CN111587253A - 抗人迁移刺激因子(msf)及其用途 - Google Patents
抗人迁移刺激因子(msf)及其用途 Download PDFInfo
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Abstract
本发明涉及能识别和结合包含在人迁移刺激因子(MSF)序列中的表位,且不识别和结合人纤连蛋白1(hFn1)的抗体,以及在诊断方法和治疗中的用途。
Description
技术领域
本发明涉及抗-MSF(迁移刺激因子)抗体,其医药用途及其在炎症疾病特别是肿瘤的治疗或预后方法中的用途。
现有技术
塑性是巨噬细胞的标志:接触细胞因子或微生物产物,其获得特定和不同的表型。M1和M2极化巨噬细胞是连续功能状态的极端[1]。M1巨噬细胞介导对胞内病原体和肿瘤的抗性,而M2极化巨噬细胞发挥免疫调控性能并协调组织修复和重建。另外,M2巨噬细胞还在严重炎症疾病,例如哮喘和过敏性疾病中,以及对寄生虫的抗性中起作用[2]。在癌症中,肿瘤相关巨噬细胞(TAM)是最广泛的宿主炎症细胞,而且是肿瘤微环境的必要组成[3-5]。TAM起到双重作用:如预期的,一方面它们能引发抗肿瘤反应,但在大多数情况下其协调癌症发作和进展的关键步骤[6-8]。接触肿瘤衍生的产物后,TAM获得M2样表型,促使肿瘤增殖和进展,血管生成和淋巴血管生成,并抑制适应性免疫。在实验模型中证实了巨噬细胞在肿瘤生长中的作用。在人类中,CD68+或CD163+TAM浸润性实体瘤,例如乳癌和胰腺癌,和不良结果有关[9-11]。类似地,TAM数量增加与患有经典霍奇金氏淋巴瘤的患者中无进展存活缩短密切相关[12]。TAM靶向是经筛选的抗癌化合物的关键性质,例如曲贝替定(trabectedin),一种EMA和FDA批准的抗肿瘤药[13]。靶向巨噬细胞集落刺激因子(M-CSF或CSF-1)途径——巨噬细胞迁移、分化和存活的主要调节剂——的抗体或单个分子及其前体本身或与检查点阻断抑制剂一起正进行临床评估[14]。因此,临床前和临床数据表明TAM是癌症患者风险分级的可能生物标志,提供了TAM定向治疗的原理保证[7,15-17]。如上所述,显然需要合适的生物标志物来鉴定肿瘤物质内的TAM,以及确定作为治疗靶标的M2极化巨噬细胞。M1和M2极化巨噬细胞以及M2样TAM的基因分型揭示了一系列的M2极化细胞选择性表达的基因[18]。这些分子之一是人纤连蛋白1(hFn1)的截短形式,称作迁移刺激因子(MSF)[18,19](图1)。人Fn1(SEQ ID No:1,NCBI登录号AB191261.1,DNA;SEQ ID No:2,NCBI登录号BAD52437.1,蛋白质)和MSF(SEQ ID No:3,NCBI登录号AJ535086.1,DNA;SEQ ID No:4,NCBI登录号CAH60958.1,蛋白质)的DNA和蛋白质序列如下所述。人MSF的cDNA与人纤连蛋白cDNA的5’端相同,直到包括外显子III-1a,止于3’端独特的195个核苷酸的序列。在转录和转录后水平上通过两步机制控制MSF的表达。初始MSF转录物最初是由纤连蛋白基因通过分隔外显子III-1a和III-1b的内含子通读,然后通过内含子内切割产生5.9-kb MSF前-mRNA(转录水平)产生的。该前体被进一步切割,形成2.1-kb的成熟MSF mRNA,含有30-bp的框内编码序列,延续到外显子III-1a(转录后水平)。成熟mRNA迅速运到胞质,在此翻译成与全长纤连蛋白的N端相同的70-kDa蛋白(直到和包括外显子III-1a编码的氨基酸序列),加入MSF-独特的(内含子编码的)长10个氨基酸的C末端(图1)。MSF是胎儿期而不是正常成体细胞产生的癌胚分子。