPS(SEQ ID NO:96)(CDR2)、SSRDSSGNHWV(SEQ ID NO:97)(CDR3)
SEQ ID NO:3 CDR:GYTFTDQTIH(SEQ ID NO:98)(CDR1)、YIYPRDDSPKYNENFKG(SEQID NO:99)(CDR2)、PDRSGYAWFIY(SEQ ID NO:100)(CDR3)
SEQ ID NO:4 CDR:KASRDVAIAVA(SEQ ID NO:101)(CDR1)、WASTRHT(SEQ ID NO:102)(CDR2)、HQYSSYPFT(SEQ ID NO:103)(CDR3)
SEQ ID NO:84 CDR:DHIFSIHWMQ(SEQ ID NO:104)(CDR1)、EIFPGSGTTDYNEKFKG(SEQ ID NO:105)(CDR2)、GAFDY(SEQ ID NO:106)(CDR3)
SEQ ID NO:85 CDR:RASQDIGNRLS(SEQ ID NO:107)(CDR1)、ATSSLDS(SEQ ID NO:108)(CDR2)、LQYASSPFT(SEQ ID NO:109)(CDR3)
SEQ ID NO:86 CDR:DHIFSIHWMQ(SEQ ID NO:110)(CDR1)、EIFPGSGTTDYNEKFKG(SEQ ID NO:111)(CDR2)、GAFDY(SEQ ID NO:112)(CDR3)
SEQ ID NO:87 CDR:RASQDIGNRLN(SEQ ID NO:112)(CDR1)、ATSSLDS(SEQ ID NO:113)(CDR2)、LQYASSPFT(SEQ ID NO:114)(CDR3)
SEQ ID NO:88 CDR:GYSFSTFFIH(SEQ ID NO:115)(CDR1)、RIDPNSGATKYNEKFES(SEQ ID NO:116)(CDR2)、GEDLLIRTDALDY(SEQ ID NO:117)(CDR3)
SEQ ID NO:89 CDR:KASQNAGIDVA(SEQ ID NO:118)(CDR1)、SKSNRYT(SEQ ID NO:119)(CDR2)、LQYRSYPRT(SEQ ID NO:120)(CDR3)
SEQ ID NO:90 CDR:GYSFSTFFIH(SEQ ID NO:121)(CDR1)、GRIDPNSGATKYNEKFES(SEQ ID NO:122)(CDR2)、GEDLLIRTDALDY(SEQ ID NO:123)(CDR3)
SEQ ID NO:91 CDR:KASQNAGIDVA(SEQ ID NO:124)(CDR1)、SKSNRYT(SEQ ID NO:125)(CDR2)、LQYRSYPRT(SEQ ID NO:126)(CDR3)
在一些实施方案中,所述化合物包含VH1、VL1、VH2、和/或VL2,所述VH1、VL1、VH2、和/或VL2包含与表1中所述的序列具有至少80%(例如85%、90%、95%、96%、97%、98%、或99%)同一性(残基数/整个序列长度的残基数)的序列。两个氨基酸序列的“同一性百分比”是使用Karlin和Altschul Proc.Natl.Acad.Sci.USA87:2264-68,1990的算法来确定,所述算法如Karlin和Altschul Proc.Natl.Acad.Sci.USA 90:5873-77,1993中所修改。这样的算法被并入Altschul等人,J.Mol.Biol.215:403-10,1990的NBLAST程序和XBLAST程序(2.0版)中。可以使用XBLAST程序(分数=50,字长=3)来进行BLAST蛋白质搜索以获得与所关注的蛋白质分子同源的氨基酸序列。在两个序列之间存在空位的情况下,可以利用空位BLAST,如Altschul等人,Nucleic Acids Res.25(17):3389-3402,1997中所述的那样。当利用BLAST程序和空位BLAST程序时,可以使用相应程序(例如XBLAST和NBLAST)的默认参数。
在一些实施方案中,所述化合物包含VH1、VL1、VH2、和/或VL2,所述VH1、VL1、VH2、和/或VL2包含在表1中所述的序列中包含一个或多个(例如1个、2个、3个、4个、5个、6个、7个、8个、9个、10个或更多个)突变的序列。这样的突变可以是保守氨基酸取代。如本文所用的“保守氨基酸取代”指的是不改变其中进行氨基酸取代的蛋白质的相对电荷或尺寸特征的氨基酸取代。氨基酸的保守取代包括例如在下组内的氨基酸之间进行的取代:(a)M、I、L、V;(b)F、Y、W;(c)K、R、H;(d)A、G;(e)S、T;(f)Q、N;以及(g)E、D。
所述化合物的铰链区、CH2以及CH3(以及任选的CH1和CL,如果所述化合物含有这些区域的话)的氨基酸序列可以源自于任何适当的来源,例如诸如IgG1、IgG2、IgG3、或IgG4的抗体的恒定区。抗体重链恒定区和轻链恒定区的氨基酸序列是本领域公知的,例如IMGT数据库(www.imgt.org)或www.vbase2.org/vbstat.php.中所提供的那些,这两者以引用的方式并入本文。此外,在一些表达系统中,CH3结构域的C末端赖氨酸残基可以在翻译后被去除。因此,CH3结构域的C末端赖氨酸残基是任选的氨基酸残基。本发明具体提供了缺少CH3结构域的C末端赖氨酸残基的分子。本发明还具体涵盖了包含CH3结构域的C末端赖氨酸残基的这样的构建体。在一些实施方案中,CH2和CH3的氨基酸序列源自于IgG1(例如SEQ IDNO:75)或IgG4(例如SEQ ID NO:73)。在一些实施方案中,CL包含κCL或λCL的氨基酸序列。在一些实施方案中,铰链区包含氨基酸序列EPKSCDKTHTCPPCP(SEQ ID NO:76)。SEQ ID NO:76的铰链区存在于例如SEQ ID NO:5多肽中。在其他实施方案中,所述铰链区包含氨基酸序列LEPKSSDKTHTCPPCP(SEQ ID NO:130)。SEQ ID NO:130的铰链区存在于例如SEQ ID NO:9多肽中。SEQ ID NO:130的铰链区还存在于SEQ ID NO:129的Fc结构域的起始处。在另外的其他实施方案中,所述铰链区包含氨基酸序列ESKYGPPCPPCP(SEQ ID NO:134)。SEQ ID NO:134的铰链区存在于例如SEQ ID NO:13多肽中。SEQ ID NO:134的铰链区还存在于SEQ IDNO:127的Fc结构域的起始处。
在一些实施方案中,所述化合物的CH2和/或CH3(以及任选的CH1和CL,如果所述化合物含有这些区域的话)可以包含不同于野生型CH2或CH3的一个或多个氨基酸取代,例如野生型IgG1CH2或CH3中的一个或多个氨基酸取代或野生型IgG4CH2或CH3中的一个或多个氨基酸取代(SEQ ID NO:39提供了示例性野生型IgG1)。这样的取代是本领域已知的(参见例如US7704497、US7083784、US6821505、US 8323962、US6737056、以及US7416727)。
在一些实施方案中,CH2在234、235、252、254、和/或256处包含氨基酸取代,所述位置是根据如Kabat中的用于常规抗体的EU索引编号的(Kabat等人,Sequences of Proteinsof Immunological Interest,U.S.Department of Health and Human Services,1991,其以引用的方式整体并入本文)。应当了解的是,本文所述的所有氨基酸位置均指的是如Kabat中的用于常规抗体的EU索引的编号。在一些实施方案中,CH2在位置252、254、和/或256处包含氨基酸取代。在一些实施方案中,位置252处的氨基酸是酪氨酸、苯丙氨酸、丝氨酸、色氨酸、或苏氨酸。在一些实施方案中,位置254处的氨基酸是苏氨酸。在一些实施方案中,位置254处的氨基酸是丝氨酸、精氨酸、谷氨酰胺、谷氨酸、或天冬氨酸。在一些实施方案中,CH2包含位置252处的酪氨酸、位置254处的苏氨酸以及位置256处的谷氨酸(在本文被称作YTE突变体)。在一些实施方案中,CH2在位置234和/或位置235处包含氨基酸取代。在一些实施方案中,CH2包含位置234处的丙氨酸和位置235处的丙氨酸,在本文也被称作KO突变体。在一些实施方案中,CH2包含位置252处的酪氨酸、位置254处的苏氨酸、位置256处的谷氨酸、位置234处的丙氨酸以及位置235处的丙氨酸,在本文也被称作KO-YTE突变体。
在一些实施方案中,可以使用一个或多个接头将第一多肽和/或第二多肽上的结构域/区连接在一起。举例来说,第一多肽可以在VL1与VH2之间包含接头。第一多肽还在VL1或VH2(这取决于如上文所述的构型)与铰链之间包含接头(例如-VL1-接头-铰链或-VH2-接头-铰链)。如果第一多肽包含CH1,那么例如第一多肽可以在VL1或VH2(这取决于如上文所述的构型)与CH1之间包含接头(例如-VL1-接头-CH1或-VH2-接头-CH1)。在另一个实例中,第二多肽可以在VL2与VH1之间包含接头。第二多肽还可以在VL2或VH1(这取决于上述构型,例如-VL2-接头或-VH1-接头)之后在多肽链的C末端处包含接头。如果第二多肽还包含CL,那么第二多肽还可以在VL2或VH1(这取决于如上文所述的构型)与CL之间包含接头(如例如-VL2-接头-CL或-VH1-接头-CL中)。应当了解的是,可以在第一多肽上使用任何数目的接头来使任何结构域或区与任何其他另外的结构域或区连接和/或可以在第二多肽上使用任何数目的接头来使任何结构域或区与任何其他另外的结构域或区连接。
本领域已知的任何合适的接头被考虑用于本文。在一些实施方案中,所述接头是肽接头。在一些实施方案中,所述肽接头包含至少两个氨基酸,例如2个、3个、4个、5个、6个、7个、8个、9个、10个或更多个氨基酸。在一些实施方案中,所述肽接头的长度不多于50个、40个、30个、25个、20个、19个、18个、17个、16个、15个、14个、13个、12个、11个、10个、9个、8个、7个、6个、5个、4个、3个、或2个氨基酸。在一些实施方案中,所述肽接头的长度为2个至50个、2个至40个、2个至30个、2个至20个、2个至10个、2个至9个、2个至8个、2个至7个、或2个至6个氨基酸。在一些实施方案中,所述肽接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)、LGGGSG(SEQ ID NO:70)、FNRGEC(SEQ ID NO:71)、VEPKSC(SEQ ID NO:72)、GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK(SEQ ID NO:82)、GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE(SEQ ID NO:83)或其组合。在一些实施方案中,所述肽接头可以包含接头序列的多个拷贝,例如以下序列的多个拷贝:GGGSGGGG(SEQ ID NO:69)、LGGGSG(SEQ ID NO:70)、FNRGEC(SEQ ID NO:71)、VEPKSC(SEQ ID NO:72)、或其组合。
在一些实施方案中,第一多肽和第二多肽具有以下构型:
第一多肽构型1:N-VL1-VH2-铰链-CH2-CH3-C;
第一多肽构型2:N-VH2-VL1-铰链-CH2-CH3-C;
第二多肽构型1:N-VL2-VH1-C;
第二多肽构型2:N-VH1-VL2-C;
其中第一多肽的VL1与VH2之间的第一接头或第二多肽的VL2与VH1之间的第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。在一些实施方案中,所述第一接头和所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。在一些实施方案中,第一多肽还在所述VH2或所述VL2与所述铰链区之间包含第三接头,并且第二多肽还在所述VH1或所述VL2(在它的C末端处)之后包含第四接头。在一些实施方案中,所述第一多肽的所述第三接头包含氨基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK(SEQ ID NO:82),并且所述第二多肽的所述第四接头包含氨基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE(SEQ ID NO:83)。在其他实施方案中,所述第一多肽的所述第三接头包含氨基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE(SEQ ID NO:83),并且所述第二多肽的所述第四接头包含氨基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK(SEQ ID NO:82)。在一些实施方案中,所述第一多肽的所述第三接头包含氨基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK(SEQ ID NO:82)或氨基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE(SEQ ID NO:83)。在其他实施方案中,所述第二多肽的所述第四接头包含氨基酸序列GGCGGGEVAACEKEVAALEKEVAALEKEVAALEK(SEQ ID NO:82)或氨基酸序列GGCGGGKVAACKEKVAALKEKVAALKEKVAALKE(SEQ ID NO:83)。在一些实施方案中,所述第三接头包含氨基酸序列VEPKSC(SEQ ID NO:72)或氨基酸序列FNRGEC(SEQ IDNO:71)。在一些实施方案中,所述第四接头包含氨基酸序列FNRGEC(SEQ ID NO:71)或氨基酸序列VEPKSC(SEQ ID NO:72)。在一些实施方案中,所述第三接头包含氨基酸序列VEPKSC(SEQ ID NO:72)并且所述第四接头包含氨基酸序列FNRGEC(SEQ ID NO:71)。氨基酸序列FNRGEC(SEQ ID NO:71)是CL结构域(SEQ ID NO:77)的最后六个氨基酸残基并且氨基酸VEPKSC(SEQ ID NO:72)包括CH1的最后一个氨基酸和SEQ ID NO:76的铰链区的前五个氨基酸残基(如在SEQ ID NO:5中)。
在一些实施方案中,第一多肽和第二多肽具有以下构型:
第一多肽构型3:N-VL1-VH2-CH1-铰链-CH2-CH3-C;
第一多肽构型4:N-VH2-VL1-CH1-铰链-CH2-CH3-C;
第二多肽构型3:N-VL2-VH1-CL-C;
第二多肽构型4:N-VH1-VL2-CL-C;
其中第一多肽的所述VL1与所述VH2之间的第一接头或第二多肽的所述VL2与所述VH1之间的所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。在一些实施方案中,所述第一接头和所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。在一些实施方案中,所述第一多肽还在所述VH2或VL1与所述CH1之间包含第三接头并且所述第二多肽还在所述VH1或所述VL2与所述CL之间包含第四接头。在一些实施方案中,所述第三接头或所述第四接头包含氨基酸序列LGGGSG(SEQ ID NO:70)。在一些实施方案中,所述第三接头和所述第四接头包含氨基酸序列LGGGSG(SEQ ID NO:70)。在一些实施方案中,所述第三接头和/或所述第四接头包含任选的半胱氨酸残基。在一些实施方案中,所述第三接头和/或所述第四接头包含氨基酸序列GGCGGG(SEQ ID NO:135)或LGGCGGGS(SEQ ID NO:136)。
在一些实施方案中,所述重链恒定区2(CH2)包含位置234处的丙氨酸和位置235处的丙氨酸,所述位置是根据如Kabat中的用于常规抗体的EU索引编号的。
在一些实施方案中,所述化合物包含两个第一多肽和两个第二多肽。在一些实施方案中,所述第一多肽中的一个的铰链、CH2以及CH3与所述第一多肽中的另一个的铰链、CH2以及CH3缔合以形成四价分子(例如,两个第一多肽经由它们相应的铰链结构域CH2结构域以及CH3结构域之间的缔合二聚化以形成包含对第一靶蛋白具有特异性的两个结合位点和对第二靶蛋白具有特异性的两个结合位点的四价分子)、如实施例部分中所述的单体或单体抗体。如果第一多肽还包含CH1结构域,并且第二多肽还包含CL结构域,那么所述CH1结构域和CL结构域也可以参与四价分子(例如,两个第一多肽经由它们相应的铰链结构域、CH2结构域以及CH3结构域之间的缔合二聚化并且每一个所述第一多肽的CH1与一个所述第二多肽的CL缔合以形成包含第一靶蛋白的两个结合位点和第二靶蛋白的两个结合位点的四价分子)如实施例部分中所述的单体、单体抗体的形成。在一些实施方案中,两个第一多肽经由至少一个二硫键缔合在一起。在一些实施方案中,所述化合物包含两个所述第一多肽和两个所述第二多肽,其中所述第一多肽中的每一个包含第三接头、铰链、CH2以及CH3,并且所述第二多肽中的每一个包含第四接头,并且其中所述第一多肽中的一个的铰链、CH2以及CH3与所述第一多肽中的另一个的铰链、CH2以及CH3缔合并且每一个所述第一多肽的第三接头与一个所述第二多肽的第四接头缔合以形成四价分子(例如实施例部分中所述的单体、单体抗体)(例如化合物U和化合物T)。
在一些实施方案中,本公开涉及一种化合物,所述化合物包含两个第一多肽和两个第二多肽;
其中所述两个第一多肽经由至少一个二硫键缔合在一起并且其中所述第一多肽中的每一个经由至少一个二硫键与一个所述第二多肽缔合;
其中所述第一多肽中的每一个包含:
(i)对第一靶蛋白具有特异性的第一免疫球蛋白的轻链可变结构域(VL1);
(ii)对第二靶蛋白具有特异性的第二免疫球蛋白的重链可变结构域(VH2);
(iii)重链恒定区1(CH1)、铰链区、重链恒定区2(CH2)以及重链恒定区3(CH3);并且
其中所述第二多肽中的每一个包含:
(i)所述对所述第二靶蛋白具有特异性的第二免疫球蛋白的轻链可变结构域(VL2);
(ii)所述对所述第一靶蛋白具有特异性的第一免疫球蛋白的重链可变结构域(VH1);
(iii)轻链恒定区结构域(CL);
其中所述第一多肽中的一个的铰链、CH2以及CH3与所述第一多肽中的另一个的铰链、CH2以及CH3缔合并且每一个所述第一多肽的CH1与所述每一个第二多肽的CL缔合以形成四价分子;
其中
a)所述VL1和所述VH1缔合以形成结合所述第一靶蛋白的结合位点;
b)所述VL2和所述VH2缔合以形成结合所述第二靶蛋白的结合位点;
c)所述重链恒定区2(CH2)包含位置252处的酪氨酸、位置254处的苏氨酸以及位置256处的谷氨酸,所述位置是根据如Kabat中的EU索引编号的;以及
d)所述第一靶蛋白是BAFF并且所述第二靶蛋白是IL-23A,或所述第一靶蛋白是IL-23A并且所述第二靶蛋白是BAFF,
并且其中:
(i)所述VL1包含SEQ ID NO:2,所述VH1包含SEQ ID NO:1,所述VL2包含SEQ IDNO:4并且所述VH2包含SEQ ID NO:3;或
(ii)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:2并且所述VH2包含SEQ ID NO:1;或
(iii)所述VL1包含SEQ ID NO:85,所述VH1包含SEQ ID NO:84,所述VL2包含SEQID NO:4并且所述VH2包含SEQ ID NO:4;或
(iv)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:85并且所述VH2包含SEQ ID NO:84;或
(v)所述VL1包含SEQ ID NO:87,所述VH1包含SEQ ID NO:86,所述VL2包含SEQ IDNO:4并且所述VH2包含SEQ ID NO:3;或
(vi)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:87并且所述VH2包含SEQ ID NO:86;或
(vii)所述VL1包含SEQ ID NO:89,所述VH1包含SEQ ID NO:88,所述VL2包含SEQID NO:4并且所述VH2包含SEQ ID NO:3;或
(viii)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:89并且所述VH2包含SEQ ID NO:88;或
(ix)所述VL1包含SEQ ID NO:91,所述VH1包含SEQ ID NO:90,所述VL2包含SEQ IDNO:4并且所述VH2包含SEQ ID NO:3;或
(x)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ IDNO:91并且所述VH2包含SEQ ID NO:90。
在与上述方面有关的一些实施方案中,所述第一多肽中的每一个还在所述VL1与所述VH2之间包含第一接头,并且所述第二多肽中的每一个还在所述VL2与所述VH1之间包含第二接头。在一些实施方案中,所述第一接头或所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。在一些实施方案中,所述第一接头和所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。在一些实施方案中,所述第一多肽中的每一个还在所述VH2或所述VL1与所述CH1之间包含第三接头,并且所述第二多肽中的每一个还在所述VH1或所述VL2与所述CL之间包含第四接头。在一些实施方案中,所述第三接头或所述第四接头包含氨基酸序列LGGGSG(SEQ ID NO:70)。在一些实施方案中,所述第三接头和所述第四接头包含氨基酸序列LGGGSG(SEQ ID NO:70)。在一些实施方案中,所述第三接头和/或所述第四接头包含任选的半胱氨酸残基。在一些实施方案中,所述第三接头和/或所述第四接头包含氨基酸序列GGCGGG(SEQ ID NO:135)或LGGCGGGS(SEQ ID NO:136)。在一些实施方案中,所述重链恒定区2(CH2)包含位置234处的丙氨酸和位置235处的丙氨酸,所述位置是根据如Kabat中的EU索引编号的。在一些实施方案中,所述铰链区、所述重链恒定区2(CH2)或所述重链恒定区3(CH3)的氨基酸序列源自于IgG1或源自于IgG4。在一些实施方案中,所述铰链区包含氨基酸序列EPKSCDKTHTCPPCP(SEQ ID NO:76)、氨基酸序列LEPKSSDKTHTCPPCP(SEQ ID NO:130)或氨基酸序列ESKYGPPCPPCP(SEQ ID NO:134)。在一些实施方案中,(i)所述第一多肽中的每一个包含SEQ ID NO:5的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:6的氨基酸序列;或
(ii)所述第一多肽中的每一个包含SEQ ID NO:7的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:8的氨基酸序列;或
(iii)所述第一多肽中的每一个包含SEQ ID NO:13的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:14的氨基酸序列;或
(iv)所述第一多肽中的每一个包含SEQ ID NO:15的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:16的氨基酸序列;或
(v)所述第一多肽中的每一个包含SEQ ID NO:21的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:22的氨基酸序列;或
(vi)所述第一多肽中的每一个包含SEQ ID NO:25的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:26的氨基酸序列;或
(vii)所述第一多肽中的每一个包含SEQ ID NO:29的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:30的氨基酸序列;或
(viii)所述第一多肽中的每一个包含SEQ ID NO:33的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:34的氨基酸序列;或
(ix)所述第一多肽中的每一个包含SEQ ID NO:37的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:38的氨基酸序列;或
(x)所述第一多肽中的每一个包含SEQ ID NO:41的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:42的氨基酸序列;或
(xi)所述第一多肽中的每一个包含SEQ ID NO:45的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:46的氨基酸序列;或
(xii)所述第一多肽中的每一个包含SEQ ID NO:49的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:50的氨基酸序列;或
(xiii)所述第一多肽中的每一个包含SEQ ID NO:53的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:54的氨基酸序列;或
(xiv)所述第一多肽中的每一个包含SEQ ID NO:55的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:56的氨基酸序列;或
(xv)所述第一多肽中的每一个包含SEQ ID NO:57的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:58的氨基酸序列;或
(xvi)所述第一多肽中的每一个包含SEQ ID NO:59的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:60的氨基酸序列;或
(xvii)所述第一多肽中的每一个包含SEQ ID NO:61的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:62的氨基酸序列;或
(xviii)所述第一多肽中的每一个包含SEQ ID NO:63的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:64的氨基酸序列;或
(xix)所述第一多肽中的每一个包含SEQ ID NO:65的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:66的氨基酸序列;或
(xx)所述第一多肽中的每一个包含SEQ ID NO:67的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:68的氨基酸序列。
本公开的其他方面涉及一种化合物,所述化合物包含两个第一多肽和两个第二多肽;其中所述两个第一多肽经由至少一个二硫键缔合在一起并且其中所述第一多肽中的每一个经由至少一个二硫键与一个所述第二多肽缔合;并且其中(i)所述第一多肽中的每一个包含SEQ ID NO:5的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:6的氨基酸序列;或
(ii)所述第一多肽中的每一个包含SEQ ID NO:7的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:8的氨基酸序列;或
(iii)所述第一多肽中的每一个包含SEQ ID NO:13的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:14的氨基酸序列;或
(iv)所述第一多肽中的每一个包含SEQ ID NO:15的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:16的氨基酸序列;或
(v)所述第一多肽中的每一个包含SEQ ID NO:21的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:22的氨基酸序列;或
(vi)所述第一多肽中的每一个包含SEQ ID NO:25的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:26的氨基酸序列;或
(vii)所述第一多肽中的每一个包含SEQ ID NO:29的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:30的氨基酸序列;或
(viii)所述第一多肽中的每一个包含SEQ ID NO:33的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:34的氨基酸序列;或
(ix)所述第一多肽中的每一个包含SEQ ID NO:37的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:38的氨基酸序列;或
(x)所述第一多肽中的每一个包含SEQ ID NO:41的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:42的氨基酸序列;或
(xi)所述第一多肽中的每一个包含SEQ ID NO:45的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:46的氨基酸序列;或
(xii)所述第一多肽中的每一个包含SEQ ID NO:49的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:50的氨基酸序列;或
(xiii)所述第一多肽中的每一个包含SEQ ID NO:53的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:54的氨基酸序列;或
(xiv)所述第一多肽中的每一个包含SEQ ID NO:55的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:56的氨基酸序列;或
(xv)所述第一多肽中的每一个包含SEQ ID NO:57的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:58的氨基酸序列;或
(xvi)所述第一多肽中的每一个包含SEQ ID NO:59的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:60的氨基酸序列;或
(xvii)所述第一多肽中的每一个包含SEQ ID NO:61的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:62的氨基酸序列;或
(xviii)所述第一多肽中的每一个包含SEQ ID NO:63的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:64的氨基酸序列;或
(xix)所述第一多肽中的每一个包含SEQ ID NO:65的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:66的氨基酸序列;或
(xx)所述第一多肽中的每一个包含SEQ ID NO:67的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:68的氨基酸序列。
本文还考虑了与如本文所述的化合物竞争结合的其他化合物,例如与如本文所述的化合物竞争结合BAFF和IL23A的测试化合物。在一些实施方案中,所述测试化合物与如本文所述的化合物可以具有至少80%、85%、90%、95%、96%、97%、98%、或99%的序列同一性(氨基酸数/整个序列长度上的氨基酸数)。竞争性结合可以使用本领域已知的任何测定,例如平衡结合、ELISA、表面等离子体共振、或光谱法来确定。
在一些实施方案中,本文所述的化合物特异性结合BAFF和IL23A这两者。“特异性结合”抗原或表位的化合物是本领域公知的术语,并且确定这样的特异性结合的方法也是本领域公知的。如果与分子与替代性靶标的反应或缔合相比,所述分子与特定的靶抗原更频繁地、更快地、以更长的持续时间和/或以更大的亲和力反应或缔合,那么所述分子被认为表现出“特异性结合”。如果与化合物与其他物质的结合相比,所述化合物以更大的亲和力、亲合力、更容易地、和/或以更长的持续时间结合靶抗原或表位,那么所述化合物“特异性结合”所述靶抗原或表位。举例来说,特异性(或优先)结合抗原(例如BAFF或IL23A)或其中的抗原表位的化合物是如下的化合物,与所述化合物与其他抗原或同一抗原中的其他表位的结合相比,所述化合物以更大的亲和力、亲合力、更容易地、和/或以更长的持续时间结合该靶抗原。通过阅读该定义还应当了解的是,例如,特异性结合第一靶抗原的化合物可能特异性或优先结合第二靶抗原或可能不特异性或优先结合第二靶抗原。因而,“特异性结合”或“优先结合”不一定需要(尽管它可以包括)独占性结合。一般来说,但是不一定,提到结合时,意指优先结合。在一些实例中,“特异性结合”靶抗原或其表位的化合物可能不结合其他抗原或同一抗原中的其他表位。
在一些实施方案中,如本文所述的化合物对BAFF和IL23或其抗原表位具有合适的结合亲和力。如本文所用的“结合亲和力”指的是表观缔合常数或KA。KA是解离常数(KD)的倒数。本文所述的化合物对所述靶抗原或抗原表位之一或这两者可以具有至少10-5M、10-6M、10-7M、10-8M、10-9M、10-10M、10-11M、10-12M或更低的结合亲和力(KD)。结合亲和力增加对应于KD降低。在一些实施方案中,本文所述的化合物对所述靶抗原或抗原表位之一或这两者具有至少10-11M或更低的结合亲和力(KD)。相对于第三抗原,化合物与第一抗原和第二抗原的更高亲和力的结合可以通过与结合第三抗原的KA(或数值KD)相比,结合第一抗原和第二抗原的KA更高(或数值KD更小)来表明。在这些情况下,相对于第三抗原(例如,呈第二构象的相同的第一蛋白或第二蛋白或其模拟物;或第三蛋白),所述化合物对第一抗原和第二抗原(例如,呈第一构象的第一蛋白或其模拟物以及呈第一构象的第二蛋白或其模拟物)具有特异性。结合亲和力的差异(例如对于特异性或其他比较)可以是至少1.5倍、2倍、3倍、4倍、5倍、10倍、15倍、20倍、37.5倍、50倍、70倍、80倍、91倍、100倍、500倍、1000倍、10,000倍或105倍。
结合亲和力(或结合特异性)可以通过多种方法来确定,所述方法包括平衡结合、ELISA、表面等离子体共振、或光谱法(例如使用荧光测定)。用于评价结合亲和力的示例性条件是在HBS-P缓冲液(10mM HEPES(pH 7.4)、150mM NaCl、0.005%(v/v)表面活性剂P20)中。可以使用这些技术来测量随靶蛋白浓度变化的结合的结合蛋白的浓度。通过以下方程式,结合的结合蛋白的浓度([结合])与游离靶蛋白的浓度([游离])和靶标上结合蛋白的结合位点的浓度有关,其中(N)是每个靶分子的结合位点的数目:
[结合]=[N][游离]/(Kd+[游离])
然而,并不总是需要对KA进行精确的确定,这是因为有时,获得例如使用诸如ELISA或FACS分析的方法确定的亲和力的定量测量值就足矣,所述定量测量值与KA成比例并且因此可以用于进行比较,如确定更高的亲和力是否是例如2倍,以获得亲和力的定性测量、或获得对亲和力的推断,例如通过功能测定,例如体外或体内测定中的活性。
在一些实施方案中,所述化合物包含如表2A中所限定的第一多肽和第二多肽。在一些实施方案中,所述化合物包含:
(i)所述第一多肽包含SEQ ID NO:5的氨基酸序列并且所述第二多肽包含SEQ IDNO:6的氨基酸序列;或
(ii)所述第一多肽包含SEQ ID NO:7的氨基酸序列并且所述第二多肽包含SEQ IDNO:8的氨基酸序列;或
(iii)所述第一多肽包含SEQ ID NO:9的氨基酸序列并且所述第二多肽包含SEQID NO:10的氨基酸序列;或
(iv)所述第一多肽包含SEQ ID NO:11的氨基酸序列并且所述第二多肽包含SEQID NO:12的氨基酸序列;或
(v)所述第一多肽包含SEQ ID NO:13的氨基酸序列并且所述第二多肽包含SEQ IDNO:14的氨基酸序列;或
(vi)所述第一多肽包含SEQ ID NO:15的氨基酸序列并且所述第二多肽包含SEQID NO:16的氨基酸序列;或
(vii)所述第一多肽包含SEQ ID NO:17的氨基酸序列并且所述第二多肽包含SEQID NO:18的氨基酸序列;或
(viii)所述第一多肽包含SEQ ID NO:19的氨基酸序列并且所述第二多肽包含SEQID NO:20的氨基酸序列;或
(ix)所述第一多肽包含SEQ ID NO:21的氨基酸序列并且所述第二多肽包含SEQID NO:22的氨基酸序列;或
(x)所述第一多肽包含SEQ ID NO:23的氨基酸序列并且所述第二多肽包含SEQ IDNO:24的氨基酸序列;或
(xi)所述第一多肽包含SEQ ID NO:25的氨基酸序列并且所述第二多肽包含SEQID NO:26的氨基酸序列;或
(xii)所述第一多肽包含SEQ ID NO:27的氨基酸序列并且所述第二多肽包含SEQID NO:28的氨基酸序列;或
(xiii)所述第一多肽包含SEQ ID NO:29的氨基酸序列并且所述第二多肽包含SEQID NO:30的氨基酸序列;或
(xiv)所述第一多肽包含SEQ ID NO:31的氨基酸序列并且所述第二多肽包含SEQID NO:32的氨基酸序列;或
(xv)所述第一多肽包含SEQ ID NO:33的氨基酸序列并且所述第二多肽包含SEQID NO:34的氨基酸序列;或
(xvi)所述第一多肽包含SEQ ID NO:35的氨基酸序列并且所述第二多肽包含SEQID NO:36的氨基酸序列;或
(xvii)所述第一多肽包含SEQ ID NO:37的氨基酸序列并且所述第二多肽包含SEQID NO:38的氨基酸序列;或
(xviii)所述第一多肽包含SEQ ID NO:39的氨基酸序列并且所述第二多肽包含SEQ ID NO:40的氨基酸序列;或
(xix)所述第一多肽包含SEQ ID NO:41的氨基酸序列并且所述第二多肽包含SEQID NO:42的氨基酸序列;或
(xx)所述第一多肽包含SEQ ID NO:43的氨基酸序列并且所述第二多肽包含SEQID NO:44的氨基酸序列;或
(xxi)所述第一多肽包含SEQ ID NO:45的氨基酸序列并且所述第二多肽包含SEQID NO:46的氨基酸序列;或
(xxii)所述第一多肽包含SEQ ID NO:47的氨基酸序列并且所述第二多肽包含SEQID NO:48的氨基酸序列;或
(xxiii)所述第一多肽包含SEQ ID NO:49的氨基酸序列并且所述第二多肽包含SEQ ID NO:50的氨基酸序列;或
(xxiv)所述第一多肽包含SEQ ID NO:51的氨基酸序列并且所述第二多肽包含SEQID NO:52的氨基酸序列;或
(xxv)所述第一多肽包含SEQ ID NO:53的氨基酸序列并且所述第二多肽包含SEQID NO:54的氨基酸序列;或
(xxvi)所述第一多肽包含SEQ ID NO:55的氨基酸序列并且所述第二多肽包含SEQID NO:56的氨基酸序列;或
(xxvii)所述第一多肽包含SEQ ID NO:57的氨基酸序列并且所述第二多肽包含SEQ ID NO:58的氨基酸序列;或
(xxviii)所述第一多肽包含SEQ ID NO:59的氨基酸序列并且所述第二多肽包含SEQ ID NO:60的氨基酸序列;或
(xxix)所述第一多肽包含SEQ ID NO:61的氨基酸序列并且所述第二多肽包含SEQID NO:62的氨基酸序列;或
(xxx)所述第一多肽包含SEQ ID NO:63的氨基酸序列并且所述第二多肽包含SEQID NO:64的氨基酸序列;或
(xxxi)所述第一多肽包含SEQ ID NO:65的氨基酸序列并且所述第二多肽包含SEQID NO:66的氨基酸序列;或
(xxxii)所述第一多肽包含SEQ ID NO:67的氨基酸序列并且所述第二多肽包含SEQ ID NO:68的氨基酸序列。
产生化合物、核酸、载体、以及细胞的方法
本公开的方面还包括编码本文所述的化合物或本文所述的多肽(例如本文所述的第一多肽或第二多肽)的核酸,所述化合物或多肽可以被共同或分开编码。可以通过本领域已知的任何方法来获得编码本文所述的化合物或本文所述的多肽的多核苷酸并且确定所述多核苷酸的核苷酸序列。
在一些实施方案中,所述核酸被包含在载体,如表达载体内。在一些实施方案中,所述载体包含与所述核酸可操作地连接的启动子。
可以使用多种启动子来表达本文所述的化合物或本文所述的多肽,包括但不限于巨细胞病毒(CMV)中间早期启动子;病毒LTR,如劳氏肉瘤病毒(Rous sarcoma virus)LTR、HIV-LTR、HTLV-1LTR;猿猴病毒40(SV40)早期启动子、大肠杆菌lac UV5启动子、以及单纯疱疹tk病毒启动子。
也可以使用调节型启动子。这样的调节型启动子包括使用来自大肠杆菌的lac阻遏子作为转录调节因子以调节来自带有lac操纵子的哺乳动物细胞启动子的转录的那些[Brown,M.等人,Cell,49:603-612(1987)];使用四环素阻遏子(tetR)的那些[Gossen,M.和Bujard,H.,Proc.Natl.Acad.Sci.USA 89:5547-5551(1992);Yao,F.等人,Human GeneTherapy,9:1939-1950(1998);Shockelt,P.等人,Proc.Natl.Acad.Sci.USA,92:6522-6526(1995)]。其他系统包括使用雌二醇(astradiol)、RU486、联苯酚米勒甾酮(murislerone)或雷帕霉素(rapamycin)的FK506二聚体、VP16或p65。诱导型系统可获自Invitrogen、Clontech以及Ariad。
可以使用包括具有操纵子的阻遏子的调节型启动子。在一个实施方案中,来自大肠杆菌的lac阻遏子可以充当转录调节因子以调节来自带有lac操纵子的哺乳动物细胞启动子的转录[M.Brown等人,Cell,49:603-612(1987)];Gossen和Bujard(1992)[M.Gossen等人,Natl.Acad.Sci.USA,89:5547-5551(1992)]将四环素阻遏子(tetR)与转录激活因子(VP16)组合以产生tetR哺乳动物细胞转录激活因子融合蛋白tTa(tetR-VP 16),与源自于人巨细胞病毒(hCMV)主要立即早期启动子的带有tetO的最小启动子组合以产生tetR-tet操纵子系统以控制哺乳动物细胞中的基因表达。在一个实施方案中,使用四环素诱导型开关(Yao等人,Human Gene Therapy;Gossen等人,Natl.Acad.Sci.USA,89:5547-5551(1992);Shockett等人,Proc.Natl.Acad.Sci.USA,92:6522-6526(1995))。
此外,载体可以含有例如以下各项中的一些或全部:选择标记基因,如用于在哺乳动物细胞中选择稳定或瞬时转染子的新霉素基因;用于高水平的转录的来自人CMV的立即早期基因的增强子/启动子序列;用于mRNA稳定性的来自SV40的转录终止和RNA加工信号;用于正确的游离型复制的SV40多瘤复制起点和ColE1;内部核糖体结合位点(IRES),即多功能多克隆位点;以及用于有义RNA和反义RNA的体外转录的T7和SP6RNA启动子。用于产生含有转基因的载体的合适的载体和方法是本领域公知的和可获得的。
可以通过常规技术(例如电穿孔、脂质体转染、以及磷酸钙沉淀)将包含核酸的表达载体转移到宿主细胞中,然后通过常规技术培养转染的细胞以产生本文所述的化合物。在一些实施方案中,通过组成型启动子、诱导型启动子或组织特异性启动子来调节本文所述的化合物的表达。
用于表达本文所述的化合物或本文所述的多肽的宿主细胞可以是细菌细胞,如大肠杆菌,或优选地是真核细胞。具体来说,哺乳动物细胞,如中国仓鼠卵巢细胞(CHO)联同诸如来自人巨细胞病毒的主要中间早期基因启动子元件的载体一起是免疫球蛋白的有效表达系统(Foecking等人(1986)“Powerful And Versatile Enhancer-Promoter Unit ForMammalian Expression Vectors”,Gene 45:101-106;Cockett等人(1990)“High LevelExpression Of Tissue Inhibitor Of Metalloproteinases In Chinese Hamster OvaryCells Using Glutamine Synthetase Gene Amplification”,Biotechnology 8:662-667)。
可以利用多种宿主表达载体系统来表达本文所述的化合物或本文所述的多肽。这样的宿主表达系统代表了可以用以产生并且随后纯化本文所述的化合物或本文所述的多肽的编码序列的运载体,而且还代表了在用适当的核苷酸编码序列转化或转染时可以原位表达本文所述的化合物的细胞。这些包括但不限于微生物,如用含有本文所述的化合物的编码序列的重组噬菌体DNA、质粒DNA或粘粒DNA表达载体转化的细菌(例如大肠杆菌和枯草芽孢杆菌(B.subtilis));用含有编码本文所述的化合物的序列的重组酵母表达载体转化的酵母(例如毕赤酵母(Saccharomyces pichia));用含有编码本文所述的化合物的序列的重组病毒表达载体(例如杆状病毒)感染的昆虫细胞系统;用重组病毒表达载体(例如花椰菜花叶病毒(CaMV)和烟草花叶病毒(TMV))感染或用重组质粒表达载体(例如Ti质粒)转化的植物细胞系统,所述重组质粒表达载体含有编码本文所述的分子化合物的序列;或携带含有源自于哺乳动物细胞的基因组(例如金属硫蛋白启动子)或源自于哺乳动物病毒(例如腺病毒晚期启动子;牛痘病毒7.5K启动子)的启动子的重组表达构建体的哺乳动物细胞系统(例如COS细胞、CHO细胞、BHK细胞、293细胞、293T细胞、3T3细胞、淋巴细胞(参见美国专利号5,807,715)、Per C.6细胞(由Crucell开发的人视网膜细胞))。
在细菌系统中,可以有利地选择许多表达载体,这取决于正被表达的化合物的预期用途。举例来说,当要产生大量这样的蛋白质以用于产生本文所述的化合物的药物组合物时,引导容易纯化的高水平的融合蛋白产物表达的载体可能是所期望的。这样的载体包括但不限于大肠杆菌表达载体pUR278(Rüther等人(1983)“Easy Identification Of cDNAClones”,EMBO J.2:1791-1794),其中编码序列可以单独地与lac Z编码区一起在框内连接到载体中以产生融合蛋白;pIN载体(Inouye等人(1985)“Up-Promoter Mutations In Thelpp Gene Of Escherichia Coli”,Nucleic Acids Res.13:3101-3110;Van Heeke等人(1989)“Expression Of Human Asparagine Synthetase In Escherichia Coli”,J.Biol.Chem.24:5503-5509);等。也可以使用pGEX载体来将外来多肽表达成与谷胱甘肽S-转移酶(GST)的融合蛋白。一般来说,这样的融合蛋白是可溶的并且可以容易地通过吸附和结合到基质谷胱甘肽-琼脂糖珠粒,继而在游离谷胱甘肽存在下洗脱来从裂解的细胞中纯化。pGEX载体被设计成包括凝血酶或因子Xa蛋白酶切割位点以使得克隆的靶基因产物可以从GST部分释放。
在昆虫系统中,使用苜蓿银纹夜蛾(Autographa californica)核型多角体病毒(AcNPV)作为载体来表达外来基因。所述病毒在草地贪夜蛾(Spodoptera frugiperda)细胞中生长。可以将编码序列单独地克隆到所述病毒的非必要区域(例如多角体蛋白基因)中并且置于AcNPV启动子(例如多角体蛋白启动子)的控制下。
在哺乳动物宿主细胞中,可以利用许多基于病毒的表达系统。在其中使用腺病毒作为表达载体的情况下,可以使所关注的编码序列与腺病毒转录/翻译控制复合物,例如晚期启动子和三联前导序列连接。然后可以通过体外或体内重组将该嵌合基因插入腺病毒基因组中。插入到病毒基因组的非必要区域(例如区域E1或E3)中将产生活的并且能够在受感染的宿主中表达免疫球蛋白分子的重组病毒(例如参见Logan等人(1984)“AdenovirusTripartite Leader Sequence Enhances Translation Of mRNAs Late AfterInfection”,Proc.Natl.Acad.Sci.USA81:3655-3659)。插入的抗体编码序列的高效翻译还可能需要特定的起始信号。这些信号包括ATG起始密码子和相邻的序列。此外,起始密码子必须与所期望的编码序列的阅读框同相以确保整个插入序列的翻译。这些外源性翻译控制信号和起始密码子可以是多种来源的,天然和合成这两者皆可。表达的效率可以通过包括适当的转录增强子元件、转录终止子等来提高(参见Bitter等人(1987)“Expression AndSecretion Vectors For Yeast”,Methods in Enzymol.153:516-544)。