然而,不同的报道描述了癌症相关的成纤维细胞和癌细胞的MSF产生。对此,发明人已经记录了M2极化和肿瘤相关巨噬细胞(TAM,其具有M2样表型,促进肿瘤增殖和进展,血管生成和淋巴血管生成以及抑制适应性免疫)中MSF产生[18]。WO9000567涉及迁移刺激因子-1,其是能刺激本身不产生该多肽的正常成体成纤维细胞迁移的多肽,聚丙烯酰胺凝胶电泳测得具有表观分子量70kD,在生理pH下是阳离子,用10%饱和或更低的硫酸铵能从水溶液中沉淀出来,在pH2而不是pH10下在溶液中稳定,在56℃变性,易受胰蛋白酶和烷基化/还原的影响,且结合肝素。其他迁移刺激因子类似,但是阴离子的。其由来自癌症病人的胚胎或胚胎样成纤维细胞产生(但不是正常成体皮肤成纤维细胞),其产生可用作各种癌症的诊断或预后指征。
本发明人对M2极化巨噬细胞产生MSF的观察促使其调查是否MSF能被用作诊断和预后标志物。已记载了针对跨越前述人MSF的C末端尾的合成肽(即,VSIPPRNLGY[SEQ IDNO:11])生成的小鼠单克隆抗体(即mAb7.1)[19,24]的产生。先前报道了抗体mAb7.1在斑点印迹设置中识别rhMSF[19],但对于该抗体在ELISA中的应用还没有数据。另外,基于现有的证据,该抗体的使用限于免疫组织化学过程[19,23,20]。因此,对于能在不同实验设定中检测MSF而不与纤连蛋白-1结合的抗体仍有需要。
发明概述
因此,发明人制备了一种小鼠单克隆抗体(称作1G5.3),其选择性识别MSF并能有效定量具有与巨噬细胞M2极化有关的病理状态的个体生物液中的MSF水平。该抗体是通过用重组人MSF(rhMSF)接种小鼠产生的,特异性识别特有的10个氨基酸长的蛋白C-末端尾(aa648-657)。在此,发明人揭示在斑点印迹和ELISA设置中当如上所述与已知抗体mAb7.1抗体(也称作mabVSI7.1,报道于Cancer Res.2005年12月1日;65(23):10742-9)比较对rhMSF及其C-末端(即生物素化合成肽形式,biot-VSIPPRNLGY[SEQ ID NO:11][MSF特异性的十肽(SEQ ID NO:4的aa.648-657,其含有通过氨基己酸(Ahx)臂与NH2末端连接的生物素部分biot-Ahx-VSIPPRNLGY)的结合时,只有本发明的抗体在典型ELISA条件下识别biot(生物素化)-VSIPPRNLGY(SEQ ID NO:11)肽(即MSF的C-端特有尾)和rhMSF。而且,本发明的抗体以剂量依赖形式在调理培养基中以及作为纯化分子都识别biot-VSIPPRNLGY(SEQ IDNO:11)肽和rhMSF。另外,本发明的纯化抗体在斑点印迹实验中特异性检测rhMSF,其将该抗体的应用范围扩大到了斑点印迹。这些结果表明,本发明的抗体在不同实验设置下,最重要的是在测定生物液中的MSF水平的ELISA免疫试验中具有独特的识别MSF的能力。
发明详述
本发明的作者制备了一种单克隆抗体称作1G5.3,其用重组人MSF(rhMSF)免疫BALB/c小鼠获得。用间接ELISA根据抗体与rhMSF结合的特异性和选择性选择分泌该抗体的杂交瘤克隆。用所选杂交瘤制备的抗体实际上不识别hFn1。
因此,本发明的一个目的是一种能识别和结合人迁移刺激因子(MSF)的序列VSIPPRNLGY(SEQ ID No:4的aa 648到aa.657[SEQ ID NO:11])中所包含的表位,且不识别和结合人纤连蛋白1(hFn1)的抗体。
优选地,所述表位由人迁移刺激因子(MSF)的序列VSIPPRNLGY(SEQ ID No:4的aa.648到aa 657(SEQ ID NO:11))组成。
本发明的另一个目的是能识别和结合人迁移刺激因子(MSF),且不识别和结合人纤连蛋白1(hFn1)的抗体。