此外,可以选择宿主细胞株,所述宿主细胞株以所期望的特定方式调节插入序列的表达,或修饰和加工基因产物。这样的对蛋白质产物的修饰(例如糖基化)和加工(例如切割)对于蛋白质的功能来说可能是重要的。举例来说,在某些实施方案中,本文所述的化合物可以被表达成单一基因产物(例如单条多肽链,即多蛋白前体),它需要通过天然或重组细胞机制进行蛋白水解切割以形成本文所述的化合物的单独的多肽。本公开因此包括将核酸序列工程改造以编码包含本文所述的化合物的多肽的多蛋白前体分子,它包括能够引导所述多蛋白前体的翻译后切割的编码序列。多蛋白前体的翻译后切割产生本文所述的化合物的多肽。包含本文所述的化合物的多肽的前体分子的翻译后切割可以在体内发生(即在宿主细胞内通过天然或重组的细胞系统/机制,例如弗林蛋白酶切割在适当的位点处发生)或可以在体外发生(例如将所述多肽链在包含具有已知活性的蛋白酶或肽酶的组合物中和/或在包含已知促进所期望的蛋白水解作用的条件或试剂的组合物中孵育)。重组蛋白的纯化和修饰是本领域公知的以使得多蛋白前体的设计可以包括本领域技术人员容易了解的许多实施方案。本领域已知的任何已知的蛋白酶或肽酶均可以用于前体分子的所述修饰,所述蛋白酶或肽酶例如凝血酶或因子Xa(Nagai等人(1985)“Oxygen BindingProperties Of Human Mutant Hemoglobins Synthesized In Escherichia Coli”,Proc.Nat.Acad.Sci.USA 82:7252-7255,并且在Jenny等人(2003)“A Critical Review OfThe Methods For Cleavage Of Fusion Proteins With Thrombin And Factor Xa”,Protein Expr.Purif.31:1-11中综述,这些文献中的每一篇以引用的方式整体并入本文)、肠激酶(Collins-Racie等人(1995)“Production Of Recombinant Bovine EnterokinaseCatalytic Subunit In Escherichia Coli Using The Novel Secretory FusionPartner DsbA”,Biotechnology 13:982-987,其在此以引用的方式整体并入本文)、弗林蛋白酶、以及AcTEV(Parks等人(1994)“Release Of Proteins And Peptides From FusionProteins Using A Recombinant Plant Virus Proteinase”,Anal.Biochem.216:413-417,其在此以引用的方式整体并入本文)以及口蹄疫病毒蛋白酶C3。
不同的宿主细胞具有用于翻译后加工和修饰蛋白质和基因产物的特征性和特定的机制。可以选择适当的细胞系或宿主系统来确保正确修饰和加工所表达的外来蛋白质。为此,可以使用具有用于正确加工初级转录物、基因产物的糖基化和磷酸化的细胞机制的真核宿主细胞。这样的哺乳动物宿主细胞包括但不限于CHO、VERY、BHK、HeLa、COS、MDCK、293、293T、3T3、WI38、BT483、Hs578T、HTB2、BT20和T47D、CRL7030以及Hs578Bst。
对于重组蛋白的长期、高产率产生,稳定的表达是优选的。举例来说,可以将稳定表达本文所述的化合物的细胞系进行工程改造。不使用含有病毒复制起点的表达载体,而是可以使用由适当的表达控制元件(例如启动子、增强子、序列、转录终止子、多聚腺苷酸化位点等)控制的DNA和选择标记来转化宿主细胞。在引入外来DNA之后,可以使工程改造的细胞在富集培养基中生长1-2天,然后转换成选择培养基。重组质粒中的选择标记赋予对选择的抗性并且允许细胞将质粒稳定地整合到它们的染色体中并且生长以形成灶,它们进而可以被克隆和扩增成细胞系。该方法可以有利地用于将表达本文所述的化合物的细胞系进行工程改造。这样的工程改造的细胞系在筛选和评价与本文所述的化合物直接或间接相互作用的化合物中可能是特别有用的。
可以使用许多选择系统,包括但不限于单纯疱疹病毒胸苷激酶基因(Wigler等人(1977)“Transfer Of Purified Herpes Virus Thymidine Kinase Gene To CulturedMouse Cells”,Cell 11:223-232)、次黄嘌呤-鸟嘌呤磷酸核糖基转移酶基因(Szybalska等人(1992)“Use Of The HPRT Gene And The HAT Selection Technique In DNA-MediatedTransformation Of Mammalian Cells First Steps Toward Developing HybridomaTechniques And Gene Therapy”,Bioessays 14:495-500)、以及腺嘌呤磷酸核糖基转移酶基因(Lowy等人(1980)“Isolation Of Transforming DNA:Cloning The Hamster aprtGene”,Cell 22:817-823)可以分别用于tk-细胞、hgprt-细胞或aprt-细胞中。此外,抗代谢物抗性可以用作针对以下基因进行选择的基础:dhfr,它赋予对甲氨蝶呤(methotrexate)的抗性(Wigler等人(1980)“Transformation Of Mammalian Cells With An AmplifiableDominant-Acting Gene”,Proc.Natl.Acad.Sci.USA 77:3567-3570;O'Hare等人(1981)“Transformation Of Mouse Fibroblasts To Methotrexate Resistance By ARecombinant Plasmid Expressing A Prokaryotic Dihydrofolate Reductase”,Proc.Natl.Acad.Sci.USA 78:1527-1531);gpt,它赋予对霉酚酸的抗性(Mulligan等人(1981)“Selection For Animal Cells That Express The Escherichia coli GeneCoding For Xanthine-Guanine Phosphoribosyltransferase”,Proc.Natl.Acad.Sci.USA78:2072-2076);neo,它赋予对氨基糖苷G-418的抗性(Tolstoshev(1993)“Gene Therapy,Concepts,Current Trials And Future Directions”,Ann.Rev.Pharmacol.Toxicol.32:573-596;Mulligan(1993)“The Basic Science Of Gene Therapy”,Science 260:926-932;以及Morgan等人(1993)“Human Gene Therapy”,Ann.Rev.Biochem.62:191-217);以及hygro,它赋予对潮霉素(hygromycin)的抗性(Santerre等人(1984)“Expression OfProkaryotic Genes For Hygromycin B And G418Resistance As Dominant-SelectionMarkers In Mouse L Cells”,Gene 30:147-156)。可以使用的重组DNA技术的本领域通常已知的方法描述于以下文献中:Ausubel等人(编著),1993,Current Protocols inMolecular Biology,John Wiley&Sons,NY;Kriegler,1990,Gene Transfer andExpression,A Laboratory Manual,Stockton Press,NY;以及第12章和第13章,Dracopoli等人(编著),1994,Current Protocols in Human Genetics,John Wiley&Sons,NY.;Colberre-Garapin等人(1981)“A New Dominant Hybrid Selective Marker For HigherEukaryotic Cells”,J.Mol.Biol.150:1-14。
本文所述的化合物或本文所述的多肽的表达水平可以通过载体扩增来增加(关于综述,参见Bebbington和Hentschel,The use of vectors based on gene amplificationfor the expression of cloned genes in mammalian cells in DNA cloning,第3卷(Academic Press,New York,1987))。当表达本文所述的化合物的载体系统中的标记是可扩增的时,宿主细胞的培养物中存在的抑制剂水平的增加将增加标记基因的拷贝数。由于扩增的区域与本文所述的化合物或本文所述的多肽的核苷酸序列相关,因此所述多肽的产生也将增加(Crouse等人(1983)“Expression And Amplification Of Engineered MouseDihydrofolate Reductase Minigenes”,Mol.Cell.Biol.3:257-266)。
可以用两种表达载体,即编码本文所述的化合物的第一多肽的第一载体和编码本文所述的化合物的第二多肽的第二载体共转染宿主细胞。这两种载体可以含有相同的选择标记,所述选择标记使得这两种多肽能够等量表达。或者,可以使用编码这两种多肽的单一载体。本文所述的化合物的多肽的编码序列可以包括cDNA或基因组DNA。
一旦本文所述的化合物或本文所述的多肽已经被重组表达,就可以将它通过本领域已知的用于纯化多肽、多蛋白或抗体的任何方法(例如类似于基于抗原选择性的抗体纯化方案)来纯化,例如通过色谱法(例如离子交换色谱法、亲和色谱法,特别是通过对特定抗原的亲和色谱法(任选地在蛋白A选择之后,其中所述化合物包含Fc结构域(或其部分))、以及分级柱色谱法)、离心、差异溶解度、或通过用于纯化多肽或抗体的任何其他标准技术。
本公开的其他方面涉及一种细胞,所述细胞包含本文所述的核酸或本文所述的载体。所述细胞可以是原核细胞或真核细胞。在一些实施方案中,所述细胞是哺乳动物细胞。示例性细胞类型描述于本文中。
本公开的另外的其他方面涉及一种制备本文所述的化合物或本文所述的多肽(例如第一多肽或第二多肽)的方法,所述方法包括获得本文所述的细胞以及使本文所述的核酸在所述细胞中表达。在一些实施方案中,所述方法还包括分离和纯化本文所述的化合物或本文所述的多肽。
治疗方法和用于医学的组合物
本公开的其他方面涉及治疗方法和用于医学的组合物。用于这样的方法和组合物中的化合物的非限制性实例是包含以下各项的那些:
(i)所述第一多肽包含SEQ ID NO:5的氨基酸序列并且所述第二多肽包含SEQ IDNO:6的氨基酸序列;或
(ii)所述第一多肽包含SEQ ID NO:7的氨基酸序列并且所述第二多肽包含SEQ IDNO:8的氨基酸序列;或
(iii)所述第一多肽包含SEQ ID NO:9的氨基酸序列并且所述第二多肽包含SEQID NO:10的氨基酸序列;或
(iv)所述第一多肽包含SEQ ID NO:11的氨基酸序列并且所述第二多肽包含SEQID NO:12的氨基酸序列;或
(v)所述第一多肽包含SEQ ID NO:13的氨基酸序列并且所述第二多肽包含SEQ IDNO:14的氨基酸序列;或
(vi)所述第一多肽包含SEQ ID NO:15的氨基酸序列并且所述第二多肽包含SEQID NO:16的氨基酸序列;或
(vii)所述第一多肽包含SEQ ID NO:17的氨基酸序列并且所述第二多肽包含SEQID NO:18的氨基酸序列;或
(viii)所述第一多肽包含SEQ ID NO:19的氨基酸序列并且所述第二多肽包含SEQID NO:20的氨基酸序列;或
(ix)所述第一多肽包含SEQ ID NO:21的氨基酸序列并且所述第二多肽包含SEQID NO:22的氨基酸序列;或
(x)所述第一多肽包含SEQ ID NO:23的氨基酸序列并且所述第二多肽包含SEQ IDNO:24的氨基酸序列;或
(xi)所述第一多肽包含SEQ ID NO:25的氨基酸序列并且所述第二多肽包含SEQID NO:26的氨基酸序列;或
(xii)所述第一多肽包含SEQ ID NO:27的氨基酸序列并且所述第二多肽包含SEQID NO:28的氨基酸序列;或
(xiii)所述第一多肽包含SEQ ID NO:29的氨基酸序列并且所述第二多肽包含SEQID NO:30的氨基酸序列;或
(xiv)所述第一多肽包含SEQ ID NO:31的氨基酸序列并且所述第二多肽包含SEQID NO:32的氨基酸序列;或
(xv)所述第一多肽包含SEQ ID NO:33的氨基酸序列并且所述第二多肽包含SEQID NO:34的氨基酸序列;或
(xvi)所述第一多肽包含SEQ ID NO:35的氨基酸序列并且所述第二多肽包含SEQID NO:36的氨基酸序列;或
(xvii)所述第一多肽包含SEQ ID NO:37的氨基酸序列并且所述第二多肽包含SEQID NO:38的氨基酸序列;或
(xviii)所述第一多肽包含SEQ ID NO:39的氨基酸序列并且所述第二多肽包含SEQ ID NO:40的氨基酸序列;或
(xix)所述第一多肽包含SEQ ID NO:41的氨基酸序列并且所述第二多肽包含SEQID NO:42的氨基酸序列;或
(xx)所述第一多肽包含SEQ ID NO:43的氨基酸序列并且所述第二多肽包含SEQID NO:44的氨基酸序列;或
(xxi)所述第一多肽包含SEQ ID NO:45的氨基酸序列并且所述第二多肽包含SEQID NO:46的氨基酸序列;或
(xxii)所述第一多肽包含SEQ ID NO:47的氨基酸序列并且所述第二多肽包含SEQID NO:48的氨基酸序列;或
(xxiii)所述第一多肽包含SEQ ID NO:49的氨基酸序列并且所述第二多肽包含SEQ ID NO:50的氨基酸序列;或
(xxiv)所述第一多肽包含SEQ ID NO:51的氨基酸序列并且所述第二多肽包含SEQID NO:52的氨基酸序列;或
(xxv)所述第一多肽包含SEQ ID NO:53的氨基酸序列并且所述第二多肽包含SEQID NO:54的氨基酸序列;或
(xxvi)所述第一多肽包含SEQ ID NO:55的氨基酸序列并且所述第二多肽包含SEQID NO:56的氨基酸序列;或
(xxvii)所述第一多肽包含SEQ ID NO:57的氨基酸序列并且所述第二多肽包含SEQ ID NO:58的氨基酸序列;或
(xxviii)所述第一多肽包含SEQ ID NO:59的氨基酸序列并且所述第二多肽包含SEQ ID NO:60的氨基酸序列;或
(xxix)所述第一多肽包含SEQ ID NO:61的氨基酸序列并且所述第二多肽包含SEQID NO:62的氨基酸序列;或
(xxx)所述第一多肽包含SEQ ID NO:63的氨基酸序列并且所述第二多肽包含SEQID NO:64的氨基酸序列;或
(xxxi)所述第一多肽包含SEQ ID NO:65的氨基酸序列并且所述第二多肽包含SEQID NO:66的氨基酸序列;或
(xxxii)所述第一多肽包含SEQ ID NO:67的氨基酸序列并且所述第二多肽包含SEQ ID NO:68的氨基酸序列。
在一些实施方案中,所述治疗方法或所述用途是治疗自身免疫性或炎症性疾病的方法或用于这样的方法中。在一些实施方案中,所述方法包括向受试者,例如患有自身免疫性或炎症性疾病或有患自身免疫性或炎症性疾病的风险的受试者施用本文所述的化合物或包含所述化合物的药物组合物。
待由本文所述的方法治疗的受试者可以是哺乳动物,更优选地是人。哺乳动物包括但不限于农畜、竞技动物、宠物、灵长类动物、马、狗、猫、小鼠以及大鼠。需要所述治疗的人受试者可以是患有疾病、有患疾病的风险、或疑似患有疾病的人受试者。患有疾病的受试者可以通过常规医学检查,例如身体检查、实验室测试、器官功能测试、CT扫描、或超声波来鉴定。疑似患有这样的疾病中的任一种的受试者可能表现出所述疾病的一种或多种症状。疾病,例如自身免疫性和炎症性疾病的体征和症状是本领域的普通技术人员公知的。有患疾病的风险的受试者可以是有该疾病的风险因素中的一种或多种的受试者。
自身免疫性疾病的非限制性实例包括狼疮性肾炎(LN)(伴有肾脏牵涉的系统性红斑狼疮(SLE))、系统性红斑狼疮(SLE)、原发性舍格伦综合征(pSS)、舍格伦氏病、移植物抗宿主病(GVHD)(例如慢性移植物抗宿主病(cGVHD))、系统性硬化(SSc)、抗中性粒细胞细胞质自身抗体(ANCA)相关血管炎(AAV)、类风湿性关节炎、银屑病、1型糖尿病、系统性红斑狼疮、移植排斥反应、自身免疫性甲状腺病(桥本氏病(Hashimoto's disease))、类肉瘤病、硬皮病、肉芽肿性血管炎、克罗恩氏病(Crohn's disease)、溃疡性结肠炎、舍格伦氏病、强直性脊柱炎、银屑病关节炎、多发性肌炎皮肌炎、结节性多动脉炎、免疫介导的疱性皮肤病、白塞氏综合征(Behcet's syndrome)、多发性硬化、古德帕斯彻氏病(Goodpasture'sdisease)或免疫介导的肾小球肾炎。
炎症性疾病的非限制性实例包括类风湿性关节炎、系统性红斑狼疮、斑形脱发、强直性脊柱炎、抗磷脂综合征、自身免疫性艾迪生氏病(autoimmune Addison's disease)、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性内耳疾病、自身免疫性淋巴增殖性综合征(ALPS)、自身免疫性血小板减少性紫癜(ATP)、白塞氏病、大疱性类天疱疮、心肌病、乳糜泻性皮炎、慢性疲劳综合征免疫缺陷综合征(CFIDS)、慢性炎症性脱髓鞘性多发性神经病、瘢痕性类天疱疮、冷凝集素病、肢端硬皮综合征(Crest syndrome)、克罗恩氏病、德戈斯病(Dego's disease)、皮肌炎、青少年皮肌炎、盘状狼疮、原发性混合型冷球蛋白血症、纤维肌痛性纤维肌炎、格雷氏病(grave's disease)、格林-巴利病(guillain-barre)、桥本氏甲状腺炎(hashimoto's thyroiditis)、特发性肺纤维化、特发性血小板减少性紫癜(ITP)、Iga肾病、胰岛素依赖性糖尿病(I型)、青少年关节炎、美尼尔氏病(Meniere's disease)、混合型结缔组织病、多发性硬化、重症肌无力、寻常天疱疮、恶性贫血、结节性多动脉炎、多软骨炎、多腺体综合征、风湿性多肌痛、多发性肌炎和皮肌炎、原发性无丙种球蛋白血症、原发性胆汁性肝硬化、银屑病、雷诺氏现象(Raynaud's phenomenon)、瑞特氏综合征(Reiter'ssyndrome)、风湿热、类肉瘤病、硬皮病、舍格伦综合征、僵人综合征、高安氏动脉炎(Takayasu arteritis)、颞动脉炎/巨细胞性动脉炎、溃疡性结肠炎、葡萄膜炎、血管炎、白癜风、以及韦格纳肉芽肿病(Wegener's granulomatosis)。在一些实施方案中,所述自身免疫性或炎症性疾病是克罗恩氏病、强直性脊柱炎、或银屑病关节炎。
为了实施本文所公开的方法,可以向需要所述治疗的受试者(例如人)施用有效量的本文所述的化合物或药物组合物。各种递送系统是已知的并且可以用于施用主题技术的化合物。施用方法包括但不限于真皮内、肌内、腹膜内、静脉内、皮下、鼻内、硬膜外、以及口服途径。主题技术的化合物可以例如通过输注、推注或注射来施用,并且可以连同诸如抗炎剂的其他生物活性剂一起施用。施用可以是全身的或局部的。在优选的实施方案中,施用是通过皮下注射。用于这样的注射的制剂可以在例如预充式注射器中制备,所述预充式注射器可以每隔一周施用一次。
如本文所用的“有效量”指的是单独或与一种或多种其他化合物组合赋予受试者以治疗作用所需的每一种化合物的量。如由本领域技术人员所认识到的那样,有效量根据以下各项而变化:所治疗的特定病况;病况的严重程度;单个受试者参数,包括年龄、身体状况、体格大小、性别以及体重;治疗的持续时间;并行治疗(如果有的话)的性质;具体的施用途径以及健康专业人员的知识和专业技能范围内的类似因素。这些因素是本领域的普通技术人员公知的并且可以仅用常规的实验来解决。一般优选的是,使用单个组分或其组合的最大剂量,即根据合理的医学判断的最高安全剂量。然而,本领域的普通技术人员将了解的是,出于医学原因、心理原因或实际上任何其他原因,受试者可能坚持更低的剂量或可耐受的剂量。
经验考虑因素,如半衰期一般将有助于确定剂量。举例来说,可以使用与人免疫系统相容的化合物,如包含来自人源化抗体或完全人抗体的区域的化合物来延长化合物的半衰期并且防止化合物受到宿主免疫系统的攻击。可以确定施用频率并且在治疗过程中调整,并且一般但不一定是基于疾病的治疗和/或抑制和/或改善和/或延迟。或者,化合物的持续连续释放制剂可能是适当的。用于实现持续释放的各种制剂和装置是本领域已知的。
在一些实施方案中,给药是每天一次、每隔一天一次、每三天一次、每四天一次、每五天一次、或每六天一次。在一些实施方案中,给药频率是每周一次、每2周一次、每4周一次、每5周一次、每6周一次、每7周一次、每8周一次、每9周一次、或每10周一次;或每月一次、每2个月一次、或每3个月一次、或更长时间一次。该治疗的进展容易通过常规技术和测定来监测。给药方案(包括所使用的化合物)可以随时间推移而变化。
在一些实施方案中,对于正常体重的成年受试者,可以施用约0.01mg/kg至1000mg/kg范围内的剂量。在一些实施方案中,剂量是1mg至200mg。具体的给药方案(即剂量、时间以及重复)将取决于具体的受试者以及该受试者的病史、以及化合物的特性(如化合物的半衰期、以及本领域公知的其他考虑因素)。
出于本公开的目的,如本文所述的化合物的适当的剂量将取决于所使用的具体化合物(或其组合物)、制剂和施用途径、疾病的类型和严重程度、施用所述化合物是用于预防目的还是治疗目的、先前的治疗、受试者的临床病史和对拮抗剂的响应、以及主治医师的判断。通常,临床医生将施用化合物直到达到实现所期望的结果的剂量为止。一种或多种化合物的施用可以是连续的或间歇的,这取决于例如接受者的生理状况、施用的目的是治疗还是预防、以及熟练的专业人员已知的其他因素。化合物的施用可以在预先选择的时间段内是基本上连续的或可以通过一系列间隔的剂量,例如在患上疾病之前、期间、或之后。
如本文所用的术语“治疗”指的是向患有疾病、所述疾病的症状、或具有对所述疾病的易感性的受试者应用或施用化合物或包括所述化合物的组合物,目的在于治愈、愈合、缓解、减轻、改变、医治、缓和、改善、或影响所述疾病、所述疾病的症状、或对所述疾病的易感性。
缓解疾病包括延迟所述疾病的发展或进展、或降低疾病的严重程度。缓解疾病不一定需要治愈结果。如其中所使用的“延迟”疾病的发展意指拖延、阻碍、减慢、延缓、稳定、和/或推迟疾病的进展。该延迟可以具有不同的时间长度,这取决于疾病的病史和/或所治疗的个体。“延迟”或缓解疾病的发展或延迟疾病的发病的方法是如下的方法,当与不使用所述方法相比时,所述方法在给定的时间范围内降低发生所述疾病的一种或多种症状的概率和/或在给定的时间范围内降低所述症状的程度。这样的比较通常是基于使用足以得到统计显著性结果的数目的受试者进行的临床研究。
疾病的“发展”或“进展”意指所述疾病的最初表现和/或随后的进展。疾病的发展可以使用本领域公知的标准临床技术来检测和评估。然而,发展也指的是可能不可检测的进展。出于本公开的目的,发展或进展指的是症状的生物学过程。“发展”包括发生、复发、以及发病。如本文所用的疾病的“发病”或“发生”包括初始发病和/或复发。
在一些实施方案中,以足以在体内或体外将BAFF或IL23A之一或这两者的活性抑制至少20%(例如30%、40%、50%、60%、70%、80%、90%或更大)的量向需要治疗的受试者施用本文所述的化合物。用于确定化合物的抑制能力的方法是本领域已知的。示例性BAFF和IL23A抑制测定提供于实施例中。
可以使用医学领域的普通技术人员已知的常规方法向受试者施用所述化合物或药物组合物,这取决于待治疗的疾病的类型或所述疾病的部位。该组合物也可以经由其他常规的途径来施用,例如口服、肠胃外、通过吸入喷雾、局部、经直肠、经鼻、颊面、经阴道或经由植入的储库来施用。如本文所用的术语“肠胃外”包括皮下、皮内、静脉内、肌内、关节内、动脉内、滑膜内、胸骨内、鞘内、病灶内、以及颅内注射或输注技术。此外,可以将它经由可注射的贮库施用途径向受试者施用,如使用1个月、3个月或6个月贮库可注射或可生物降解的材料和方法。
药物组合物
本公开的另外的其他方面涉及包含本文所述的化合物的药物组合物。可以向患有自身免疫性或炎症性疾病或有患自身免疫性或炎症性疾病的风险的受试者施用包含主题技术的化合物(例如对BAFF和IL23A这两者具有特异性的化合物)的组合物。主题技术还提供了主题技术的化合物用于制造用于治疗自身免疫性或炎症性疾病的药物的用途。可以单独或与其他组合物组合施用所述化合物以预防或治疗自身免疫性或炎症性疾病。用于这样的药物组合物中的主题技术的化合物的非限制性实例是包含以下各项的那些:
(i)所述第一多肽包含SEQ ID NO:5的氨基酸序列并且所述第二多肽包含SEQ IDNO:6的氨基酸序列;或
(ii)所述第一多肽包含SEQ ID NO:7的氨基酸序列并且所述第二多肽包含SEQ IDNO:8的氨基酸序列;或
(iii)所述第一多肽包含SEQ ID NO:9的氨基酸序列并且所述第二多肽包含SEQID NO:10的氨基酸序列;或
(iv)所述第一多肽包含SEQ ID NO:11的氨基酸序列并且所述第二多肽包含SEQID NO:12的氨基酸序列;或
(v)所述第一多肽包含SEQ ID NO:13的氨基酸序列并且所述第二多肽包含SEQ IDNO:14的氨基酸序列;或
(vi)所述第一多肽包含SEQ ID NO:15的氨基酸序列并且所述第二多肽包含SEQID NO:16的氨基酸序列;或
(vii)所述第一多肽包含SEQ ID NO:17的氨基酸序列并且所述第二多肽包含SEQID NO:18的氨基酸序列;或
(viii)所述第一多肽包含SEQ ID NO:19的氨基酸序列并且所述第二多肽包含SEQID NO:20的氨基酸序列;或
(ix)所述第一多肽包含SEQ ID NO:21的氨基酸序列并且所述第二多肽包含SEQID NO:22的氨基酸序列;或
(x)所述第一多肽包含SEQ ID NO:23的氨基酸序列并且所述第二多肽包含SEQ IDNO:24的氨基酸序列;或
(xi)所述第一多肽包含SEQ ID NO:25的氨基酸序列并且所述第二多肽包含SEQID NO:26的氨基酸序列;或
(xii)所述第一多肽包含SEQ ID NO:27的氨基酸序列并且所述第二多肽包含SEQID NO:28的氨基酸序列;或
(xiii)所述第一多肽包含SEQ ID NO:29的氨基酸序列并且所述第二多肽包含SEQID NO:30的氨基酸序列;或
(xiv)所述第一多肽包含SEQ ID NO:31的氨基酸序列并且所述第二多肽包含SEQID NO:32的氨基酸序列;或
(xv)所述第一多肽包含SEQ ID NO:33的氨基酸序列并且所述第二多肽包含SEQID NO:34的氨基酸序列;或
(xvi)所述第一多肽包含SEQ ID NO:35的氨基酸序列并且所述第二多肽包含SEQID NO:36的氨基酸序列;或
(xvii)所述第一多肽包含SEQ ID NO:37的氨基酸序列并且所述第二多肽包含SEQID NO:38的氨基酸序列;或
(xviii)所述第一多肽包含SEQ ID NO:39的氨基酸序列并且所述第二多肽包含SEQ ID NO:40的氨基酸序列;或
(xix)所述第一多肽包含SEQ ID NO:41的氨基酸序列并且所述第二多肽包含SEQID NO:42的氨基酸序列;或
(xx)所述第一多肽包含SEQ ID NO:43的氨基酸序列并且所述第二多肽包含SEQID NO:44的氨基酸序列;或
(xxi)所述第一多肽包含SEQ ID NO:45的氨基酸序列并且所述第二多肽包含SEQID NO:46的氨基酸序列;或
(xxii)所述第一多肽包含SEQ ID NO:47的氨基酸序列并且所述第二多肽包含SEQID NO:48的氨基酸序列;或
(xxiii)所述第一多肽包含SEQ ID NO:49的氨基酸序列并且所述第二多肽包含SEQ ID NO:50的氨基酸序列;或
(xxiv)所述第一多肽包含SEQ ID NO:51的氨基酸序列并且所述第二多肽包含SEQID NO:52的氨基酸序列;或
(xxv)所述第一多肽包含SEQ ID NO:53的氨基酸序列并且所述第二多肽包含SEQID NO:54的氨基酸序列;或
(xxvi)所述第一多肽包含SEQ ID NO:55的氨基酸序列并且所述第二多肽包含SEQID NO:56的氨基酸序列;或
(xxvii)所述第一多肽包含SEQ ID NO:57的氨基酸序列并且所述第二多肽包含SEQ ID NO:58的氨基酸序列;或
(xxviii)所述第一多肽包含SEQ ID NO:59的氨基酸序列并且所述第二多肽包含SEQ ID NO:60的氨基酸序列;或
(xxix)所述第一多肽包含SEQ ID NO:61的氨基酸序列并且所述第二多肽包含SEQID NO:62的氨基酸序列;或
(xxx)所述第一多肽包含SEQ ID NO:63的氨基酸序列并且所述第二多肽包含SEQID NO:64的氨基酸序列;或
(xxxi)所述第一多肽包含SEQ ID NO:65的氨基酸序列并且所述第二多肽包含SEQID NO:66的氨基酸序列;或
(xxxii)所述第一多肽包含SEQ ID NO:67的氨基酸序列并且所述第二多肽包含SEQ ID NO:68的氨基酸序列。
如本文所用,术语“药物组合物”指的是本文所述的化合物与药学上可接受的载体组合的制剂。所述药物组合物还可以包含另外的试剂(例如为了特异性递送、延长半衰期、或其他治疗性化合物)。
如在此所用的术语“药学上可接受的载体”意指药学上可接受的材料、组合物或媒介物,如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石粉硬脂酸镁、硬脂酸钙或硬脂酸锌、或硬脂酸)、或溶剂封装材料,它涉及将化合物从身体的一个部位(例如递送部位)运送或输送到另一个部位(例如器官、组织或身体的一部分)。药学上可接受的载体在与制剂的其他成分相容并且对受试者的组织无害(例如生理学上相容、无菌、生理pH值等)的意义上是“可接受的”。可以用作药学上可接受的载体的材料的一些实例包括:(1)糖,如乳糖、葡萄糖以及蔗糖;(2)淀粉,如玉米淀粉和马铃薯淀粉;(3)纤维素和它的衍生物,如羧甲基纤维素钠、甲基纤维素、乙基纤维素、微晶纤维素以及乙酸纤维素;(4)粉状黄蓍胶;(5)麦芽;(6)明胶;(7)润滑剂,如硬脂酸镁、月桂基硫酸钠以及滑石粉;(8)赋形剂,如可可脂和栓剂蜡;(9)油,如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油以及大豆油;(10)二醇,如丙二醇;(11)多元醇,如甘油、山梨糖醇、甘露糖醇以及聚乙二醇(PEG);(12)酯,如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,如氢氧化镁和氢氧化铝;(15)藻酸;(16)无热原水;(17)等渗盐水;(18)林格氏溶液(Ringer's solution);(19)乙醇;(20)pH缓冲溶液;(21)聚酯、聚碳酸酯和/或聚酐;(22)膨胀剂,如多肽和氨基酸;(23)血清组分,如血清白蛋白、HDL以及LDL;(22)C2-C12醇,如乙醇;以及(23)用于药物制剂中的其他无毒的相容物质。润湿剂、着色剂、脱模剂、包衣剂、甜味剂、调味剂、加香剂、防腐剂以及抗氧化剂也可以存在于制剂中。诸如“赋形剂”、“载体”、“药学上可接受的载体”等术语在本文可互换使用。
在一些实施方案中,通过注射、借助于导管、借助于栓剂、或借助于植入物来施用组合物中的主题技术的化合物,所述植入物具有多孔、无孔、或凝胶状材料,包括膜,如硅橡胶膜、或纤维。通常,当施用所述组合物时,使用不吸收主题技术的化合物的材料。
在其他实施方案中,在受控释放系统中递送主题技术的化合物。在一个实施方案中,可以使用泵(参见例如Langer,1990,Science 249:1527-1533;Sefton,1989,CRCCrit.Ref.Biomed.Eng.14:201;Buchwald等人,1980,Surgery 88:507;Saudek等人,1989,N.Engl.J.Med.321:574)。在另一个实施方案中,可以使用聚合物材料。(参见例如MedicalApplications of Controlled Release(Langer和Wise编著,CRC Press,Boca Raton,Fla.,1974);Controlled Drug Bioavailability,Drug Product Design andPerformance(Smolen和Ball编著,Wiley,New York,1984);Ranger和Peppas,1983,Macromol.Sci.Rev.Macromol.Chem.23:61。还参见Levy等人,1985,Science 228:190;During等人,1989,Ann.Neurol.25:351;Howard等人,1989,J.Neurosurg.71:105。)其他受控释放系统论述于例如Langer(同上)中。
主题技术的化合物可以作为药物组合物来施用,所述药物组合物包含治疗有效量的结合剂和一种或多种药学上相容的成分。
在典型的实施方案中,根据常规程序将所述药物组合物配制成适合于向受试者,例如人静脉内或皮下施用的药物组合物。通常,用于通过注射施用的组合物是于无菌等渗水性缓冲液中的溶液。在必要时,所述药物还可以包括增溶剂和局部麻醉剂,如利多卡因(lignocaine)以缓解注射部位的疼痛。一般来说,所述成分是以单位剂型单独供应的或混合在一起供应的,例如指示活性剂的量的诸如安瓿或小药囊的密封容器中的干燥的冻干粉末或无水浓缩物。在所述药物要通过输注来施用的情况下,可以将它用容纳无菌医药级水或盐水的输注瓶来分配。在所述药物通过注射施用的情况下,可以提供无菌注射用水或盐水的安瓿以在施用之前可以混合所述成分。
用于全身施用的药物组合物可以是液体,例如无菌盐水、乳酸林格氏溶液或汉克斯氏溶液(Hank's solution)。此外,药物组合物可以呈固体形式并且在临用前重新溶解或悬浮。冻干形式也被考虑。
所述药物组合物可以被容纳在脂质颗粒或囊泡,如脂质体或微晶内,它也适用于肠胃外施用。所述颗粒可以具有任何合适的结构,如单层或多层,只要组合物被容纳在其中即可。化合物可以被包封在‘稳定化的质粒-脂质颗粒’(SPLP)中,所述SPLP含有融合脂质二油酰基磷脂酰乙醇胺(DOPE)、低水平(5摩尔%-10摩尔%)的阳离子脂质,并且通过聚乙二醇(PEG)包衣稳定化(Zhang Y.P.等人,Gene Ther.1999,6:1438-47)。带正电荷的脂质,如N-[1-(2,3-二油酰氧基)丙基]-N,N,N-三甲基-铵甲基硫酸盐或“DOTAP”对于这样的颗粒和囊泡来说是特别优选的。这样的脂质颗粒的制备是公知的。参见例如美国专利号4,880,635;4,906,477;4,911,928;4,917,951;4,920,016;以及4,921,757。
本公开的药物组合物可以作为例如单位剂量被施用或包装。当在提到本公开的药物组合物时使用时术语“单位剂量”指的是适合作为单位剂量用于受试者的物理离散单位,每一个单位含有经过计算以产生所期望的治疗作用的预定量的活性材料联同所需要的稀释剂,即载体或媒介物。
在一些实施方案中,本文所述的化合物可以与治疗部分,例如抗炎剂缀合。用于使这样的治疗部分与包括例如Fc结构域的多肽缀合的技术是公知的;参见例如Amon等人,“Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”,Monoclonal Antibodies And Cancer Therapy,Reisfeld等人(编著),1985,第243-56页,Alan R.Liss公司;Hellstrom等人,“Antibodies For Drug Delivery”,Controlled DrugDelivery(第2版),Robinson等人(编著),1987,第623-53页,Marcel Dekker Inc.);Thorpe,“Antibody Carriers Of Cytotoxic Agents In Cancer Therapy:A Review”,Monoclonal Antibodies'84:Biological And Clinical Applications,Pinchera等人(编著),1985,第475-506页);“Analysis,Results,And Future Prospective Of TheTherapeutic Use Of Radiolabeled Antibody In Cancer Therapy”,MonoclonalAntibodies For Cancer Detection And Therapy,Baldwin等人(编著),1985,第303-16页,Academic Press;以及Thorpe等人(1982)“The Preparation And CytotoxicProperties Of Antibody-Toxin Conjugates”,Immunol.Rev.,62:119-158。
此外,所述药物组合物可以作为药物试剂盒来提供,所述药物试剂盒包括(a)容纳呈冻干形式的主题技术的化合物的容器;以及(b)容纳用于注射的药学上可接受的稀释剂(例如无菌水)的第二容器。药学上可接受的稀释剂可以用于复水或稀释主题技术的冻干化合物。任选地,告示可以与所述一个或多个容器结合,所述告示呈监管药物或生物制品的制造、使用或销售的政府机构所规定的形式,所述告示反映了由所述机构批准制造、使用或销售以用于人施用。
在另一个方面,包括含有可用于治疗上文所述的疾病的材料的制品。在一些实施方案中,所述制品包括容器和标签。合适的容器包括例如瓶子、小瓶、注射器、以及试管。所述容器可以由多种材料,如玻璃或塑料形成。在一些实施方案中,所述容器容纳有效治疗本文所述的疾病的组合物并且可以具有无菌存取口。举例来说,所述容器可以是具有可由皮下注射针刺穿的塞子的静脉内溶液袋或小瓶。组合物中的活性剂是主题技术的化合物。在一些实施方案中,容器上或与容器结合的标签指示了所述组合物用于治疗所选择的疾病。所述制品还可以包括第二容器,所述第二容器包括药学上可接受的缓冲液,如磷酸盐缓冲盐水、林格氏溶液、或右旋糖溶液。它还可以包括从商业和使用者的观点来看所期望的其他材料,包括其他缓冲液、稀释剂、过滤器、针、注射器、以及具有使用说明书的包装插页。
在没有进一步详细描述的情况下,认为本领域技术人员可以基于上述说明将本公开利用到它的最大程度。以下具体实施方案因此仅应当被视作是说明性的,而无论如何不会以任何方式限制本公开的其余部分。本文所引用的所有出版物以引用的方式并入本文用于本文所提到的目的或主题。
实施例
实施例1:构建靶向IL23A和BAFF的示例性化合物
通过本领域已知的重组方法产生主题技术的化合物(参见例如PCT公开WO 2006/113665、WO 2008/157379、以及WO 2010/080538,所有这些PCT公开的内容以引用的方式并入本文)。表2A提供了以下实施例中所利用的结合IL23A和BAFF这两者的示例性化合物。简单地说,使用FreeStyle MAX试剂(CHO)将编码每一种化合物的第一多肽和第二多肽的质粒共同转染到CHO-S细胞中。将所述细胞培养13天-14天并且使用蛋白A色谱法纯化由所述细胞产生的化合物。使用尺寸排阻色谱法进一步纯化所述化合物。
表2A:示例性IL23A和BAFF结合化合物
VL=可变结构域轻链,VH=可变结构域重链,每一条链在VL与VH之间包含接头GGGSGGG(SEQ ID NO:69)。
还使用对照抗体以用于实现比较的目的。所述对照是靶向BAFF或IL23的单克隆抗体。
表2B:对照抗体/拮抗剂
实施例2:化合物的热稳定性
方法
经由自动化毛细管DSC(MicroCal,LLC,Boston)以60℃/小时的扫描速率从20℃到110℃监测2mg/ml化合物于磷酸盐缓冲液中的溶液的热解折叠和聚集。用相应的缓冲液进行两次扫描以建立仪器热史并且获得每一个样品的仪器基线,其中将这些扫描的平均值从后续的蛋白质热谱中减去以获得表观热容。然后使用Origin 7.0分析归一化的扫描。将转变前基线从每一个所得的热容热谱中减去,得到作为温度的函数的所得的过剩热容(Cp,ex)。转变温度(Tm)的报告值表示通过目视检查实验热谱所确定的峰最大值的位置。
结果
结果示于表3中。数据显示靶向IL23A和BAFF的示例性化合物具有一系列第一峰转变温度(Tm1),范围为51.59℃至71.25℃。结果是惊人的,这是因为所述示例性化合物均具有相同的总体结构并且含有相同的靶向IL-23A的VH基因序列和VL基因序列。具有更高的转变温度的化合物更稳定并且被预测具有长的保存期。
表3:化合物的热解折叠转变温度
实施例3:示例性化合物的表面等离子体共振(SPR)亲和力
通过SPR分析测试化合物以确定对BAFF和IL23A的亲和力。
材料和方法:
在ProteOn XPR36仪器(Bio Rad)上进行SPR实验。在垂直方向和水平方向上以30微升/分钟的流速连续注入60秒的0.5%SDS、50mM NaOH、以及100mM HCl来预处理GLM芯片。
然后通过在6个水平通道中注入1:1比率的EDC(76.7mg/ml)和磺基-NHS(21.7mg/ml)的混合物来活化预处理的GLM芯片。将于10mM的pH 5.0乙酸钠缓冲液中30μg/ml浓度的山羊抗人IgG(GAHA)Fcγ(Invitrogen)在6个水平通道中的活化的GLM芯片上固定到8,000个共振单位。最终在6个水平通道中用1M乙醇胺盐酸盐将芯片去活化。将准备好的GAHA芯片旋转到垂直方向以在5个垂直通道上捕捉测试化合物并且使用最后一个通道作为柱参考。
然后将捕捉的芯片再次旋转到水平方向以用于结合。将具有五种浓度10.0nM、5.00nM、2.50nM、1.25nM以及0.625nM的连接的人IL-23(Boehringer IngelheimPharmaceuticals,Inc.)于以下运行缓冲液(Bio Rad)中以40微升/分钟的流速在测试化合物表面上水平注入10分钟:磷酸盐缓冲盐水(pH 7.4)、0.005%Tween 20。允许解离2小时。在10分钟缔合和2小时解离之后,在水平方向和垂直方向上以100微升/分钟的流速使用0.85%磷酸(Bio Rad)的短脉冲注入(18秒)使GAHA表面再生。再生的GAHA准备用于另一个结合循环。以类似的方式进行化合物与食蟹猴IL23、人BAFF或食蟹猴BAFF的结合,但是与人BAFF或食蟹猴BAFF结合的滴定浓度是6.25nM、3.12nM、1.56nM、0.78nM、以及0.39nM。
结果:
表4中的结果显示所测试的化合物均能够以皮摩尔范围内的解离常数(KD)结合BAFF和IL23。
表4:化合物结合BAFF和IL23的亲和力
实施例4:在BAFFR-CHO荧光素酶报告细胞中抑制人和食蟹猴BAFF三聚体诱导的
NFkB激活
材料/方法:
简单地说,收获人BAFFR CHO NFkB荧光素酶报告细胞,将所述细胞洗涤、计数并且以每毫升1.6×106个细胞的浓度重悬在1%(v/v)青霉素/链霉素于X-VIVO15(化学成分确定的无血清培养基)(Lonza)中的测定培养基(AM)中。在AM中以单一浓度(52pM)制备重组人或食蟹猴BAFF三聚体(Boehringer Ingelheim Pharmaceuticals Inc.)并且在加湿的孵育箱中在37℃、5%CO2下与单独的AM或测试化合物的连续滴定液一起预孵育30分钟。在BAFF+测试化合物的预孵育之后,将50μl的一种或多种混合物添加到50μl的细胞中并且将测试板在37℃(如所述)进一步孵育24小时。对照样品接受AM(未刺激对照)或在AM中稀释的重组BAFF三聚体(刺激对照)。在孵育24小时之后,遵循制造商的说明书用100μl STEADY-Glo试剂(Promega)处理细胞悬浮液,并且测定荧光素酶表达。绘制所得的相对发光单位(RLU)与测试化合物的Log10纳摩尔浓度的关系图,其中使用由Excel插件Xlfit(ID BusinessSolutions Limited)支持的4参数逻辑模型计算IC50值和IC90值。如上文所述计算测试化合物的IC50值和IC90值并且通过多次实验计算几何平均值并且示于表5和表6中。
结果:
测试化合物以剂量依赖性方式在BAFFR-CHO荧光素酶报告细胞中抑制人和食蟹猴BAFF三聚体诱导的NFkB激活。表5和表6中所示的结果表明测试化合物的IC50几何平均值和IC90几何平均值与对照BAFF拮抗剂相比是相当的或更强效。
表5:在BAFFR-CHO报告细胞中抑制人BAFF三聚体的IC50几何平均值和IC90几何平均值
表6:在BAFFR-CHO报告细胞中抑制食蟹猴BAFF三聚体的IC50几何平均值和IC90几何平均值
实施例5:在TACI-CHO荧光素酶报告细胞中抑制人BAFF三聚体诱导的NFkB激活
材料/方法:
简单地说,收获人TACI CHO NFkB荧光素酶报告细胞,将所述细胞洗涤、计数并且以每毫升1.6×106个细胞的浓度重悬在1%(v/v)青霉素/链霉素于X-VIVO15(化学成分确定的无血清培养基)(Lonza)中的测定培养基(AM)中。在AM中以单一浓度(222pM)制备重组人BAFF三聚体(Boehringer Ingelheim Pharmaceuticals,Inc)并且在加湿的孵育箱中在37℃、5%CO2下与单独的AM或测试化合物的连续滴定液一起预孵育30分钟。在BAFF+测试化合物的预孵育之后,将50μl的一种或多种混合物添加到50μl的细胞中并且将测试板在37℃(如所述)进一步孵育24小时。对照样品接受AM(未刺激对照)或在AM中稀释的重组人BAFF三聚体(刺激对照)。在孵育24小时之后,遵循制造商的说明书用100μl STEADY-Glo试剂(Promega)处理细胞悬浮液,并且测定荧光素酶表达。绘制所得的相对发光单位(RLU)与测试化合物的Log10纳摩尔浓度的关系图,其中使用由Excel插件Xlfit(ID BusinessSolutions Limited)支持的4参数逻辑模型计算IC50值和IC90值。如上文所述计算测试化合物的IC50值和IC90值并且通过多次实验计算几何平均值并且示于表7中。
结果:
测试化合物以剂量依赖性方式在TACI-CHO荧光素酶报告细胞中抑制人BAFF三聚体诱导的NFkB激活。表7中所示的结果表明测试化合物的IC50几何平均值和IC90几何平均值与对照BAFF拮抗剂相比是相当的或更强效。
表7:在TACI-CHO报告细胞中抑制人BAFF三聚体的IC50几何平均值和IC90几何平均值
实施例6:在BAFFR-CHO荧光素酶报告细胞中抑制BAFF 60聚体诱导的NFkB激活
材料/方法:
简单地说,收获人BAFFR CHO NFkB荧光素酶报告细胞,将所述细胞洗涤、计数并且以每毫升1.6×106个细胞的浓度重悬在1%(v/v)青霉素/链霉素于X-VIVO15(化学成分确定的无血清培养基)(Lonza)中的测定培养基(AM)中。在AM中以单一浓度(4.2pM)制备重组人BAFF 60聚体(Boehringer Ingelheim Pharmaceuticals,Inc)并且在加湿的孵育箱中在37℃、5%CO2下与单独的AM或测试化合物的连续滴定液一起预孵育30分钟。在BAFF+测试化合物的预孵育之后,将50μl的一种或多种混合物添加到50μl的细胞中并且将测试板在37℃(如所述)进一步孵育24小时。对照样品接受AM(未刺激对照)或在AM中稀释的重组人BAFF60聚体(刺激对照)。在孵育24小时之后,遵循制造商的说明书用100μl STEADY-Glo试剂(Promega)处理细胞悬浮液,并且测定荧光素酶表达。绘制所得的相对发光单位(RLU)与测试化合物的Log10纳摩尔浓度的关系图,其中使用由Excel插件Xlfit(ID BusinessSolutions Limited)支持的4参数逻辑模型计算IC50值和IC90值。如上文所述计算测试化合物的IC50值和IC90值并且通过多次实验计算几何平均值并且示于表8中。
结果:
测试化合物以剂量依赖性方式在BAFFR-CHO荧光素酶报告细胞中抑制人BAFF 60聚体诱导的NFkB激活。表8中所示的结果表明测试化合物A、B、C、D、O、P、Q以及R的IC50几何平均值和IC90几何平均值比所有三种对照BAFF拮抗剂更强效。
表8:在BAFFR-CHO报告细胞中抑制人BAFF 60聚体的IC50几何平均值和IC90几何平均值
实施例7:在BAFFR-CHO荧光素酶报告细胞中中和膜结合BAFF诱导的NFkB激活
材料/方法
将表达人BAFF的CHO-K1细胞计数并且以每毫升2×106个细胞的浓度重悬在标准生长培养基中。为了停止膜结合BAFF的切割,将细胞用0.125%多聚甲醛(ElectronMicroscopy)处理并且在室温下孵育1小时。然后将固定的人BAFF CHO-K1细胞洗涤并且以每毫升2×106个细胞重悬在标准生长培养基中并且在37℃、5%CO2下孵育过夜。然后收获固定的人BAFF CHO-K1细胞并且以每毫升3.2×106个细胞的浓度重悬在含有1%青霉素/链霉素(v/v)的X-VIVO15化学成分确定的无血清(Lonza)测定培养基(AM)中。
收获人BAFFR CHO NFkB荧光素酶报告细胞,洗涤,并且以每毫升1.6×106个细胞的浓度重悬在测定培养基中。然后将在AM中以每毫升3.2×106个细胞制备并且与测试化合物的连续滴定液一起预孵育30分钟的固定的人BAFF CHO-K1细胞添加到50μl的人BAFFRCHO NFkB荧光素酶报告细胞中并且在37℃进一步孵育24小时。对照报告细胞接受单独的AM(未刺激对照)或在AM中稀释的固定的人BAFF CHO-K1细胞(刺激对照)。在孵育24小时之后,用100μl STEADY-Glo试剂(Promega)处理样品,并且测定荧光素酶表达。绘制相对发光单位(RLU)与测试化合物的Log10纳摩尔浓度的关系图,其中使用由Excel插件Xlfit(IDBusiness Solutions Limited)支持的4参数逻辑模型计算IC50值和IC90值。如上文所述计算测试化合物的IC50值和IC90值并且通过多次实验计算几何平均值并且示于表9中。