优选本发明的抗体特征是其利用序列VSIPPRNLGY的肽(SEQ ID No:4的aa648-657(SEQ ID NO:11))获得。在用于获得本发明抗体的序列VSIPPRNLGY(SEQ ID NO:11)肽中,优选在COOH端加上半胱氨酸(见SEQ ID NO:9),更优选地,肽与匙孔血蓝蛋白(KLH)偶联。
在一个优选实施方式中,本发明的抗体选自IgG、IgM、IgA和IgE抗体。
在一个优选实施方式中,本发明的抗体能在免疫试验中,优选在酶联免疫吸附试验(ELISA)中识别和结合MSF。
优选本发明抗体包含:
-重链的互补决定区3(CDRH3),与氨基酸序列WDY(SEQ ID NO:12)(SEQ.ID No.6的aa.120-122)具有至少80%相同性,和/或
-轻链的互补决定区3(CDRL3),与氨基酸序列QSYNLHT(SEQ ID NO:15)(SEQ.IDNo.8的aa.116-122)具有至少80%相同性。
更优选包括:
-重链的互补决定区3(CDRH3),包含序列SEQ.ID No.12,和/或
-轻链的互补决定区3(CDRL3),包含序列SEQ.ID No.15。
优选本发明抗体包含:
-重链的互补决定区3(CDRH3),与氨基酸序列WDY(SEQ ID NO:12)(SEQ.ID No.6的aa.120-122)具有至少80%相同性,优选所述CDRH3包含SEQ ID NO:12的序列,和/或
-重链的互补决定区2(CDRH2),与氨基酸序列EIRMKSDNYATYYAESVKG(SEQ ID NO:13)(SEQ.ID No.6的aa.69-87)具有至少80%相同性,优选所述CDRH2包含SEQ ID NO:13的序列,和/或
-重链的互补决定区1(CDRH1),与氨基酸序列NDWMN(SEQ ID NO:14)(SEQ.ID No.6的aa.50-54)具有至少80%相同性,优选所述CDRH1包含SEQ ID NO:14的序列,和/或
-轻链的互补决定区3(CDRL3),与氨基酸序列QSYNLHT(SEQ ID NO:15)(SEQ.IDNo.8的aa.116-122)具有至少80%相同性,优选所述CDRL3包含SEQ ID NO:15的序列,和/或
-轻链的互补决定区2(CDRL2),与氨基酸序列WASTRYS(SEQ ID NO:16)(SEQ.IDNo.8的aa.76-82)具有至少80%相同性,优选所述CDRL2包含SEQ ID NO:16,和/或
-轻链的互补决定区1(CDRL1),与氨基酸序列RSSHYLLNSRTRKNFLS(SEQ ID NO:17)(SEQ.ID No.8的aa.44-60)具有至少80%相同性,优选所述CDRL1包含SEQ ID NO:17的序列。
所述互补决定区(CDR)肽优选是CDR3肽,包含选自以下的氨基酸序列:WDY(SEQ IDNO:12)(SEQ.ID No.6的aa.120-122)和QSYNLHT(SEQ ID NO:15)(SEQ.ID No.8的aa.116-122)。
更优选地,本发明抗体包含:
-重链的互补决定区3(CDRH3),与氨基酸序列WDY(SEQ ID NO:12)(SEQ.ID No.6的aa.120-122)具有至少80%相同性,优选所述CDRH3包含SEQ ID NO:12的序列,或
-轻链的互补决定区3(CDRL3),与氨基酸序列QSYNLHT(SEQ ID NO:15)(SEQ.IDNo.8的aa.116-122)具有至少80%相同性,优选所述CDRL3包含SEQ ID NO:15的序列。
甚至更优选地,本发明抗体包含:
-重链的互补决定区3(CDRH3),与氨基酸序列WDY(SEQ ID NO:12)(SEQ.ID No.6的aa.120-122)具有至少80%相同性,优选所述CDRH3包含SEQ ID NO:12的序列,和
-轻链的互补决定区3(CDRL3),与氨基酸序列QSYNLHT(SEQ ID NO:15)(SEQ.IDNo.8的aa.116-122)具有至少80%相同性,优选所述CDRL3包含SEQ ID NO:15的序列。
本发明的抗体优选包含重链可变区,其包含与以下氨基酸序列具有至少80%相同性的序列:EVKIEESGGGLVQPGGSMKLSCVASGFTFSNDWMNWVRQSPEKGLEWVAEIRMKSDNYATYYAESVKGRFTISRDDSKNSVYLQMNNLRAEDNGIYYCTSWDYWGQGTTLTVSS(SEQ ID NO:18)(SEQ ID No.6的aa.20-133)和/或
轻链可变区,其包含与以下氨基酸序列具有至少80%相同性的序列:
DIVMSQSPSSLAVSTGEKVTMNCRSSHYLLNSRTRKNFLSWYQQKPGQSPQLLIYWASTRYSGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCKQSYNLHTFGGGTKLEIK(SEQ ID NO:19)(SEQ ID No.8的aa.21-132)。
更优选地,本发明抗体包含:
-重链可变区,包含以下氨基酸序列:
EVKIEESGGGLVQPGGSMKLSCVASGFTFSNDWMNWVRQSPEKGLEWVAEIRMKSDNYATYYAESVKGRFTISRDDSKNSVYLQMNNLRAEDNGIYYCTSWDYWGQGTTLTVSS(SEQ ID NO:18)(SEQ ID No.6的aa.20-133)和/或
-轻链可变区,包含以下氨基酸序列:
DIVMSQSPSSLAVSTGEKVTMNCRSSHYLLNSRTRKNFLSWYQQKPGQSPQLLIYWASTRYSGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCKQSYNLHTFGGGTKLEIK(SEQ ID NO:19)(SEQ ID No.8的aa.21-132)。
甚至更优选地,本发明的抗体包含与SEQ ID NO:6和/或SEQ ID NO:8的氨基酸序列具有至少80%相同性的序列。更优选地,本发明的抗体包含主要由SEQ ID No.6的氨基酸序列组成的重链和/或主要由SEQ ID No.8的氨基酸序列组成的轻链。
本发明的还有一个目的是能够识别和结合上述抗体识别的表位,而且不识别和结合人纤连蛋白1(hFn1)的抗体。
优选本发明的抗体选自以下:单克隆抗体、嵌合抗体、人源化抗体、去免疫化抗体、全人抗体、单链抗体、双特异性抗体、双抗体、scFv、Fab、F(ab)’2及其二聚、寡聚或多聚物。
本发明的还有一个目的是一种选择性检测和/或测定蛋白MSF或其片段的量的体外或离体方法,包括步骤:在从个体获得的分离的生物样品中检测MSF或其片段,通过能识别和结合人迁移刺激因子(MSF)的序列VSIPPRNLGY(SEQ ID NO:11)(SEQ ID No.4的aa.648到aa 657)中包含的表位,而不识别和结合人纤连蛋白1(hFn1)的特异性配体,优选所述配体是抗体,更优选所述抗体是上述抗体。
本发明的另一个目的是一种在个体内对癌症或炎症病状,优选哮喘或过敏评估风险和/或诊断和/或预后和/或监测进展和/或监测治疗处理的效力和/或筛选治疗处理的体外或离体方法,包括步骤:
a)在获自个体的分离生物样品中检测或测定蛋白质MSF或其片段,或编码所述蛋白质或其片段的多核苷酸的量或活性,和
b)与合适的对照进行比较。