结果
测试化合物以剂量依赖性方式在BAFFR-CHO荧光素酶报告细胞中抑制膜结合人BAFF诱导的NFkB激活。表9中所示的结果表明测试化合物的IC50值和IC90值比所有三种对照BAFF拮抗剂更强效。
表9:在BAFFR-CHO报告细胞中抑制mbBAFF的IC50几何平均值和IC90几何平均值
实施例8:在具有STAT3荧光素酶报告基因的成淋巴细胞B细胞(DB细胞)中抑制人
IL-23活性
材料/方法
用慢病毒STAT-3/荧光素酶报告基因(Qiagen)稳定转导成淋巴细胞B细胞(DB细胞;ATCC目录号:CRL-2289)。将转导的细胞保持在使用嘌呤霉素(Life Technologies)进行的选择下。完全培养基是补充有10%FBS(Hyclone)和2μg/mL嘌呤霉素(LifeTechnologies)的RPMI-1640培养基(Life Technologies)。测定培养基是补充有10%FBS(Hyclone)的RPMI-1640培养基(Life Technologies)。
将工程改造的DB-STAT3细胞以20,000个细胞/孔于测定培养基中以80微升/孔接种到白色平底96孔板中。在聚丙烯圆底96孔板中在测定培养基中制备测试化合物(10×),并且相应地稀释以产生1μg/mL至10pg/mL的剂量范围。将10μL的稀释过的测试分子或测定培养基(对照孔)按一式三份添加到每一个孔中。将10μL的10×人IL-23(达到每板75ng/mL的最终浓度)添加到每一个孔中。或者,将10μL的培养基添加到对照孔中。被选用于测定中的IL-23剂量代表如在先前的研究中所确定的人IL-23对DB工程改造细胞的EC60刺激剂量。将板在37℃下在5%CO2中孵育过夜。制备ONE-GloTM荧光素酶测定试剂(Promega)并且将100μL添加到每一个孔中并且混合。在Envision板读数器上测量发光,然后相对于抗体浓度(x轴)作图(y轴)。通过使用GraphPad Prism 6软件将数据应用于4参数S形剂量-反应函数来确定化合物的IC50值。通过使用GraphPad Prism 6软件以Find ECanything计算数据来确定IC90值。通过多次实验计算几何平均值并且示于表10中。
结果
结果显示测试化合物能够在具有STAT3荧光素酶报告基因的DB细胞中抑制人IL-23活性。
表10:在成淋巴细胞B细胞中抑制人IL-23的IC50几何平均值和IC90几何平均值
实施例9:在小鼠脾细胞中抑制人和食蟹猴IL-23活性
材料和方法
分离来自小鼠脾脏(雌性C57BL/6,不到13周龄;Jackson Laboratories)的单核细胞,将所述单核细胞洗涤,计数,并且在标准T细胞培养基(TCM)中重悬到4×106个细胞/毫升。将100微升的mIL-2/脾细胞悬浮液添加到96孔微量滴定板中。将重组人IL-23(Boehringer Ingelheim Pharmaceuticals,Inc)或重组食蟹猴IL-23(BoehringerIngelheim Pharmaceuticals,Inc)在TCM中稀释并且在37℃下与单独的TCM或测试样品的滴定液一起预孵育2小时。在测试样品+IL-23的预孵育之后,将100μl的混合物添加到细胞中并且在37℃下将测试板在5%CO2-加湿空气下孵育48小时。对照样品接受TCM(未刺激对照)或在TCM中稀释的重组IL-23(刺激对照)。在孵育之后,使用小鼠IL-17免疫测定,根据制造商的说明书(R&D Systems)从上清液中确定小鼠IL-17水平。确定每一个样品的内插mIL-17pg/ml值并且转换成相对于对照的百分比(POC)。绘制POC与测试样品的浓度的关系图,并且使用通过Excel插件XLfit(Activity Base软件,ID BusinessSolutions Ltd)实现的4参数逻辑模型来计算IC90值。关于如上文所述的IC50和IC90分析测试化合物,并且通过多次实验计算每一种测试化合物的几何平均值并且示于表11中。
结果
结果显示测试化合物能够抑制人IL23和食蟹猴IL23这两者诱导的小鼠脾细胞的小鼠IL-17释放。
表11:在小鼠脾细胞中抑制人和食蟹猴IL-23的IC50几何平均值和IC90几何平均值
实施例10:在食蟹猴中化合物的药物代谢动力学
材料和方法:
在雄性食蟹猴(每种分子n=2)中对测试化合物A、B、C、以及D进行单次静脉内(IV)剂量PK研究。剂量是作为缓慢的1mg/kg静脉内推注施用的。在给药前以及在给药当天给药后0.25小时、2小时和6小时以及在给药后1天、2天、3天、4天、7天、10天、14天、21天、以及28天收集全血样品。通过基于MSD的配体结合测定来测量所给予的分子的血清浓度。
在100%汇集的食蟹猴血清中制备校准标准曲线和质量控制(QC)样品。每一个标准曲线由从512ng/mL开始,然后连续稀释三倍的七个非零点组成。还包括空白样品(没有分析物的基质)。从256ng/mL开始制备低范围、中范围、以及高范围的五个QC样品,然后连续稀释四倍到8ng/mL,然后使用2倍稀释液制备4ng/mL的最低QC。在每一次分析运行期间按一式两份包括标准曲线和QC样品。定量的下限和上限被定义为具有不超过标称浓度的百分之(%)30的可再现的反算浓度的最低QC点和最高QC点。标准曲线点的接受标准是标称浓度的百分之(%)30。
为了测量血清样品中的活性药物浓度,制备主混合物,从而在结合缓冲液(于含有0.05%Tween 20的1×PBS中5%的BSA)中组合0.5μg/mL的生物素化的重组人BAFF和0.5μg/mL的磺基标记的山羊抗人IgG检测。将主混合物以每孔50μL添加到96孔非结合和遮光板中。将每孔25μL的标准品和QC(在结合缓冲液中1:20稀释的原液)按一式两份添加到容纳主混合物的非结合板中。将未知的血清样品在结合缓冲液中1:20稀释并且在含有5%血清的结合缓冲液中1:400稀释。将每孔25μL的稀释过的样品添加到容纳主混合物的非结合板中。将非结合板在板振荡器上在室温下孵育(500rpm,1.5小时)。同时,使用150μL封闭缓冲液(含有0.05%Tween 20的1×PBS中5%的BSA)封闭MSD链霉亲和素金板并且在室温下在板振荡器上孵育(500rpm,1.5小时)。在孵育之后,用每孔300μL的洗涤缓冲液(于1×PBS中0.05%的Tween 20)将MSD板洗涤三次。将50μL的来自非结合板的样品添加到MSD板中并且在室温下孵育(1.5小时,600rpm)。在孵育之后,用洗涤缓冲液将板洗涤三次,并且将150μL的2×读数缓冲液T添加到每一个孔中并且立即在MSD Sector成像仪2400上读数。使用MSDDiscovery Workbench软件将标准曲线拟合成四参数逻辑方程。在Phoenix WinNonlin 6.3(Certara,MD,USA)中使用非隔室分析计算药代动力学参数。
结果:
测试化合物的平均(SD)血清浓度相对于时间的曲线示于图2中。测试化合物的平均(SD)药物代谢动力学参数汇总于表12中。被确认为抗药物抗体阳性的显示出药物浓度随时间推移急剧下降的血清样品被排除在药物代谢动力学参数计算以外。
表12:在雄性食蟹猴中在单次1mg/kg静脉内剂量之后测试化合物的平均(SD)药物代谢动力学参数
实施例11:预测示例性化合物的人PK和人剂量
使用基本Dedrick按比例缩放以使用1.0(分布体积)和0.85(清除率)的异速指数将化合物B的平均猴血清浓度按比例缩放到人。将预测的人静脉内血清浓度-时间曲线拟合成线性双隔室模型。通过将来自双隔室静脉内模型的参数与对于市售的治疗性mAb所观测到的平均皮下吸收速率和生物利用度相组合来预测人皮下血清浓度-时间曲线。预测在健康人中清除率和终末半衰期分别是0.34L/d和9.9d。在每两周一次施用100mg皮下剂量后化合物B的预测人血清浓度-时间曲线示于图3中。
预测的人有效剂量是每两周一次皮下递送的1mg/kg。预测该剂量方案在每两周一次或更不频繁的皮下施用的情况下维持Cmin≥30nM(6μg/mL)。预测的有效剂量可以基于在SLE患者和RA患者中对于贝利单抗他巴卢单抗(tabalumab)以及布斯莫徳(blisibimod)所观测到的浓度-PD生物标志物反应。在这些研究中,对BAFF相关生物标志物的最大抑制与30nM-40nM的稳态Cmin有关。中和IL23所需的浓度比中和BAFF所需的浓度低得多,并且因此不影响双重拮抗剂的总体所需Cmin。
实施例12:化合物的纯化
方法:
使用Mab Select SuRe作为亲和纯化步骤来纯化化合物。
使用乙酸钠缓冲液(pH 3.5)进行洗脱。在Mab Select SuRe纯化之后,中和样品并且将所述样品施加于Poros 50HS树脂并且使用于柠檬酸钠缓冲液中氯化钠的梯度来洗脱。单体峰在20mM柠檬酸钠和120mM NaCl(pH 6.0)处洗脱。在离子交换色谱后,样品始终是>95%单体。
使用经由分析超速离心(AUC)进行的沉降速度(SV)实验来提供有关样品纯度和聚集状态的信息。在optima XL-I(Beckman Coulter,Fullerton,CA)中在20℃使用以40,000rpm运行的An60Ti四孔转子将样品离心。使用相应的稀释缓冲液作为参考缓冲液,通过在280nm处的紫外吸光度来监测沉降过程。使用XL-I操作软件收集超速离心池中随时间推移浓度分布的变化并且在SEDFIT软件(14.1版)中使用连续c(S)分布模型分析以得到沉降系数的分布。基于积分峰面积计算单体百分比。
结果:
化合物的纯化的结果示于表13中。数据显示所述化合物具有高纯度和均一性,这表明良好的稳定性。
表13
参数名称 | 化合物A、B、C、D |
单体百分比(沉降速度) | 99%单体/1%聚集体 |
实施例13:化合物的质谱特征
方法:
天然样品
该程序得到了化合物或蛋白质的完整质量。将0.15μl的样品注入到AgilentPoroShell 300SB-C3柱(5μm)(30×1.0mm)上。柱温是80℃并且流速是150微升/分钟。用从10%B(在0分钟)到85%B(在6分钟)的梯度将化合物或蛋白质从柱上洗脱。流动相A是水/乙腈/甲酸/乙酸铵(99/1/0.1/2mM)并且流动相B是正丙醇/乙腈/水/甲酸(70/20/10/0.1)。将流出物引导到Agilent 6224TOF质谱仪中,从质量600到质量3200进行扫描。使用程序MassHunter对原始数据解卷积。
还原样品
该程序得到了蛋白质或轻链的质量以及重链的质量。将5μl的样品添加到5μL的8M盐酸胍:TCEP的20:1混合物中并且在室温下孵育15分钟。如上注入0.15μl的该样品,有以下不同之处:使用从5%B(在0分钟)到85%B(在6分钟)的梯度将化合物或蛋白质从柱上洗脱,柱温是60℃并且质量范围是600-2000。
去糖基化样品
该程序得到了蛋白质或轻链和重链的去糖基化的质量。将7.5μl的样品添加到3.2μL的400mM碳酸氢铵:PNG酶F的20:1混合物中并且在37℃孵育3小时。然后,将10μl的8M盐酸胍:TCEP的20:1混合物添加到样品中并且在室温下孵育15分钟。如上文对于还原样品所述注入该样品。
通过质谱进行的肽作图
将样品稀释到由6M GdHCl、250mM Tris-HCL(pH 7.5)以及10mM DTT组成的变性缓冲液中,然后在37℃孵育30分钟。然后使用碘乙酰胺将样品烷基化,并且在暗处在室温下孵育30分钟。使用葡聚糖凝胶G-25超细滤筒将反应混合物纯化并且缓冲液交换到100mMTris-HCL(pH 7.5)中。然后在37℃下4小时孵育期间使用胰蛋白酶消化样品。随后通过添加TFA淬灭消化的反应混合物。
经由Dionex Ultimate 3000HPLC的自动进样器将所获得的胰蛋白酶消化物注入到Phenomenex Jupiter C18反相柱上。利用梯度溶剂体系,所述梯度溶剂体系由溶剂A:0.1%甲酸/99%水/1%乙腈以及溶剂B:0.1%甲酸/5%水/95%乙腈组成。溶剂B的百分比在140分钟内从0%增加到38%。在室温下以100微升/分钟的流速进行色谱分离。自动进样器中的样品储存在4℃。在色谱分离之后,样品进入以正离子电喷雾电离模式操作的ThermoScientific Orbitrap Fusion质谱仪中。所使用的方法包括利用30,000的分辨率、10,000的最小信号、1.0的隔离宽度以及35.0V的归一化的碰撞能的活化类型的CID。S-透镜RF水平被设定在20%。数据收集类型是全MS扫描的轮廓质谱图和CID MS/MS数据的棒状质谱图(centroid)。在250Da-2000Da的质量范围内以每秒1张光谱的采集速率收集数据。
利用Proteome Discover 1.4(Thermo Scientific)针对给定的序列分析来自酶消化物的收集的原始LC-MS和LC-MS/MS片段化数据。然后通过手动提取糖基化肽的EIC来分析含有N-X-S/T的共有序列(X不是P)的鉴定的肽。使用EIC中糖基化肽的MS强度来估计它们占糖型的总丰度的百分比。
结果:
结果示于表14中。数据表明预期的氨基酸序列和结构已经被表达和回收而没有出乎意料的异质性。糖基化模式是在CHO细胞中表达的常规抗体的典型特征,并且没有显示出任何非典型的结构。
表14:
参数 | 化合物B |
质谱:完整分子量特征 | 完整/匹配序列 |
质谱:糖基化特征 | 类似于CHO表达的IgG |
实施例14:在高浓度下的单体含量
该过程描述的目的在于通过评价在浓度递增的情况下的聚集来评估化合物B的固有特性。使用20mM柠檬酸钠、120mM NaCl(pH6)的标准缓冲液而不进行制剂评估以了解分子聚集的倾向。
方法:
将化合物B逐渐浓缩到尽可能高的浓度而使用具有50,000道尔顿的截止分子量的Amicon超速离心过滤器(Millipore,Billerica)没有观测到沉淀。然后对浓缩的蛋白质溶液进行分析型sec分析以提供有关样品纯度和聚集状态的信息。使用Agilent 1200系列HPLC系统运行色谱。以1.0毫升/分钟将系统运行23分钟。将约30μg的材料注入到TosohBiosciences TSKgel G3000SWXL柱(5μm,250a,7.8cm×30cm)中并且在280nm处读取结果。所使用的运行缓冲液是50mM磷酸钠、0.2M L-精氨酸(pH 6.8)。
结果:
在浓缩过程期间化合物B的分析型SEC数据的汇总列于表15和图4中。呈现了显示在递增浓度下的聚集和样品纯度的数据,表明化合物B在浓度递增的情况下没有聚集的倾向。
表15:在浓缩过程期间化合物B的分析型SEC数据的汇总
M=单体,A=聚集体
实施例15:化合物的化合价
方法:
使用分析型膜约束电泳来测量先前已经透析到10mM乙酸盐50mM KCl(pH 5.0)缓冲液中过夜的化合物的化合价。在实验设置中,将20μL的1mg/mL的样品加入2×2×4mm3的石英比色皿中,该比色皿的两端由10MWCO半透性再生纤维素生物技术级膜密封。这些膜截留大分子,而允许水和溶剂组分通过。然后通过比色皿施加1mA电流,从而沿着它的长度建立电场,其中带电荷的大分子在电场中随着新鲜缓冲液的连续流动而移动。使用沿比色皿间隔的提供强度读数的线性光电二极管阵列(LPDA)检测实时移动浓度边界。使用浓度边界的速度计算电泳迁移率并且随后计算有效化合价。然后使用另外的信息,如斯托克斯半径(Stokes Radius)(从AUC中的沉降速度运行获得)、抗衡离子半径(氯离子是0.122nm)、缓冲液电导(6.35mS)以及离子强度(0.05M)来揭示大分子的潜在化合价。
结果:
化合价数据(参见表16)表明了化合物在溶液中的胶体稳定性,即蛋白质和蛋白质在溶液中的净相互作用。具有大于15的化合价的化合物具有强的净排斥相互作用和以高浓度配制的高潜能。
表16:化合物的化合价数据
实施例16:化合物的全血稳定性
方法
在Octet RED96上开发全血干扰测定以检测在全血(WB)存在下化合物的非特异性结合或脱靶结合的影响。将全血中的化合物溶液和1×动力学运行缓冲液(1×kb)在37℃的温度下孵育48小时。在27℃使用配备有链霉亲和素(SA)生物传感器尖端的Octet RED96(ForteBio,Menlo Park,CA)对孵育的化合物样品进行动力学测量。报告在缓冲液和全血中缔合速率/结合信号的比率。比率<2被认为是显示没有干扰。
结果
结果示于表17中。对于测试化合物没有观测到全血干扰。
表17:化合物的全血结合结果
实施例17:计算机免疫原性的预测
方法
通过利用计算工具,即由EpiVax,Inc(Providence,RI)开发的EpiMatrix来在计算机中预测蛋白质治疗剂的免疫原性。
EpiMatrix包括对T辅助细胞表位以及T-reg表位的预测,其中前者会激发免疫应答,而后者是抑制性的。简单地说,首先将蛋白质序列解析成重叠的9-mer肽框架,其已经被证实是II类HLA结合的核心。基于实验数据或计算预测来评价9-mer肽与八种常见的II类HLA等位基因中的每一种的结合潜能。生成分数以反映9-mer肽与每一种HLA等位基因的结合潜能并且进行归一化以使得有可能在多种HLA等位基因间比较任何9-mer并且使得能够在全局规模上进行免疫原性预测。最后,所述程序生成总‘免疫原性分数’,即tReg调整Epx分数,这是化合物在体内将激发免疫应答的可能性。
结果
结果示于表18中。测试化合物的总免疫原性分数是低的并且预测这些化合物不可能在体内引发强烈的免疫应答。
表18:EpiVax分数
实施例18:在原代人B细胞增殖测定中抑制人BAFF
材料和方法
用于该研究中的正常健康的血液样品(n=3个供体)购自Biological SpecialtyCorporation,Philadelphia,PA。完全培养基是补充有10%FBS(Life Technologies)加上青霉素/链霉素(Life Technologies)的IMDM(Life Technologies)。B细胞分离缓冲液由无菌的无Mg++和Ca++DPBS(Life Technologies)加上2%FBS加上2mM EDTA(LifeTechnologies)组成。
从健康人全血中分离人B细胞
将400mL的肝素化的全血转移到1000mL无菌聚苯乙烯瓶中并且添加等体积的DPBS。将35mL的PBS稀释的血液放置在预先加入50mL聚苯乙烯圆底管中的15mL Ficoll-PaqueTMPlus(GE Healthcare)梯度的顶部上。在室温下将管以2000rpm离心20分钟而不制动。随后,抽吸顶部上清液的三分之二,并且将含有外周血液单核细胞(PBMC)的中间灰色层转移到50mL锥形管中。添加DPBS(无Ca++和Mg++)+2%FBS,达到50mL的体积。将管以1200rpm短暂离心10分钟。将所得的细胞沉淀物用DPBS(无Ca++和Mg++)+2%FBS(洗涤缓冲液)重悬,并且重复离心步骤(1200rpm,10分钟)。将细胞沉淀物在洗涤缓冲液中再次重悬达到50mL。此时测量细胞活力和细胞浓度。
然后将管以1200rpm短暂离心10分钟,并且弃去上清液。将细胞沉淀物用完全培养基重悬并且将细胞浓度调整到5×106个细胞/毫升。将悬浮的细胞放入75cm2组织培养烧瓶中并且在5%CO2孵育箱(在37℃)中孵育过夜。然后通过使用UntouchedTM人B细胞试剂盒(Life Technologies),遵循制造商的方案分离B细胞。在测量细胞浓度和活力之后调整细胞浓度以适用于下游程序。
使用3H-胸苷掺入测定评价B细胞增殖
将B细胞接种到Falcon组织培养96孔圆底板(每孔1×105个细胞/100μL培养基)中。然后,以0.028nM至20nM范围内的4×系列浓度制备测试制品并且用完全培养基以4×浓度(分别是8μg/mL和20ng/mL)制备B细胞刺激物(抗IgM抗体和人BAFF)。将50μL预稀释的测试制品添加到对应的孔中(0.007nM至5nM,最终浓度)。然后,将50μL预稀释的山羊抗人IgM(2μg/mL,最终浓度)和hBAFF(5ng/mL或98pM,最终浓度)添加到相应的孔中(参见图6)。将B细胞在5%CO2 37℃加湿孵育箱中培养72小时。在孵育结束之前18小时,将20μL的1μCi3H-胸苷(Pelkin Elmer)添加到每一个孔中。使用细胞收集器将3H-胸苷掺入的DNA/孔转移到微纤维玻璃过滤板,其中在将板空气干燥至少4小时之后将30μL的闪烁增强剂添加到孔中。使用MicroBeta Topcount测量每一个孔的每分钟计数(cpm)值,并且绘制cpm值(y轴)与测试制品的浓度(x轴)的关系图。
统计分析
通过使用GraphPad Prism 6软件将数据曲线拟合成4参数S形剂量-反应函数来确定IC50和IC90。通过三次实验计算几何平均值并且示于表19中。
结果
结果显示当比较IC50值和IC90值时,化合物B的效力似乎是对照抗体3的约2倍。
表19:在原代人B细胞增殖测定中抑制人BAFF的IC50几何平均值和IC90几何平均值
实施例19:在B10.RIII小鼠中抑制由人BAFF过表达所诱导的B220+B细胞数
材料和方法
简单地说,在第1天,将B10.RIII雌性小鼠(6周-8周龄,Jackson Laboratory)随机分成10组,10只动物/组并且分别给予柠檬酸盐缓冲液(20mM柠檬酸钠、115mM NaCl,pH6.0)或1.3mg/kg、0.4mg/kg以及0.13mg/kg相比于1mg/kg、3mg/kg以及0.1mg/kg的当量摩尔剂量的测试化合物的100μl腹膜内注射。首次接受实验的未处理的小鼠是另外的对照。在处理第1天后立即经由流体动力学注射向小鼠施用单次3mg剂量(1.5mg/mL)的人BAFF微环DNA(System Biosciences),相比于空载体(EV)对照组。在第3天、第6天、第9天以及第12天每72小时重复用柠檬酸盐缓冲液或测试化合物进行腹膜内处理。
在第14天,经由异氟烷(Butler Schein)使小鼠麻醉并且经由颈椎脱臼处死。取出脾脏并且通过流式细胞术分析细胞悬浮液的B220+B细胞。确定每一个处理组的平均数,并且使用单因素方差分析,继而使用杜奈特氏多重比较检验(Dunnett's multiplecomparisons test)计算与对照相比的显著性。结果示于图5中。
结果
结果显示用化合物B处理14天能够显著地抑制人BAFF微环DNA诱导的B220+B细胞的扩增。
实施例20:在C57/Bl6小鼠中抑制人IL23诱导的小鼠IL17A和IL22释放
材料和方法
简单地说,将C57BL/6雌性小鼠(7周-10周龄,Charles River)随机分成8组,8只动物/组并且分别给予柠檬酸盐缓冲液(20mM柠檬酸钠、115mM NaCl,pH 6.0)或1.3mg/kg、0.4mg/kg和0.13mg/kg相比于1mg/kg、3mg/kg和0.1mg/kg的当量摩尔剂量的测试化合物的100μl腹膜内注射。
在测试化合物给药之后1小时,经由异氟烷(Butler Schein)使小鼠麻醉并且向两只耳朵给予0.1%BSA(Sigma)对照或在盐水(Invitrogen)中稀释的15μg/ml(0.3μg)rhIL23(内部产生)的20μl真皮内注射。每天重复真皮内攻击,持续连续2天。在第二次攻击之后24小时,经由颈椎脱臼处死小鼠并且取下每一只耳朵。使用MP Biomedicals Fast-Prep 24匀浆器将耳朵组织在1ml匀浆缓冲液(HBSS(Gibco);0.4%Triton X-100(Sigma);1×SigmaFast蛋白酶抑制剂(Sigma))中匀浆。将匀浆的样品在4C离心10分钟并且收集上清液。使用小鼠IL-17和小鼠IL-22免疫测定,根据制造商的说明书(R&D Systems)测定上清液中小鼠IL17A和IL22的存在。确定每一个样品的内插细胞因子pg/ml值。确定每一个处理组的平均pg/ml水平,并且使用单因素方差分析,继而使用杜奈特氏多重比较检验计算与对照相比的显著性。
结果
图6中的结果显示用单次腹膜内剂量的化合物B处理能够显著地抑制由重组人IL23的两次每日连续真皮内注射所诱导的皮肤中小鼠IL17和IL22的释放。
序列
其他实施方案
本说明书中所公开的所有特征均可以任何组合进行组合。本说明书中所公开的每一个特征均可以被用于相同的、等同的、或类似的目的的替代特征代替。因此,除非另外明确说明,否则所公开的每一个特征只是一系列通用的等同或类似特征的一个实例。
从上述说明,本领域技术人员可以容易地确定本公开的基本特征,并且在不脱离其精神和范围的情况下,可以对本公开作出各种变化和修改以使它适应于各种使用和条件。因此,其他实施方案也落入权利要求书内。
序列表
<110> Boehringer Ingelheim International GmbH
MacroGenics, Inc.
<120> 靶向IL-23A和B细胞激活因子(BAFF)的化合物和其用途
<130> B1204.70008WO00
<140> 尚未指定
<141> 2016-07-21
<150> US 62/196,170
<151> 2015-07-23
<150> US 62/201,067
<151> 2015-08-04
<150> US 62/355,302
<151> 2016-06-27
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50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Thr Phe
130 135 140
Asn Asn Asn Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser
165 170 175
Gln Asn Phe Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly
180 185 190
Thr Ala Ser Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala
210 215 220
Leu Ser Pro Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser Leu Gly
225 230 235 240
Gly Gly Ser Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
245 250 255
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
260 265 270
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
275 280 285
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
290 295 300
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
305 310 315 320
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
325 330 335
Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
340 345 350
Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe
355 360 365
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro
370 375 380
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
385 390 395 400
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
405 410 415
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
420 425 430
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
435 440 445
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
450 455 460
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
465 470 475 480
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
485 490 495
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
500 505 510
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
515 520 525
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
530 535 540
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
545 550 555 560
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
565 570
<210> 8
<211> 349
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 8
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Val 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 Ser Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr
165 170 175
Asn Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr
180 185 190
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile
210 215 220
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly
225 230 235 240
Ser Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser
245 250 255
Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
260 265 270
Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala
275 280 285
Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys
290 295 300
Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
305 310 315 320
Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu
325 330 335
Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345
<210> 9
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 9
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Val 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 Ser Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr
165 170 175
Asn Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr
180 185 190
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile
210 215 220
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly
225 230 235 240
Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu Glu Lys
245 250 255
Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Leu Glu
260 265 270
Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
275 280 285
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
290 295 300
Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val
305 310 315 320
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
325 330 335
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
340 345 350
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
355 360 365
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
370 375 380
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
385 390 395 400
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
405 410 415
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
420 425 430
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
435 440 445
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
450 455 460
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
465 470 475 480
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
485 490 495
Leu Ser Leu Ser Pro Gly
500
<210> 10
<211> 272
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 10
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Thr Phe
130 135 140
Asn Asn Asn Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser
165 170 175
Gln Asn Phe Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly
180 185 190
Thr Ala Ser Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala
210 215 220
Leu Ser Pro Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser Gly Gly
225 230 235 240
Cys Gly Gly Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu
245 250 255
Lys Glu Lys Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu
260 265 270
<210> 11
<211> 504
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 11
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Thr Phe
130 135 140
Asn Asn Asn Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser
165 170 175
Gln Asn Phe Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly
180 185 190
Thr Ala Ser Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala
210 215 220
Leu Ser Pro Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser Gly Gly
225 230 235 240
Cys Gly Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu
245 250 255
Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys
260 265 270
Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
275 280 285
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
290 295 300
Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val
305 310 315 320
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
325 330 335
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
340 345 350
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
355 360 365
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
370 375 380
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
385 390 395 400
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
405 410 415
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
420 425 430
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
435 440 445
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
450 455 460
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
465 470 475 480
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
485 490 495
Lys Ser Leu Ser Leu Ser Pro Gly
500
<210> 12
<211> 270
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 12
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Val 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 Ser Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr
165 170 175
Asn Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr
180 185 190
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile
210 215 220
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly
225 230 235 240
Gly Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu
245 250 255
Lys Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu
260 265 270
<210> 13
<211> 568
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 13
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Val 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 Ser Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr
165 170 175
Asn Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr
180 185 190
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile
210 215 220
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly
225 230 235 240
Ser Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys
245 250 255
Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys
260 265 270
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
275 280 285
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
290 295 300
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
305 310 315 320
Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val
325 330 335
Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
340 345 350
Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
355 360 365
Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val
370 375 380
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
385 390 395 400
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
405 410 415
Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
420 425 430
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
435 440 445
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
450 455 460
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
465 470 475 480
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
485 490 495
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
500 505 510
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
515 520 525
Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val
530 535 540
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
545 550 555 560
Lys Ser Leu Ser Leu Ser Leu Gly
565
<210> 14
<211> 351
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 14
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Thr Phe
130 135 140
Asn Asn Asn Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser
165 170 175
Gln Asn Phe Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly
180 185 190
Thr Ala Ser Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala
210 215 220
Leu Ser Pro Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser Leu Gly
225 230 235 240
Gly Gly Ser Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
245 250 255
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu
260 265 270
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
275 280 285
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
290 295 300
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
305 310 315 320
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln
325 330 335
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345 350
<210> 15
<211> 570
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 15
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Thr Phe
130 135 140
Asn Asn Asn Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser
165 170 175
Gln Asn Phe Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly
180 185 190
Thr Ala Ser Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala
210 215 220
Leu Ser Pro Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser Leu Gly
225 230 235 240
Gly Gly Ser Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
245 250 255
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
260 265 270
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
275 280 285
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
290 295 300
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
305 310 315 320
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
325 330 335
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
340 345 350
Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
355 360 365
Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr
370 375 380
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
385 390 395 400
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
405 410 415
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
420 425 430
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
435 440 445
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
450 455 460
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
465 470 475 480
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
485 490 495
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
500 505 510
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
515 520 525
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
530 535 540
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
545 550 555 560
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
565 570
<210> 16
<211> 349
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 16
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Val 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 Ser Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr
165 170 175
Asn Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr
180 185 190
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile
210 215 220
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly
225 230 235 240
Ser Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser
245 250 255
Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
260 265 270
Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala
275 280 285
Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys
290 295 300
Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
305 310 315 320
Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu
325 330 335
Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345
<210> 17
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 17
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Val 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 Ser Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr
165 170 175
Asn Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr
180 185 190
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile
210 215 220
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly
225 230 235 240
Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu Glu Lys
245 250 255
Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Ser
260 265 270
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly
275 280 285
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr
290 295 300
Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
305 310 315 320
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
325 330 335
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
340 345 350
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
355 360 365
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
370 375 380
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
385 390 395 400
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
405 410 415
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
420 425 430
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
435 440 445
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val
450 455 460
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
465 470 475 480
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
485 490 495
Leu Gly
<210> 18
<211> 272
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 18
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Thr Phe
130 135 140
Asn Asn Asn Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser
165 170 175
Gln Asn Phe Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly
180 185 190
Thr Ala Ser Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala
210 215 220
Leu Ser Pro Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser Gly Gly
225 230 235 240
Cys Gly Gly Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu
245 250 255
Lys Glu Lys Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu
260 265 270
<210> 19
<211> 500
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 19
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Arg Val Ser Cys Lys Ala Ser Gly Gly Thr Phe
130 135 140
Asn Asn Asn Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser
165 170 175
Gln Asn Phe Gln Gly Arg Val Ala Ile Thr Ala Asp Glu Ser Thr Gly
180 185 190
Thr Ala Ser Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Ser Arg Asp Leu Leu Leu Phe Pro His His Ala
210 215 220
Leu Ser Pro Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser Gly Gly
225 230 235 240
Cys Gly Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu
245 250 255
Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys
260 265 270
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
275 280 285
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
290 295 300
Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val
305 310 315 320
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
325 330 335
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
340 345 350
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
355 360 365
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
370 375 380
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
385 390 395 400
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
405 410 415
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
420 425 430
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
435 440 445
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
450 455 460
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
465 470 475 480
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
485 490 495
Leu Ser Leu Gly
500
<210> 20
<211> 270
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 20
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Val 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 Ser Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Trp Val Phe Gly Gly Gly Thr Glu Leu Thr Val Leu Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr
165 170 175
Asn Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr
180 185 190
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile
210 215 220
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly
225 230 235 240
Gly Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu
245 250 255
Lys Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu
260 265 270
<210> 21
<211> 564
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 21
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe
130 135 140
Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn
165 170 175
Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr
210 215 220
Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Ala Ser Thr Lys Gly
225 230 235 240
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
245 250 255
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
260 265 270
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
275 280 285
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
290 295 300
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
305 310 315 320
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
325 330 335
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
340 345 350
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
355 360 365
Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val
370 375 380
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
385 390 395 400
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
405 410 415
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
420 425 430
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
435 440 445
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
450 455 460
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
465 470 475 480
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
485 490 495
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
500 505 510
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
515 520 525
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
530 535 540
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
545 550 555 560
Leu Ser Pro Gly
<210> 22
<211> 348
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 22
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Gly Asn Arg
20 25 30
Leu Ser Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
245 250 255
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
260 265 270
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
275 280 285
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
290 295 300
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
305 310 315 320
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
325 330 335
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345
<210> 23
<211> 495
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 23
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe
130 135 140
Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn
165 170 175
Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr
210 215 220
Val Thr Val Ser Ser Gly Gly Cys Gly Gly Gly Glu Val Ala Ala Cys
225 230 235 240
Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys
245 250 255
Glu Val Ala Ala Leu Glu Lys Leu Glu Pro Lys Ser Ser Asp Lys Thr
260 265 270
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
275 280 285
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg
290 295 300
Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
305 310 315 320
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
325 330 335
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
340 345 350
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
355 360 365
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
370 375 380
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
385 390 395 400
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
405 410 415
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
420 425 430
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
435 440 445
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
450 455 460
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
465 470 475 480
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
485 490 495
<210> 24
<211> 269
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 24
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 Asp Ile Gly Asn Arg
20 25 30
Leu Ser Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly
225 230 235 240
Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys
245 250 255
Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu
260 265
<210> 25
<211> 561
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 25
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe
130 135 140
Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn
165 170 175
Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr
210 215 220
Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Ala Ser Thr Lys Gly
225 230 235 240
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
245 250 255
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
260 265 270
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
275 280 285
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
290 295 300
Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val
305 310 315 320
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
325 330 335
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
340 345 350
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile
355 360 365
Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
370 375 380
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
385 390 395 400
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
405 410 415
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
420 425 430
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
435 440 445
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
450 455 460
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
465 470 475 480
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
485 490 495
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
500 505 510
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
515 520 525
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
530 535 540
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
545 550 555 560
Gly
<210> 26
<211> 348
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 26
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 Asp Ile Gly Asn Arg
20 25 30
Leu Ser Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
245 250 255
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
260 265 270
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
275 280 285
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
290 295 300
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
305 310 315 320
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
325 330 335
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345
<210> 27
<211> 491
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 27
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe
130 135 140
Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn
165 170 175
Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr
210 215 220
Val Thr Val Ser Ser Gly Gly Cys Gly Gly Gly Glu Val Ala Ala Cys
225 230 235 240
Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys
245 250 255
Glu Val Ala Ala Leu Glu Lys Glu Ser Lys Tyr Gly Pro Pro Cys Pro
260 265 270
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
275 280 285
Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val
290 295 300
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
305 310 315 320
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
325 330 335
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
340 345 350
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
355 360 365
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
370 375 380
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
385 390 395 400
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
405 410 415
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
420 425 430
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
435 440 445
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
450 455 460
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
465 470 475 480
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
485 490
<210> 28
<211> 269
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 28
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 Asp Ile Gly Asn Arg
20 25 30
Leu Ser Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly
225 230 235 240
Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys
245 250 255
Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu
260 265
<210> 29
<211> 564
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 29
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe
130 135 140
Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn
165 170 175
Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr
210 215 220
Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Ala Ser Thr Lys Gly
225 230 235 240
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
245 250 255
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
260 265 270
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
275 280 285
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
290 295 300
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
305 310 315 320
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
325 330 335
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
340 345 350
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
355 360 365
Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val
370 375 380
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
385 390 395 400
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
405 410 415
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
420 425 430
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
435 440 445
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
450 455 460
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
465 470 475 480
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
485 490 495
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
500 505 510
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
515 520 525
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
530 535 540
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
545 550 555 560
Leu Ser Pro Gly
<210> 30
<211> 348
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 30
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 Asp Ile Gly Asn Arg
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
245 250 255
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
260 265 270
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
275 280 285
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
290 295 300
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
305 310 315 320
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
325 330 335
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345
<210> 31
<211> 495
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 31
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe
130 135 140
Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn
165 170 175
Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr
210 215 220
Val Thr Val Ser Ser Gly Gly Cys Gly Gly Gly Glu Val Ala Ala Cys
225 230 235 240
Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys
245 250 255
Glu Val Ala Ala Leu Glu Lys Leu Glu Pro Lys Ser Ser Asp Lys Thr
260 265 270
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
275 280 285
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg
290 295 300
Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
305 310 315 320
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
325 330 335
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
340 345 350
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
355 360 365
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
370 375 380
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
385 390 395 400
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
405 410 415
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
420 425 430
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
435 440 445
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
450 455 460
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
465 470 475 480
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
485 490 495
<210> 32
<211> 269
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 32
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 Asp Ile Gly Asn Arg
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly
225 230 235 240
Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys
245 250 255
Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu
260 265
<210> 33
<211> 561
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 33
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe
130 135 140
Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn
165 170 175
Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr
210 215 220
Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Ala Ser Thr Lys Gly
225 230 235 240
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
245 250 255
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
260 265 270
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
275 280 285
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
290 295 300
Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val
305 310 315 320
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
325 330 335
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
340 345 350
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile
355 360 365
Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
370 375 380
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
385 390 395 400
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
405 410 415
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
420 425 430
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
435 440 445
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
450 455 460
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
465 470 475 480
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
485 490 495
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
500 505 510
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
515 520 525
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
530 535 540
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
545 550 555 560
Gly
<210> 34
<211> 348
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 34
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 Asp Ile Gly Asn Arg
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
245 250 255
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
260 265 270
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
275 280 285
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
290 295 300
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
305 310 315 320
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
325 330 335
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345
<210> 35
<211> 491
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 35
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe
130 135 140
Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn
165 170 175
Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr
210 215 220
Val Thr Val Ser Ser Gly Gly Cys Gly Gly Gly Glu Val Ala Ala Cys
225 230 235 240
Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys
245 250 255
Glu Val Ala Ala Leu Glu Lys Glu Ser Lys Tyr Gly Pro Pro Cys Pro
260 265 270
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
275 280 285
Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val
290 295 300
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
305 310 315 320
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
325 330 335
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
340 345 350
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
355 360 365