优选在评估上述所定义的癌症或炎症病理风险和/或诊断和/或预后和/或监测进展和/或监测治疗处理的效力和/或筛选治疗处理的体外或离体方法中,蛋白质MSF或其片段的量的检测和/或测定是通过一种特异性配体,其能够识别和结合包含在以下序列(VSIPPRNLGY(SEQ ID NO:11),来自人迁移刺激因子(MSF)的SEQ ID No.4的aa.648到aa.657)中的表位,且不识别和结合人纤连蛋白1(hFn1),优选所述配体是抗体,更优选所述抗体如上定义。
蛋白质MSF或其片段的所述检测和/或测定优选通过免疫试验,优选ELISA试验进行。
本发明的体外或离体方法优选包括步骤:
a)生物样品与上述抗体接触并孵育,从而如MSF存在形成MSF-抗体复合物;
b)将生物样品与MSF-抗体复合物分离;
c)用抗体的检测手段选择性检测与抗体结合的MSF和/或对与抗体结合的MSF定量;
d)将c)中获得的结果与对照结果比较。
优选抗体固定于固相支持物,优选固定的抗体包被在板上,优选微量滴定板上。
检测手段优选是可检测抗体。可检测抗体优选可直接检测,可任选的可检测抗体可通过荧光剂放大,还可任选可检测抗体被生物素化,检测手段是亲和素或链霉亲和素-过氧化酶和3,3',5,5'-四甲基联苯胺,或可检测抗体与碱性磷酸酶偶联,则检测手段是对硝基苯基磷酸盐和/或4-甲基伞形基磷酸盐。
蛋白质MSF或其片段的量的所述检测和/或测定优选通过ELISA试验进行。
本发明的另一个目的是上述抗体在分离的生物样品中检测和/或定量蛋白质MSF或其片段的用途,优选其中MSF或其片段的检测能确定M2极化巨噬细胞和/或M2样肿瘤相关巨噬细胞在个体中的存在。
本发明的还有一个目的是上述抗体的医药用途。
本发明的另一个目的是能调节MSF表达和/或功能的分子,用于预防和/或治疗癌症或炎症病状,优选哮喘或过敏,其中所述分子优选能选择性耗竭M2极化巨噬细胞和/或M2样肿瘤相关巨噬细胞,所述分子优选是上述抗体。
本发明的另一个目的是包含至少一种上述抗体和药学上可接受的赋形剂的药学组合物,优选所述组合物用于肠胃外给药,优选静脉内使用。
本发明的其他目的是编码上述抗体的核酸分子,优选包括主要由以下序列组成的核苷酸序列:
GAAGTGAAAATTGAGGAGTCTGGAGGAGGCTTGGTGCAACCTGGAGGATCCATGAAACTCTCCTGTGTTGCCTCTGGATTCACTTTCAGTAACGACTGGATGAACTGGGTCCGCCAGTCTCCAGAGAAGGGGCTTGAGTGGGTTGCTGAAATTAGAATGAAATCTGATAATTATGCAACATATTATGCGGAGTCTGTGAAAGGGAGGTTCACCATCTCAAGAGATGATTCCAAAAATAGTGTCTACCTGCAAATGAACAATTTAAGAGCTGAAGACAATGGCATTTATTACTGTACCAGTTGGGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA(SEQ ID No.5的nt.58-399)(SEQ IDNO:20)和/或
GACATTGTGATGTCACAGTCTCCATCCTCCCTGGCTGTGTCAACAGGAGAGAAGGTCACTATGAACTGCAGATCCAGTCACTATCTGCTCAACAGTAGAACCCGAAAGAACTTCTTGTCTTGGTACCAACAGAAACCAGGACAGTCTCCTCAACTGCTGATCTACTGGGCATCCACTAGGTATTCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTGTGCAGGCTGAAGACCTGGCAGTTTATTACTGCAAACAATCTTATAATCTTCACACGTTCGGAGGGGGGACCAAGTTGGAAATAAAG(SEQ ID No.7的nt.61-396)(SEQ ID NO:21),编码上述抗体的表达载体,优选包含所述核酸或包含所述核酸的宿主细胞,或所述表达载体。
甚至更优选地,本发明的核酸序列与SEQ ID NO:20和/或SEQ ID NO:21的序列具有至少80%相同性。更优选地,本发明的核酸序列主要由SEQ ID No.20和/或SEQ ID No.21组成。甚至更优选地,本发明的核酸主要由SEQ ID No.5和/或SEQ ID No.7组成。
本发明的另一个目的是检测和/或定量生物样品中的蛋白质MSF或其片段的试剂盒,其包含上述抗体和可任选的复合物抗原-抗体的检测和/或定量手段,以及所述试剂盒实施上述方法的用途。
优选试剂盒还包含固定抗体的固相支持物,所述固相支持物优选是微量滴定板。
本发明的另一个目的是上述试剂盒用于实施上述方法的用途,和上述试剂盒在个体生物样品中对癌症或炎症病状进行诊断和/或预测发生的风险和/或预后和/或监测进展和/或监测治疗处理的效力和/或筛选治疗处理方法的用途。
优选上述方法是免疫试验,优选ELISA,和/或其检测和/或定量生物样品中的人MSF。
在上述方法中,所述蛋白质MSF或其片段,或所述多核苷酸或其片段在从个体获得的分离的生物样品中的量或活性高于对照量或活性,表明个体有提高的发病风险或受到疾病影响。
优选生物样品分离自人个体,可任选的其中人个体是癌症患者或具有炎症病状的患者,以及测量步骤a)还包括与标准曲线比较,以确定与正常个体相比的MSF水平。优选生物样品是肿瘤裂解物、血浆、血清或尿液。
监测进展和/或监测疾病治疗处理的效力的体外方法如上所述,优选包括步骤:
a)在获自个体的分离生物样品中测定蛋白质MSF或其片段,或编码所述蛋白质或其片段的多核苷酸的量的改变或活性的改变,和
b)将步骤a)测定的改变与合适的对照改变比较。
优选如上所述对癌症或炎症病状,优选哮喘或过敏评估风险和/或诊断和/或预后的体外方法包括步骤:
a)在获自个体的分离生物样品中测定蛋白质MSF或其片段,或编码所述蛋白质或其片段的多核苷酸的量或活性,和
b)将步骤a)测定的量或活性与合适的对照量或活性比较,
其中所述蛋白质MSF或其片段,或所述多核苷酸或其片段在从个体获得的分离的生物样品中的量或活性高于对照量或活性,表明个体有提高的发病风险或受到癌症或炎症病状的影响。
优选监测进展和/或监测癌症或炎症病状的治疗处理的效力的体外方法如上所述,包括步骤:
a)在获自个体的分离生物样品中测定蛋白质MSF或其片段,或编码所述蛋白质或其片段的多核苷酸的量的改变或活性的改变,和
b)将步骤a)测定的改变与合适的对照改变比较。
在本发明的一个优选方面,上述方法的步骤a)是通过如上所述检测和/或测定MSF蛋白质或其片段的量的方法进行的。本发明的抗体可用于如上所述通过免疫亲和层析(IAC)纯化培养上清液,例如用编码rhMSF的DNA序列转染的细胞系中的分泌的rhMSF,和/或体内和体外例如M2巨噬细胞,癌胚成纤维细胞和癌细胞表达和分泌的天然(非重组)MSF蛋白质。本发明的抗体也可用于免疫组织化学,在生理条件和主要与癌症相关的病理条件下识别人组织中的MSF。
在优选的实施方式中,获自个体的分离生物样品中MSF量比对照量高,这表示该个体患有癌症或炎症病状或者发展成癌症或炎症病状的风险增加。