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
370 375 380
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
385 390 395 400
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
405 410 415
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
420 425 430
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
435 440 445
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
450 455 460
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
465 470 475 480
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
485 490
<210> 36
<211> 269
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 36
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 Asp Ile Gly Asn Arg
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly
225 230 235 240
Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys
245 250 255
Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu
260 265
<210> 37
<211> 572
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 37
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe
130 135 140
Ser Thr Phe Phe Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn
165 170 175
Glu Lys Phe Glu Ser Lys Val Thr Leu Thr Arg Asp Thr Ser Ile Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly
225 230 235 240
Gly Ser Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
245 250 255
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
260 265 270
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
275 280 285
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
290 295 300
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
305 310 315 320
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
325 330 335
Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
340 345 350
Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu
355 360 365
Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu
370 375 380
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
385 390 395 400
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
405 410 415
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
420 425 430
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
435 440 445
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
450 455 460
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
465 470 475 480
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
485 490 495
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
500 505 510
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
515 520 525
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
530 535 540
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
545 550 555 560
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
565 570
<210> 38
<211> 348
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 38
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Lys Ser Asn Arg Tyr Thr 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 Asp Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
245 250 255
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
260 265 270
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
275 280 285
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
290 295 300
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
305 310 315 320
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
325 330 335
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345
<210> 39
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 39
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe
130 135 140
Ser Thr Phe Phe Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn
165 170 175
Glu Lys Phe Glu Ser Lys Val Thr Leu Thr Arg Asp Thr Ser Ile Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Cys
225 230 235 240
Gly Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu Glu
245 250 255
Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Leu
260 265 270
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
275 280 285
Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
290 295 300
Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val
305 310 315 320
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
325 330 335
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
340 345 350
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
355 360 365
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
370 375 380
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
385 390 395 400
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
405 410 415
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
420 425 430
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
435 440 445
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
450 455 460
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
465 470 475 480
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
485 490 495
Ser Leu Ser Leu Ser Pro Gly
500
<210> 40
<211> 269
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 40
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Lys Ser Asn Arg Tyr Thr 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 Asp Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly
225 230 235 240
Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys
245 250 255
Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu
260 265
<210> 41
<211> 569
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 41
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe
130 135 140
Ser Thr Phe Phe Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn
165 170 175
Glu Lys Phe Glu Ser Lys Val Thr Leu Thr Arg Asp Thr Ser Ile Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly
225 230 235 240
Gly Ser Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
245 250 255
Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val
260 265 270
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
275 280 285
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
290 295 300
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
305 310 315 320
Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys
325 330 335
Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys
340 345 350
Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
355 360 365
Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys
370 375 380
Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp
385 390 395 400
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
405 410 415
Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
420 425 430
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
435 440 445
Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
450 455 460
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu
465 470 475 480
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
485 490 495
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
500 505 510
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
515 520 525
Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn
530 535 540
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
545 550 555 560
Gln Lys Ser Leu Ser Leu Ser Leu Gly
565
<210> 42
<211> 348
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 42
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Lys Ser Asn Arg Tyr Thr 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 Asp Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
245 250 255
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
260 265 270
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
275 280 285
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
290 295 300
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
305 310 315 320
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
325 330 335
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345
<210> 43
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 43
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe
130 135 140
Ser Thr Phe Phe Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn
165 170 175
Glu Lys Phe Glu Ser Lys Val Thr Leu Thr Arg Asp Thr Ser Ile Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Cys
225 230 235 240
Gly Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu Glu
245 250 255
Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Glu
260 265 270
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu
275 280 285
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
290 295 300
Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser
305 310 315 320
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
325 330 335
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
340 345 350
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
355 360 365
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
370 375 380
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
385 390 395 400
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
405 410 415
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
420 425 430
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
435 440 445
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
450 455 460
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
465 470 475 480
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
485 490 495
Ser Leu Gly
<210> 44
<211> 269
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 44
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Lys Ser Asn Arg Tyr Thr 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 Asp Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly
225 230 235 240
Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys
245 250 255
Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu
260 265
<210> 45
<211> 572
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 45
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe
130 135 140
Ser Thr Phe Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn
165 170 175
Glu Lys Phe Glu Ser Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly
225 230 235 240
Gly Ser Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
245 250 255
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
260 265 270
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
275 280 285
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
290 295 300
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
305 310 315 320
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
325 330 335
Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
340 345 350
Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu
355 360 365
Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu
370 375 380
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
385 390 395 400
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
405 410 415
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
420 425 430
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
435 440 445
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
450 455 460
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
465 470 475 480
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
485 490 495
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
500 505 510
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
515 520 525
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
530 535 540
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
545 550 555 560
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
565 570
<210> 46
<211> 348
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 46
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Lys Ser Asn Arg Tyr Thr 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 Tyr Arg Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
245 250 255
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
260 265 270
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
275 280 285
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
290 295 300
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
305 310 315 320
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
325 330 335
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345
<210> 47
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 47
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe
130 135 140
Ser Thr Phe Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn
165 170 175
Glu Lys Phe Glu Ser Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Cys
225 230 235 240
Gly Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu Glu
245 250 255
Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Leu
260 265 270
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
275 280 285
Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
290 295 300
Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val
305 310 315 320
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
325 330 335
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
340 345 350
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
355 360 365
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
370 375 380
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
385 390 395 400
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
405 410 415
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
420 425 430
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
435 440 445
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
450 455 460
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
465 470 475 480
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
485 490 495
Ser Leu Ser Leu Ser Pro Gly
500
<210> 48
<211> 269
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 48
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Lys Ser Asn Arg Tyr Thr 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 Tyr Arg Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly
225 230 235 240
Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys
245 250 255
Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu
260 265
<210> 49
<211> 569
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 49
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe
130 135 140
Ser Thr Phe Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn
165 170 175
Glu Lys Phe Glu Ser Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly
225 230 235 240
Gly Ser Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
245 250 255
Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val
260 265 270
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
275 280 285
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
290 295 300
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
305 310 315 320
Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys
325 330 335
Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys
340 345 350
Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
355 360 365
Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys
370 375 380
Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp
385 390 395 400
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
405 410 415
Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
420 425 430
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
435 440 445
Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
450 455 460
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu
465 470 475 480
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
485 490 495
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
500 505 510
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
515 520 525
Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn
530 535 540
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
545 550 555 560
Gln Lys Ser Leu Ser Leu Ser Leu Gly
565
<210> 50
<211> 348
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 50
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Lys Ser Asn Arg Tyr Thr 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 Tyr Arg Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
245 250 255
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
260 265 270
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
275 280 285
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
290 295 300
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
305 310 315 320
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
325 330 335
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345
<210> 51
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 51
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe
130 135 140
Ser Thr Phe Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn
165 170 175
Glu Lys Phe Glu Ser Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Cys
225 230 235 240
Gly Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu Glu
245 250 255
Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Glu
260 265 270
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu
275 280 285
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
290 295 300
Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser
305 310 315 320
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
325 330 335
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
340 345 350
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
355 360 365
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
370 375 380
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
385 390 395 400
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
405 410 415
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
420 425 430
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
435 440 445
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
450 455 460
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
465 470 475 480
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
485 490 495
Ser Leu Gly
<210> 52
<211> 269
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 52
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Lys Ser Asn Arg Tyr Thr 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 Tyr Arg Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Cys Gly Gly
225 230 235 240
Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys
245 250 255
Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu
260 265
<210> 53
<211> 570
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<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 Asp Ile Gly Asn Arg
20 25 30
Leu Ser Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
245 250 255
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
260 265 270
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
275 280 285
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
290 295 300
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
305 310 315 320
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
325 330 335
Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
340 345 350
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
355 360 365
Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr
370 375 380
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
385 390 395 400
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
405 410 415
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
420 425 430
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
435 440 445
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
450 455 460
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
465 470 475 480
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
485 490 495
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
500 505 510
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
515 520 525
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
530 535 540
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
545 550 555 560
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
565 570
<210> 54
<211> 342
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 54
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe
130 135 140
Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn
165 170 175
Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr
210 215 220
Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Arg Thr Val Ala Ala
225 230 235 240
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
245 250 255
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
260 265 270
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
275 280 285
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
290 295 300
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
305 310 315 320
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
325 330 335
Phe Asn Arg Gly Glu Cys
340
<210> 55
<211> 567
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 55
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 Asp Ile Gly Asn Arg
20 25 30
Leu Ser Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
245 250 255
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
260 265 270
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
275 280 285
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
290 295 300
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
305 310 315 320
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
325 330 335
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
340 345 350
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
355 360 365
Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val
370 375 380
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
385 390 395 400
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
405 410 415
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
420 425 430
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
435 440 445
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
450 455 460
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
465 470 475 480
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
485 490 495
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
500 505 510
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
515 520 525
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
530 535 540
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
545 550 555 560
Ser Leu Ser Leu Ser Leu Gly
565
<210> 56
<211> 342
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 56
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe
130 135 140
Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn
165 170 175
Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr
210 215 220
Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Arg Thr Val Ala Ala
225 230 235 240
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
245 250 255
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
260 265 270
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
275 280 285
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
290 295 300
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
305 310 315 320
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
325 330 335
Phe Asn Arg Gly Glu Cys
340
<210> 57
<211> 570
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 57
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 Asp Ile Gly Asn Arg
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
245 250 255
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
260 265 270
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
275 280 285
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
290 295 300
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
305 310 315 320
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
325 330 335
Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
340 345 350
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
355 360 365
Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr
370 375 380
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
385 390 395 400
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
405 410 415
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
420 425 430
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
435 440 445
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
450 455 460
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
465 470 475 480
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
485 490 495
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
500 505 510
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
515 520 525
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
530 535 540
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
545 550 555 560
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
565 570
<210> 58
<211> 342
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 58
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe
130 135 140
Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn
165 170 175
Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr
210 215 220
Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Arg Thr Val Ala Ala
225 230 235 240
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
245 250 255
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
260 265 270
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
275 280 285
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
290 295 300
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
305 310 315 320
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
325 330 335
Phe Asn Arg Gly Glu Cys
340
<210> 59
<211> 567
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 59
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 Asp Ile Gly Asn Arg
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
245 250 255
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
260 265 270
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
275 280 285
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
290 295 300
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
305 310 315 320
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
325 330 335
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
340 345 350
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
355 360 365
Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val
370 375 380
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
385 390 395 400
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
405 410 415
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
420 425 430
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
435 440 445
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
450 455 460
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
465 470 475 480
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
485 490 495
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
500 505 510
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
515 520 525
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
530 535 540
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
545 550 555 560
Ser Leu Ser Leu Ser Leu Gly
565
<210> 60
<211> 342
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Pro Asp His Ile Phe
130 135 140
Ser Ile His Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn
165 170 175
Glu Lys Phe Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr
210 215 220
Val Thr Val Ser Ser Leu Gly Gly Gly Ser Gly Arg Thr Val Ala Ala
225 230 235 240
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
245 250 255
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
260 265 270
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
275 280 285
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
290 295 300
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
305 310 315 320
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
325 330 335
Phe Asn Arg Gly Glu Cys
340
<210> 61
<211> 570
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 61
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Lys Ser Asn Arg Tyr Thr 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 Asp Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
245 250 255
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
260 265 270
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
275 280 285
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
290 295 300
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
305 310 315 320
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
325 330 335
Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
340 345 350
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
355 360 365
Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr
370 375 380
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
385 390 395 400
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
405 410 415
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
420 425 430
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
435 440 445
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
450 455 460
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
465 470 475 480
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
485 490 495
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
500 505 510
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
515 520 525
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
530 535 540
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
545 550 555 560
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
565 570
<210> 62
<211> 350
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 62
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe
130 135 140
Ser Thr Phe Phe Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn
165 170 175
Glu Lys Phe Glu Ser Lys Val Thr Leu Thr Arg Asp Thr Ser Ile Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly
225 230 235 240
Gly Ser Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
245 250 255
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
260 265 270
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
275 280 285
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
290 295 300
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
305 310 315 320
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
325 330 335
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345 350
<210> 63
<211> 567
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<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 Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Lys Ser Asn Arg Tyr Thr 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 Asp Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
245 250 255
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
260 265 270
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
275 280 285
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
290 295 300
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
305 310 315 320
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
325 330 335
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
340 345 350
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
355 360 365
Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val
370 375 380
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
385 390 395 400
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
405 410 415
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
420 425 430
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
435 440 445
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
450 455 460
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
465 470 475 480
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
485 490 495
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
500 505 510
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
515 520 525
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
530 535 540
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
545 550 555 560
Ser Leu Ser Leu Ser Leu Gly
565
<210> 64
<211> 350
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 64
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe
130 135 140
Ser Thr Phe Phe Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn
165 170 175
Glu Lys Phe Glu Ser Lys Val Thr Leu Thr Arg Asp Thr Ser Ile Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly
225 230 235 240
Gly Ser Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
245 250 255
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
260 265 270
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
275 280 285
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
290 295 300
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
305 310 315 320
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
325 330 335
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345 350
<210> 65
<211> 570
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 65
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Lys Ser Asn Arg Tyr Thr 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 Tyr Arg Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
245 250 255
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
260 265 270
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
275 280 285
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
290 295 300
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
305 310 315 320
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
325 330 335
Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
340 345 350
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
355 360 365
Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr
370 375 380
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
385 390 395 400
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
405 410 415
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
420 425 430
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
435 440 445
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
450 455 460
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
465 470 475 480
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
485 490 495
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
500 505 510
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
515 520 525
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
530 535 540
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
545 550 555 560
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
565 570
<210> 66
<211> 350
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 66
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe
130 135 140
Ser Thr Phe Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn
165 170 175
Glu Lys Phe Glu Ser Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly
225 230 235 240
Gly Ser Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
245 250 255
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
260 265 270
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
275 280 285
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
290 295 300
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
305 310 315 320
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
325 330 335
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345 350
<210> 67
<211> 567
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 67
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Lys Ser Asn Arg Tyr Thr 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 Tyr Arg Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Asp Gln Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn
165 170 175
Glu Asn Phe Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Leu Gly Gly Gly Ser
225 230 235 240
Gly Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
245 250 255
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
260 265 270
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
275 280 285
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
290 295 300
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
305 310 315 320
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
325 330 335
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
340 345 350
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
355 360 365
Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val
370 375 380
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
385 390 395 400
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
405 410 415
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
420 425 430
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
435 440 445
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
450 455 460
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
465 470 475 480
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
485 490 495
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
500 505 510
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
515 520 525
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
530 535 540
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
545 550 555 560
Ser Leu Ser Leu Ser Leu Gly
565
<210> 68
<211> 350
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 68
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 Lys Ala Ser Arg Asp Val Ala Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe
130 135 140
Ser Thr Phe Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Ile Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn
165 170 175
Glu Lys Phe Glu Ser Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
180 185 190
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Leu Gly Gly
225 230 235 240
Gly Ser Gly Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
245 250 255
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
260 265 270
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
275 280 285
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
290 295 300
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
305 310 315 320
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
325 330 335
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345 350
<210> 69
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 69
Gly Gly Gly Ser Gly Gly Gly Gly
1 5
<210> 70
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 70
Leu Gly Gly Gly Ser Gly
1 5
<210> 71
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 71
Phe Asn Arg Gly Glu Cys
1 5
<210> 72
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 72
Val Glu Pro Lys Ser Cys
1 5
<210> 73
<211> 326
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 73
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly
325
<210> 74
<211> 326
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 74
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly
325
<210> 75
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 75
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 76
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 76
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
<210> 77
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 77
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 78
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 78
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 79
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 79
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 80
<211> 285
<212> PRT
<213> 智人
<400> 80
Met Asp Asp Ser Thr Glu Arg Glu Gln Ser Arg Leu Thr Ser Cys Leu
1 5 10 15
Lys Lys Arg Glu Glu Met Lys Leu Lys Glu Cys Val Ser Ile Leu Pro
20 25 30
Arg Lys Glu Ser Pro Ser Val Arg Ser Ser Lys Asp Gly Lys Leu Leu
35 40 45
Ala Ala Thr Leu Leu Leu Ala Leu Leu Ser Cys Cys Leu Thr Val Val
50 55 60
Ser Phe Tyr Gln Val Ala Ala Leu Gln Gly Asp Leu Ala Ser Leu Arg
65 70 75 80
Ala Glu Leu Gln Gly His His Ala Glu Lys Leu Pro Ala Gly Ala Gly
85 90 95
Ala Pro Lys Ala Gly Leu Glu Glu Ala Pro Ala Val Thr Ala Gly Leu
100 105 110
Lys Ile Phe Glu Pro Pro Ala Pro Gly Glu Gly Asn Ser Ser Gln Asn
115 120 125
Ser Arg Asn Lys Arg Ala Val Gln Gly Pro Glu Glu Thr Val Thr Gln
130 135 140
Asp Cys Leu Gln Leu Ile Ala Asp Ser Glu Thr Pro Thr Ile Gln Lys
145 150 155 160
Gly Ser Tyr Thr Phe Val Pro Trp Leu Leu Ser Phe Lys Arg Gly Ser
165 170 175
Ala Leu Glu Glu Lys Glu Asn Lys Ile Leu Val Lys Glu Thr Gly Tyr
180 185 190
Phe Phe Ile Tyr Gly Gln Val Leu Tyr Thr Asp Lys Thr Tyr Ala Met
195 200 205
Gly His Leu Ile Gln Arg Lys Lys Val His Val Phe Gly Asp Glu Leu
210 215 220
Ser Leu Val Thr Leu Phe Arg Cys Ile Gln Asn Met Pro Glu Thr Leu
225 230 235 240
Pro Asn Asn Ser Cys Tyr Ser Ala Gly Ile Ala Lys Leu Glu Glu Gly
245 250 255
Asp Glu Leu Gln Leu Ala Ile Pro Arg Glu Asn Ala Gln Ile Ser Leu
260 265 270
Asp Gly Asp Val Thr Phe Phe Gly Ala Leu Lys Leu Leu
275 280 285
<210> 81
<211> 189
<212> PRT
<213> 智人
<400> 81
Met Leu Gly Ser Arg Ala Val Met Leu Leu Leu Leu Leu Pro Trp Thr
1 5 10 15
Ala Gln Gly Arg Ala Val Pro Gly Gly Ser Ser Pro Ala Trp Thr Gln
20 25 30
Cys Gln Gln Leu Ser Gln Lys Leu Cys Thr Leu Ala Trp Ser Ala His
35 40 45
Pro Leu Val Gly His Met Asp Leu Arg Glu Glu Gly Asp Glu Glu Thr
50 55 60
Thr Asn Asp Val Pro His Ile Gln Cys Gly Asp Gly Cys Asp Pro Gln
65 70 75 80
Gly Leu Arg Asp Asn Ser Gln Phe Cys Leu Gln Arg Ile His Gln Gly
85 90 95
Leu Ile Phe Tyr Glu Lys Leu Leu Gly Ser Asp Ile Phe Thr Gly Glu
100 105 110
Pro Ser Leu Leu Pro Asp Ser Pro Val Gly Gln Leu His Ala Ser Leu
115 120 125
Leu Gly Leu Ser Gln Leu Leu Gln Pro Glu Gly His His Trp Glu Thr
130 135 140
Gln Gln Ile Pro Ser Leu Ser Pro Ser Gln Pro Trp Gln Arg Leu Leu
145 150 155 160
Leu Arg Phe Lys Ile Leu Arg Ser Leu Gln Ala Phe Val Ala Val Ala
165 170 175
Ala Arg Val Phe Ala His Gly Ala Ala Thr Leu Ser Pro
180 185
<210> 82
<211> 34
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 82
Gly Gly Cys Gly Gly Gly Glu Val Ala Ala Cys Glu Lys Glu Val Ala
1 5 10 15
Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu
20 25 30
Glu Lys
<210> 83
<211> 34
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 83
Gly Gly Cys Gly Gly Gly Lys Val Ala Ala Cys Lys Glu Lys Val Ala
1 5 10 15
Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu
20 25 30
Lys Glu
<210> 84
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 84
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 Pro Asp His Ile Phe Ser Ile His
20 25 30
Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 85
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 85
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 Asp Ile Gly Asn Arg
20 25 30
Leu Ser Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 86
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 86
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 Pro Asp His Ile Phe Ser Ile His
20 25 30
Trp Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 87
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 87
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 Asp Ile Gly Asn Arg
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Val Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 88
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 88
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Ser Thr Phe
20 25 30
Phe Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Glu Ser Lys Val Thr Leu Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 89
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 89
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Lys Ser Asn Arg Tyr Thr 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 Asp Tyr Tyr Cys Leu Gln Tyr Arg Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 90
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 90
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Ser Thr Phe
20 25 30
Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Glu Ser Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 91
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 91
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Ala Gly Ile Asp
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Lys Ser Asn Arg Tyr Thr 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 Tyr Arg Ser Tyr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 92
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 92
Gly Gly Thr Phe Asn Asn Asn Ala Ile Asn
1 5 10
<210> 93
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 93
Gly Ile Ile Pro Met Phe Gly Thr Ala Lys Tyr Ser Gln Asn Phe Gln
1 5 10 15
Gly
<210> 94
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 94
Ser Arg Asp Leu Leu Leu Phe Pro His His Ala Leu Ser Pro
1 5 10
<210> 95
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 95
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser
1 5 10
<210> 96
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 96
Gly Lys Asn Asn Arg Pro Ser
1 5
<210> 97
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 97
Ser Ser Arg Asp Ser Ser Gly Asn His Trp Val
1 5 10
<210> 98
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 98
Gly Tyr Thr Phe Thr Asp Gln Thr Ile His
1 5 10
<210> 99
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 99
Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn Glu Asn Phe Lys
1 5 10 15
Gly
<210> 100
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 100
Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr
1 5 10
<210> 101
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 101
Lys Ala Ser Arg Asp Val Ala Ile Ala Val Ala
1 5 10
<210> 102
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 102
Trp Ala Ser Thr Arg His Thr
1 5
<210> 103
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 103
His Gln Tyr Ser Ser Tyr Pro Phe Thr
1 5
<210> 104
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 104
Asp His Ile Phe Ser Ile His Trp Met Gln
1 5 10
<210> 105
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 105
Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 106
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 106
Gly Ala Phe Asp Tyr
1 5
<210> 107
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 107
Arg Ala Ser Gln Asp Ile Gly Asn Arg Leu Ser
1 5 10
<210> 108
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 108
Ala Thr Ser Ser Leu Asp Ser
1 5
<210> 109
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 109
Leu Gln Tyr Ala Ser Ser Pro Phe Thr
1 5
<210> 110
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 110
Asp His Ile Phe Ser Ile His Trp Met Gln
1 5 10
<210> 111
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 111
Glu Ile Phe Pro Gly Ser Gly Thr Thr Asp Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 112
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 112
Gly Ala Phe Asp Tyr
1 5
<210> 113
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 113
Arg Ala Ser Gln Asp Ile Gly Asn Arg Leu Asn
1 5 10
<210> 114
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 114
Ala Thr Ser Ser Leu Asp Ser
1 5
<210> 115
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 115
Gly Tyr Ser Phe Ser Thr Phe Phe Ile His
1 5 10
<210> 116
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 116
Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn Glu Lys Phe Glu
1 5 10 15
Ser
<210> 117
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 117
Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu Asp Tyr
1 5 10
<210> 118
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 118
Lys Ala Ser Gln Asn Ala Gly Ile Asp Val Ala
1 5 10
<210> 119
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 119
Ser Lys Ser Asn Arg Tyr Thr
1 5
<210> 120
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 120
Leu Gln Tyr Arg Ser Tyr Pro Arg Thr
1 5
<210> 121
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 121
Gly Tyr Ser Phe Ser Thr Phe Phe Ile His
1 5 10
<210> 122
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 122
Gly Arg Ile Asp Pro Asn Ser Gly Ala Thr Lys Tyr Asn Glu Lys Phe
1 5 10 15
Glu Ser
<210> 123
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 123
Gly Glu Asp Leu Leu Ile Arg Thr Asp Ala Leu Asp Tyr
1 5 10
<210> 124
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 124
Lys Ala Ser Gln Asn Ala Gly Ile Asp Val Ala
1 5 10
<210> 125
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 125
Ser Lys Ser Asn Arg Tyr Thr
1 5
<210> 126
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 126
Leu Gln Tyr Arg Ser Tyr Pro Arg Thr
1 5
<210> 127
<211> 228
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 127
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly
225
<210> 128
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 128
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 129
<211> 232
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 129
Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
20 25 30
Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val
35 40 45
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
50 55 60
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
65 70 75 80
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
85 90 95
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
100 105 110
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
115 120 125
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
130 135 140
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
145 150 155 160
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
165 170 175
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
180 185 190
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
195 200 205
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
210 215 220
Lys Ser Leu Ser Leu Ser Pro Gly
225 230
<210> 130
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 130
Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
<210> 131
<211> 290
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 131
Gly Cys Lys Trp Asp Leu Leu Ile Lys Gln Trp Val Cys Asp Pro Leu
1 5 10 15
Gly Ser Gly Ser Ala Thr Gly Gly Ser Gly Ser Thr Ala Ser Ser Gly
20 25 30
Ser Gly Ser Ala Thr His Met Leu Pro Gly Cys Lys Trp Asp Leu Leu
35 40 45
Ile Lys Gln Trp Val Cys Asp Pro Leu Gly Gly Gly Gly Gly Val Asp
50 55 60
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
65 70 75 80
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
85 90 95
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
100 105 110
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
115 120 125
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
130 135 140
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
145 150 155 160
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
165 170 175
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
180 185 190
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
195 200 205
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
210 215 220
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
225 230 235 240
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
245 250 255
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
260 265 270
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
275 280 285
Gly Lys
290
<210> 132
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 132
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Tyr Tyr Asp Ile Leu Thr Gly Tyr Tyr Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 133
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 133
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Ser Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 134
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 134
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
1 5 10
<210> 135
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 135
Gly Gly Cys Gly Gly Gly
1 5
<210> 136
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 136
Leu Gly Gly Cys Gly Gly Gly Ser
1 5
Claims (40)
1.一种化合物,所述化合物包含第一多肽和第二多肽,其中:
(A)所述第一多肽包含:
(i)对第一靶蛋白具有特异性的第一免疫球蛋白的轻链可变结构域(VL1);
(ii)对第二靶蛋白具有特异性的第二免疫球蛋白的重链可变结构域(VH2);以及
(iii)铰链区、重链恒定区2(CH2)以及重链恒定区3(CH3);并且
(B)所述第二多肽包含:
(i)所述对所述第二靶蛋白具有特异性的第二免疫球蛋白的轻链可变结构域(VL2);
(ii)所述对所述第一靶蛋白具有特异性的第一免疫球蛋白的重链可变结构域(VH1);
其中:
a)所述VL1和所述VH1缔合以形成结合所述第一靶蛋白的结合位点;
b)所述VL2和所述VH2缔合以形成结合所述第二靶蛋白的结合位点;
c)所述重链恒定区2(CH2)包含位置252处的酪氨酸、位置254处的苏氨酸以及位置256处的谷氨酸,所述位置是根据如Kabat中的EU索引编号的;以及
d)所述第一靶蛋白是BAFF并且所述第二靶蛋白是IL-23A,或所述第一靶蛋白是IL-23A并且所述第二靶蛋白是BAFF,
并且其中:
(i)所述VL1包含SEQ ID NO:2,所述VH1包含SEQ ID NO:1,所述VL2包含SEQ ID NO:4并且所述VH2包含SEQ ID NO:3;或
(ii)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ ID NO:2并且所述VH2包含SEQ ID NO:1;或
(iii)所述VL1包含SEQ ID NO:89,所述VH1包含SEQ ID NO:88,所述VL2包含SEQ IDNO:4并且所述VH2包含SEQ ID NO:3;或
(iv)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ ID NO:89并且所述VH2包含SEQ ID NO:88;或
(v)所述VL1包含SEQ ID NO:91,所述VH1包含SEQ ID NO:90,所述VL2包含SEQ ID NO:4并且所述VH2包含SEQ ID NO:3;或
(vi)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ ID NO:91并且所述VH2包含SEQ ID NO:90。
2.根据权利要求1所述的化合物,其中所述第一多肽还在所述VL1与所述VH2之间包含第一接头并且所述第二多肽还在所述VL2与所述VH1之间包含第二接头。
3.根据权利要求2所述的化合物,其中所述第一接头或所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。
4.根据权利要求2所述的化合物,其中所述第一接头和所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。
5.根据权利要求1所述的化合物,其中所述第一多肽还包含重链恒定区1结构域(CH1)并且所述第二多肽还包含轻链恒定区结构域(CL),其中所述CL和所述CH1经由二硫键缔合在一起以形成C1结构域。
6.根据权利要求5所述的化合物,其中所述第一多肽还在所述VH2与所述CH1之间包含第三接头并且所述第二多肽还在所述VH1与所述CL之间包含第四接头。
7.根据权利要求6所述的化合物,其中所述第三接头或所述第四接头包含氨基酸序列LGGGSG(SEQ ID NO:70)。
8.根据权利要求6所述的化合物,其中所述第三接头和所述第四接头包含氨基酸序列LGGGSG(SEQ ID NO:70)。
9.根据前述权利要求中任一项所述的化合物,其中所述重链恒定区2(CH2)包含位置234处的丙氨酸和位置235处的丙氨酸,所述位置是根据如Kabat中的EU索引编号的。
10.根据前述权利要求中任一项所述的化合物,其中所述铰链区、所述重链恒定区2(CH2)或所述重链恒定区3(CH3)的氨基酸序列源自于IgG1或源自于IgG4。
11.根据前述权利要求中任一项所述的化合物,其中所述铰链区包含氨基酸序列EPKSCDKTHTCPPCP(SEQ ID NO:76)、氨基酸序列LEPKSSDKTHTCPPCP(SEQ ID NO:130)或氨基酸序列ESKYGPPCPPCP(SEQ ID NO:134)。
12.根据前述权利要求中任一项所述的化合物,其中所述化合物包含两个所述第一多肽和两个所述第二多肽,其中所述两个第一多肽经由至少一个二硫键缔合在一起。
13.根据权利要求1所述的化合物,其中:
(i)所述第一多肽包含SEQ ID NO:5的氨基酸序列并且所述第二多肽包含SEQ ID NO:6的氨基酸序列;或
(ii)所述第一多肽包含SEQ ID NO:7的氨基酸序列并且所述第二多肽包含SEQ ID NO:8的氨基酸序列;或
(iii)所述第一多肽包含SEQ ID NO:9的氨基酸序列并且所述第二多肽包含SEQ IDNO:10的氨基酸序列;或
(iv)所述第一多肽包含SEQ ID NO:11的氨基酸序列并且所述第二多肽包含SEQ IDNO:12的氨基酸序列;或
(v)所述第一多肽包含SEQ ID NO:13的氨基酸序列并且所述第二多肽包含SEQ ID NO:14的氨基酸序列;或
(vi)所述第一多肽包含SEQ ID NO:15的氨基酸序列并且所述第二多肽包含SEQ IDNO:16的氨基酸序列;或
(vii)所述第一多肽包含SEQ ID NO:17的氨基酸序列并且所述第二多肽包含SEQ IDNO:18的氨基酸序列;或
(viii)所述第一多肽包含SEQ ID NO:19的氨基酸序列并且所述第二多肽包含SEQ IDNO:20的氨基酸序列;或
(ix)所述第一多肽包含SEQ ID NO:37的氨基酸序列并且所述第二多肽包含SEQ IDNO:38的氨基酸序列;或
(x)所述第一多肽包含SEQ ID NO:39的氨基酸序列并且所述第二多肽包含SEQ ID NO:40的氨基酸序列;或
(xi)所述第一多肽包含SEQ ID NO:41的氨基酸序列并且所述第二多肽包含SEQ IDNO:42的氨基酸序列;或
(xii)所述第一多肽包含SEQ ID NO:43的氨基酸序列并且所述第二多肽包含SEQ IDNO:44的氨基酸序列;或
(xiii)所述第一多肽包含SEQ ID NO:45的氨基酸序列并且所述第二多肽包含SEQ IDNO:46的氨基酸序列;或
(xiv)所述第一多肽包含SEQ ID NO:47的氨基酸序列并且所述第二多肽包含SEQ IDNO:48的氨基酸序列;或
(xv)所述第一多肽包含SEQ ID NO:49的氨基酸序列并且所述第二多肽包含SEQ IDNO:50的氨基酸序列;或
(xvi)所述第一多肽包含SEQ ID NO:51的氨基酸序列并且所述第二多肽包含SEQ IDNO:52的氨基酸序列;或
(xvii)所述第一多肽包含SEQ ID NO:61的氨基酸序列并且所述第二多肽包含SEQ IDNO:62的氨基酸序列;或
(xviii)所述第一多肽包含SEQ ID NO:63的氨基酸序列并且所述第二多肽包含SEQ IDNO:64的氨基酸序列;或
(xix)所述第一多肽包含SEQ ID NO:65的氨基酸序列并且所述第二多肽包含SEQ IDNO:66的氨基酸序列;或
(xx)所述第一多肽包含SEQ ID NO:67的氨基酸序列并且所述第二多肽包含SEQ IDNO:68的氨基酸序列。
14.根据权利要求13所述的化合物,其中所述化合物包含两个所述第一多肽和两个所述第二多肽,其中所述两个第一多肽经由至少一个二硫键缔合在一起并且其中所述第一多肽中的每一个经由至少一个二硫键与一个所述第二多肽缔合。
15.根据权利要求13或14所述的化合物,其中所述化合物包含两个所述第一多肽和两个所述第二多肽,其中所述第一多肽中的每一个包含CH1、铰链、CH2以及CH3并且所述第二多肽中的每一个包含CL并且其中所述第一多肽中的一个的铰链、CH2以及CH3与所述第一多肽中的另一个的铰链、CH2以及CH3缔合并且每一个所述第一多肽的CH1与一个所述第二多肽的CL缔合以形成四价分子。
16.一种第一化合物,所述第一化合物与第二化合物竞争结合IL-23A和结合BAFF,其中所述第一化合物包含第三多肽和第四多肽,其中:
(A)所述第三多肽包含:
(i)对第一靶蛋白具有特异性的第一免疫球蛋白的轻链可变结构域(VL1);
(ii)对第二靶蛋白具有特异性的第二免疫球蛋白的重链可变结构域(VH2);以及
(iii)铰链区、重链恒定区2(CH2)以及重链恒定区3(CH3);并且
(B)所述第四多肽包含:
(i)所述对所述第二靶蛋白具有特异性的第二免疫球蛋白的轻链可变结构域(VL2);
(ii)所述对所述第一靶蛋白具有特异性的第一免疫球蛋白的重链可变结构域(VH1);
并且其中
a)所述VL1和所述VH1缔合以形成结合所述第一靶蛋白的结合位点;
b)所述VL2和所述VH2缔合以形成结合所述第二靶蛋白的结合位点;以及
c)所述第一靶蛋白是BAFF并且所述第二靶蛋白是IL-23A,或所述第一靶蛋白是IL-23A并且所述第二靶蛋白是BAFF,
并且其中所述第二化合物包含第一多肽和第二多肽,其中:
(i)所述第一多肽包含SEQ ID NO:5的氨基酸序列并且所述第二多肽包含SEQ ID NO:6的氨基酸序列;或
(ii)所述第一多肽包含SEQ ID NO:7的氨基酸序列并且所述第二多肽包含SEQ ID NO:8的氨基酸序列;或
(iii)所述第一多肽包含SEQ ID NO:9的氨基酸序列并且所述第二多肽包含SEQ IDNO:10的氨基酸序列;或
(iv)所述第一多肽包含SEQ ID NO:11的氨基酸序列并且所述第二多肽包含SEQ IDNO:12的氨基酸序列;或
(v)所述第一多肽包含SEQ ID NO:13的氨基酸序列并且所述第二多肽包含SEQ ID NO:14的氨基酸序列;或
(vi)所述第一多肽包含SEQ ID NO:15的氨基酸序列并且所述第二多肽包含SEQ IDNO:16的氨基酸序列;或
(vii)所述第一多肽包含SEQ ID NO:17的氨基酸序列并且所述第二多肽包含SEQ IDNO:18的氨基酸序列;或
(viii)所述第一多肽包含SEQ ID NO:19的氨基酸序列并且所述第二多肽包含SEQ IDNO:20的氨基酸序列;或
(ix)所述第一多肽包含SEQ ID NO:37的氨基酸序列并且所述第二多肽包含SEQ IDNO:38的氨基酸序列;或
(x)所述第一多肽包含SEQ ID NO:39的氨基酸序列并且所述第二多肽包含SEQ ID NO:40的氨基酸序列;或
(xi)所述第一多肽包含SEQ ID NO:41的氨基酸序列并且所述第二多肽包含SEQ IDNO:42的氨基酸序列;或
(xii)所述第一多肽包含SEQ ID NO:43的氨基酸序列并且所述第二多肽包含SEQ IDNO:44的氨基酸序列;或
(xiii)所述第一多肽包含SEQ ID NO:45的氨基酸序列并且所述第二多肽包含SEQ IDNO:46的氨基酸序列;或
(xiv)所述第一多肽包含SEQ ID NO:47的氨基酸序列并且所述第二多肽包含SEQ IDNO:48的氨基酸序列;或
(xv)所述第一多肽包含SEQ ID NO:49的氨基酸序列并且所述第二多肽包含SEQ IDNO:50的氨基酸序列;或
(xvi)所述第一多肽包含SEQ ID NO:51的氨基酸序列并且所述第二多肽包含SEQ IDNO:52的氨基酸序列;或
(xvii)所述第一多肽包含SEQ ID NO:61的氨基酸序列并且所述第二多肽包含SEQ IDNO:62的氨基酸序列;或
(xviii)所述第一多肽包含SEQ ID NO:63的氨基酸序列并且所述第二多肽包含SEQ IDNO:64的氨基酸序列;或
(xix)所述第一多肽包含SEQ ID NO:65的氨基酸序列并且所述第二多肽包含SEQ IDNO:66的氨基酸序列;或
(xx)所述第一多肽包含SEQ ID NO:67的氨基酸序列并且所述第二多肽包含SEQ IDNO:68的氨基酸序列。
17.一种化合物,所述化合物包含两个第一多肽和两个第二多肽;
其中所述两个第一多肽经由至少一个二硫键缔合在一起并且其中所述第一多肽中的每一个经由至少一个二硫键与一个所述第二多肽缔合;
其中所述第一多肽中的每一个包含:
(i)对第一靶蛋白具有特异性的第一免疫球蛋白的轻链可变结构域(VL1);
(ii)对第二靶蛋白具有特异性的第二免疫球蛋白的重链可变结构域(VH2);
(iii)重链恒定区1(CH1)、铰链区、重链恒定区2(CH2)以及重链恒定区3(CH3);并且
其中所述第二多肽中的每一个包含:
(i)所述对所述第二靶蛋白具有特异性的第二免疫球蛋白的轻链可变结构域(VL2);
(ii)所述对所述第一靶蛋白具有特异性的第一免疫球蛋白的重链可变结构域(VH1);
(iii)轻链恒定区结构域(CL);
其中所述第一多肽中的一个的铰链、CH2以及CH3与所述第一多肽中的另一个的铰链、CH2以及CH3缔合并且每一个所述第一多肽的CH1与所述每一个第二多肽的CL缔合以形成四价分子;
其中
a)所述VL1和所述VH1缔合以形成结合所述第一靶蛋白的结合位点;
b)所述VL2和所述VH2缔合以形成结合所述第二靶蛋白的结合位点;
c)所述重链恒定区2(CH2)包含位置252处的酪氨酸、位置254处的苏氨酸以及位置256处的谷氨酸,所述位置是根据如Kabat中的EU索引编号的;以及
d)所述第一靶蛋白是BAFF并且所述第二靶蛋白是IL-23A,或所述第一靶蛋白是IL-23A并且所述第二靶蛋白是BAFF,
并且其中:
(i)所述VL1包含SEQ ID NO:2,所述VH1包含SEQ ID NO:1,所述VL2包含SEQ ID NO:4并且所述VH2包含SEQ ID NO:3;或
(ii)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ ID NO:2并且所述VH2包含SEQ ID NO:1;或
(iii)所述VL1包含SEQ ID NO:89,所述VH1包含SEQ ID NO:88,所述VL2包含SEQ IDNO:4并且所述VH2包含SEQ ID NO:3;或
(iv)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ ID NO:89并且所述VH2包含SEQ ID NO:88;或
(v)所述VL1包含SEQ ID NO:91,所述VH1包含SEQ ID NO:90,所述VL2包含SEQ ID NO:4并且所述VH2包含SEQ ID NO:3;或
(vi)所述VL1包含SEQ ID NO:4,所述VH1包含SEQ ID NO:3,所述VL2包含SEQ ID NO:91并且所述VH2包含SEQ ID NO:90。
18.根据权利要求17所述的化合物,其中所述第一多肽中的每一个还在所述VL1与所述VH2之间包含第一接头,并且所述第二多肽中的每一个还在所述VL2与所述VH1之间包含第二接头。
19.根据权利要求18所述的化合物,其中所述第一接头或所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。
20.根据权利要求18所述的化合物,其中所述第一接头和所述第二接头包含氨基酸序列GGGSGGGG(SEQ ID NO:69)。
21.根据权利要求18所述的化合物,其中所述第一多肽中的每一个还在所述VH2与所述CH1之间包含第三接头,并且所述第二多肽中的每一个还在所述VH1与所述CL之间包含第四接头。
22.根据权利要求21所述的化合物,其中所述第三接头或所述第四接头包含氨基酸序列LGGGSG(SEQ ID NO:70)。
23.根据权利要求21所述的化合物,其中所述第三接头和所述第四接头包含氨基酸序列LGGGSG(SEQ ID NO:70)。
24.根据权利要求17所述的化合物,其中所述重链恒定区2(CH2)包含位置234处的丙氨酸和位置235处的丙氨酸,所述位置是根据如Kabat中的EU索引编号的。
25.根据权利要求17所述的化合物,其中所述铰链区、所述重链恒定区2(CH2)或所述重链恒定区3(CH3)的氨基酸序列源自于IgG1或IgG4。
26.根据权利要求17所述的化合物,其中所述铰链区包含氨基酸序列EPKSCDKTHTCPPCP(SEQ ID NO:76)、氨基酸序列LEPKSSDKTHTCPPCP(SEQ ID NO:130)或氨基酸序列ESKYGPPCPPCP(SEQ ID NO:134)。
27.根据权利要求17所述的化合物,其中:
(i)所述第一多肽中的每一个包含SEQ ID NO:5的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:6的氨基酸序列;或
(ii)所述第一多肽中的每一个包含SEQ ID NO:7的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:8的氨基酸序列;或
(iii)所述第一多肽中的每一个包含SEQ ID NO:13的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:14的氨基酸序列;或
(iv)所述第一多肽中的每一个包含SEQ ID NO:15的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:16的氨基酸序列;或
(v)所述第一多肽中的每一个包含SEQ ID NO:37的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:38的氨基酸序列;或
(vi)所述第一多肽中的每一个包含SEQ ID NO:41的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:42的氨基酸序列;或
(vii)所述第一多肽中的每一个包含SEQ ID NO:45的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:46的氨基酸序列;或
(viii)所述第一多肽中的每一个包含SEQ ID NO:49的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:50的氨基酸序列;或
(ix)所述第一多肽中的每一个包含SEQ ID NO:61的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:62的氨基酸序列;或
(x)所述第一多肽中的每一个包含SEQ ID NO:63的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:64的氨基酸序列;或
(xi)所述第一多肽中的每一个包含SEQ ID NO:65的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:66的氨基酸序列;或
(xii)所述第一多肽中的每一个包含SEQ ID NO:67的氨基酸序列并且所述第二多肽中的每一个包含SEQ ID NO:68的氨基酸序列。
28.一种药物组合物,所述药物组合物包含根据权利要求1至27中任一项所述的化合物。
29.一种治疗自身免疫性或炎症性疾病的方法,所述方法包括向受试者施用根据权利要求1至27中任一项所述的化合物或包含所述化合物的药物组合物。
30.根据权利要求1至27中任一项所述的化合物,所述化合物用于药物中。
31.根据权利要求30所述的化合物,其中所述用途是治疗自身免疫性或炎症性疾病。
32.一种药物组合物,所述药物组合物包含用于药物中的根据权利要求1至27中任一项所述的化合物。
33.根据权利要求32所述的药物组合物,其中所述用途是治疗自身免疫性或炎症性疾病。
34.一种核酸,所述核酸包含编码根据权利要求1至27中任一项所述的多肽的核苷酸序列。
35.一种载体,所述载体包含根据权利要求34所述的核酸。
36.根据权利要求35所述的载体,所述载体还包含与所述核酸可操作地连接的启动子。
37.一种细胞,所述细胞包含根据权利要求34所述的核酸或根据权利要求35或36所述的载体。
38.一种产生根据权利要求1至27中任一项所述的多肽的方法,所述方法包括获得根据权利要求37所述的细胞以及使所述核酸在所述细胞中表达。
39.根据权利要求38所述的方法,所述方法还包括分离和纯化所述多肽。
40.根据权利要求29所述的方法、根据权利要求31所述的化合物或根据权利要求32所述的组合物,其中所述自身免疫性或炎症性疾病包括系统性红斑狼疮(SLE)、伴有肾脏牵涉/狼疮性肾炎(LN)的系统性红斑狼疮、ANCA相关血管炎(AAV)、原发性舍格伦综合征(pSS)、慢性移植物抗宿主病(cGVHD)、系统性硬化(SSc)、类风湿性关节炎(RA)、银屑病(Ps)、强直性脊柱炎(AS)或银屑病关节炎(PA)。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023051798A1 (zh) * | 2021-09-30 | 2023-04-06 | 江苏恒瑞医药股份有限公司 | 抗il23抗体融合蛋白及用途 |
WO2024140930A1 (en) * | 2022-12-28 | 2024-07-04 | Suzhou Transcenta Therapeutics Co., Ltd. | Bispecific binding protein comprising anti-baff antibody and use thereof |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9963510B2 (en) | 2005-04-15 | 2018-05-08 | Macrogenics, Inc. | Covalent diabodies and uses thereof |
ES2593754T3 (es) | 2010-11-04 | 2016-12-13 | Boehringer Ingelheim International Gmbh | Anticuerpos anti-IL-23 |
CN109206516A (zh) | 2012-05-03 | 2019-01-15 | 勃林格殷格翰国际有限公司 | 抗IL-23p19抗体 |
JP2017524359A (ja) | 2014-07-24 | 2017-08-31 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Il−23a関連疾患の処置に有用なバイオマーカー |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102369021A (zh) * | 2008-12-19 | 2012-03-07 | 宏观基因有限公司 | 共价双抗体及其用途 |
CN103038251A (zh) * | 2010-02-19 | 2013-04-10 | Xencor公司 | 新颖ctla4-ig免疫粘附素 |
CN103154025A (zh) * | 2010-08-02 | 2013-06-12 | 宏观基因有限公司 | 共价双抗体及其用途 |
CN103282382A (zh) * | 2010-11-04 | 2013-09-04 | 勃林格殷格翰国际有限公司 | 抗il-23抗体 |
US20130315911A1 (en) * | 2012-05-22 | 2013-11-28 | Bristol-Myers Squibb Company | Bispecific antibodies and methods of using the same |
CN103429261A (zh) * | 2010-12-22 | 2013-12-04 | 塞法隆澳大利亚股份有限公司 | 半寿期改进的修饰抗体 |
CN104220455A (zh) * | 2012-04-20 | 2014-12-17 | 伊莱利利公司 | 抗-baff-抗-il-17双特异性抗体 |
WO2015100246A1 (en) * | 2013-12-24 | 2015-07-02 | Ossianix, Inc. | Baff selective binding compounds and related methods |
US20150218267A1 (en) * | 2014-01-31 | 2015-08-06 | Boehringer Ingelheim International Gmbh | Novel anti-baff antibodies |
Family Cites Families (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4880635B1 (en) | 1984-08-08 | 1996-07-02 | Liposome Company | Dehydrated liposomes |
US5807715A (en) | 1984-08-27 | 1998-09-15 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin |
US4921757A (en) | 1985-04-26 | 1990-05-01 | Massachusetts Institute Of Technology | System for delayed and pulsed release of biologically active substances |
US4920016A (en) | 1986-12-24 | 1990-04-24 | Linear Technology, Inc. | Liposomes with enhanced circulation time |
JPH0825869B2 (ja) | 1987-02-09 | 1996-03-13 | 株式会社ビタミン研究所 | 抗腫瘍剤包埋リポソ−ム製剤 |
US4911928A (en) | 1987-03-13 | 1990-03-27 | Micro-Pak, Inc. | Paucilamellar lipid vesicles |
US4917951A (en) | 1987-07-28 | 1990-04-17 | Micro-Pak, Inc. | Lipid vesicles formed of surfactants and steroids |
US6277375B1 (en) | 1997-03-03 | 2001-08-21 | Board Of Regents, The University Of Texas System | Immunoglobulin-like domains with increased half-lives |
US6737056B1 (en) | 1999-01-15 | 2004-05-18 | Genentech, Inc. | Polypeptide variants with altered effector function |
KR101155294B1 (ko) * | 2000-06-16 | 2013-03-07 | 캠브리지 안티바디 테크놀로지 리미티드 | 면역특이적으로 BLyS에 결합하는 항체 |
CA2431600C (en) | 2000-12-12 | 2012-04-17 | Medimmune, Inc. | Molecules with extended half-lives, compositions and uses thereof |
ES2971647T3 (es) | 2005-04-15 | 2024-06-06 | Macrogenics Inc | Diacuerpos covalentes y usos de los mismos |
US9284375B2 (en) | 2005-04-15 | 2016-03-15 | Macrogenics, Inc. | Covalent diabodies and uses thereof |
JP2010513245A (ja) | 2006-12-14 | 2010-04-30 | アクトジェニックス・エヌブイ | 免疫調節を誘起するための結合分子の送達 |
KR101599735B1 (ko) | 2007-06-21 | 2016-03-07 | 마크로제닉스, 인크. | 공유결합형 디아바디 및 이것의 사용 |
EP3211010A1 (en) | 2007-12-21 | 2017-08-30 | Medimmune Limited | Binding members for interleukin-4 receptor alpha (il-4r) - 173 |
KR101603917B1 (ko) | 2008-05-09 | 2016-03-17 | 애브비 인코포레이티드 | 최종 당화 산물의 수용체(rage)에 대한 항체 및 이의 용도 |
US20130129723A1 (en) | 2009-12-29 | 2013-05-23 | Emergent Product Development Seattle, Llc | Heterodimer Binding Proteins and Uses Thereof |
GB201002238D0 (en) | 2010-02-10 | 2010-03-31 | Affitech As | Antibodies |
EP4012714A1 (en) * | 2010-03-23 | 2022-06-15 | Iogenetics, LLC. | Bioinformatic processes for determination of peptide binding |
AR080794A1 (es) * | 2010-03-26 | 2012-05-09 | Hoffmann La Roche | Anticuerpos bivalentes biespecificos anti- vegf/ anti-ang-2 |
GB201020738D0 (en) | 2010-12-07 | 2011-01-19 | Affitech Res As | Antibodies |
ES2668895T3 (es) * | 2011-03-16 | 2018-05-23 | Amgen Inc. | Variantes de Fc |
TWI622597B (zh) * | 2011-03-28 | 2018-05-01 | 賽諾菲公司 | 具有交叉結合區定向之雙重可變區類抗體結合蛋白 |
EP2814587B1 (en) | 2012-02-15 | 2018-05-02 | F.Hoffmann-La Roche Ag | Fc-receptor based affinity chromatography |
GB201203071D0 (en) * | 2012-02-22 | 2012-04-04 | Ucb Pharma Sa | Biological products |
KR102181776B1 (ko) * | 2012-06-05 | 2020-11-24 | 삼성전자주식회사 | 범용 디바이스에서의 파일 송/수신 장치 및 방법 |
WO2014100490A1 (en) * | 2012-12-19 | 2014-06-26 | Adimab, Llc | Multivalent antibody analogs, and methods of their preparation and use |
JP2015088330A (ja) * | 2013-10-30 | 2015-05-07 | トヨタ自動車株式会社 | 硫黄含有全固体電池 |
-
2016
- 2016-07-21 KR KR1020187004892A patent/KR102644875B1/ko active IP Right Grant
- 2016-07-21 UA UAA201801854A patent/UA125433C2/uk unknown
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- 2016-07-21 US US15/215,690 patent/US10280231B2/en active Active
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- 2018-01-18 PH PH12018500151A patent/PH12018500151A1/en unknown
- 2018-01-22 CL CL2018000182A patent/CL2018000182A1/es unknown
- 2018-01-23 SA SA518390788A patent/SA518390788B1/ar unknown
- 2018-02-07 CO CONC2018/0001264A patent/CO2018001264A2/es unknown
-
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- 2019-02-18 US US16/278,216 patent/US10844138B2/en active Active
-
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- 2020-10-22 US US17/076,894 patent/US11884744B2/en active Active
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102369021A (zh) * | 2008-12-19 | 2012-03-07 | 宏观基因有限公司 | 共价双抗体及其用途 |
CN103038251A (zh) * | 2010-02-19 | 2013-04-10 | Xencor公司 | 新颖ctla4-ig免疫粘附素 |
CN103154025A (zh) * | 2010-08-02 | 2013-06-12 | 宏观基因有限公司 | 共价双抗体及其用途 |
CN103282382A (zh) * | 2010-11-04 | 2013-09-04 | 勃林格殷格翰国际有限公司 | 抗il-23抗体 |
CN103429261A (zh) * | 2010-12-22 | 2013-12-04 | 塞法隆澳大利亚股份有限公司 | 半寿期改进的修饰抗体 |
CN104220455A (zh) * | 2012-04-20 | 2014-12-17 | 伊莱利利公司 | 抗-baff-抗-il-17双特异性抗体 |
US20130315911A1 (en) * | 2012-05-22 | 2013-11-28 | Bristol-Myers Squibb Company | Bispecific antibodies and methods of using the same |
WO2015100246A1 (en) * | 2013-12-24 | 2015-07-02 | Ossianix, Inc. | Baff selective binding compounds and related methods |
US20150218267A1 (en) * | 2014-01-31 | 2015-08-06 | Boehringer Ingelheim International Gmbh | Novel anti-baff antibodies |
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WO2023051798A1 (zh) * | 2021-09-30 | 2023-04-06 | 江苏恒瑞医药股份有限公司 | 抗il23抗体融合蛋白及用途 |
WO2024140930A1 (en) * | 2022-12-28 | 2024-07-04 | Suzhou Transcenta Therapeutics Co., Ltd. | Bispecific binding protein comprising anti-baff antibody and use thereof |
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