在本发明方法的其它实施方式中,获自个体的分离生物样品中MSF的量比对照量低,这表示该个体朝着病状改善的方向发展。在本发明中,合适的对照可选自健康患者中的测定值,患有非炎性病状或不受癌症影响的患者,在治疗处理前受炎症或癌症病状影响的患者,在治疗处理期间受炎症病状或癌症影响的患者,在疾病过程的不同时间点患有炎症病状或癌症的患者。上述方法的分离生物样品优选血浆,血液,血清,通过手术切除获得的组织,通过活检获得的组织,细胞培养物,细胞上清液,细胞裂解物,组织样品,器官,骨髓。本发明的另一个目的是治疗和/或预防癌症或其他炎症疾病的方法,包括对个体施用本发明的抗体。本发明的另一个目的是编码上述抗体的表达载体,优选包含上述核酸。本发明的另一个目的是宿主细胞,其包含上述核酸,或上述载体,和一种产生上述抗体的方法,包括培养上述宿主细胞并从细胞培养物中纯化抗体的步骤。在本发明的其它实施方式中,提供了用于分析患者样品的装置或试剂盒。或者,试剂可以这样的试剂盒提供,所述试剂盒包括处于悬浮(suspension)或可悬浮(suspendable)形式的试剂,例如,与适合流式细胞术的珠结合的试剂,优选用抗体捕获包覆的磁珠,或用于多色分析的定制干燥抗体混合物和/或具有一定大小滤芯的柱和/或联合特异性抗体过滤器(SAF)等。说明书可以包括进行基于抗体的流式细胞术试验的说明。检测手段优选能够检测和/或测量MSF量的手段,例如,能够检测复合物抗原-抗体的手段,如酶偶联的二抗,发光底物,抗体捕获包覆的磁珠,定制干燥抗体混合物和/或具有一定大小滤芯的柱和/或联合特异性抗体过滤器(SAF)。优选所述试剂盒还包括固相支持物,其中抗体被固定。优选本发明的试剂盒是免疫试验试剂盒,更优选是ELISA试剂盒。检测和/或定量抗原-抗体复合物的手段可以是检测和/或定量MSF的催化活性的手段,例如与酶、发光底物偶联的二抗。这些手段也为本领域熟知。根据本发明的试剂盒还可包含典型助剂,如缓冲液、运载体、染料等和/或使用说明书。试剂盒还可包含将MSF量的提高与合适对照值比较的对照手段。例如,参考的已知标准,可以由正常个体或正常群体获得对照值。在本发明中,“对照结果”可以是分离自健康个体,或来自患有癌症或炎症疾病外的其他疾病的患者的样品获得的结果。
对于监测癌症和炎症疾病的进展的方法,对照结果可以是在开始治疗前的不同时间点,在治疗期间的不同时间点等的同一个体分离的样品的结果。
在监测治疗效力的方法中,对照样品可以是取自开始治疗前或在治疗期间取自不同时间的同一个体的样品。“监测效力”指监测药物的药物学概况。在筛选癌症和炎症疾病的治疗的方法中,对照样品可以是取自未治疗个体或用待测试物质治疗的个体,或用参照治疗治疗的个体的样品。特定癌症和炎症疾病的参照治疗是本领域技术人员已知的。“筛选”指评估药物是否对癌症和炎症疾病有生物或药物学活性。在本发明中,表述“检测”指任何例如通过化学发光、荧光、分光光度等观察、评估或定量抗体在样品中的存在或所述抗体在样品中的绝对或相对量的方法的任何用途。在本发明中,表述“定量”可以理解为测定MSF或相关抗体的量、浓度或水平,优选通过半定量或定量法。说明书中使用术语“量”表示但不限于蛋白质的绝对或相对量,以及任何与后者相关或可从其衍生出的其他值或参数。这样的值或参数包括获得自蛋白质的物理或化学性质的信号强度值,通过直接测量,例如,免疫试验、质谱或核磁共振中强度值获得的信号强度值。另外,这些值或参数包括间接测定获得的那些值或参数。
上述抗体包括人和动物单克隆抗体或其片段,单链抗体及其片段和小抗体,双特异性抗体,双抗体,三抗体,或其二聚、寡聚或多聚物。还包括衍生自本发明抗体的肽模拟物或肽,例如其包括一个或多个CDR区,优选CDR3区。还包括人单克隆抗体和肽序列,其基于结构活性连接,由人工建模过程产生(Greer J.等,J.Med.Chem.,1994,卷37,第1035-1054页)。优选抗体选自下组:完整免疫球蛋白(或抗体),Fv,scFv(单链Fv片段),Fab,F(ab)’2,抗体样结构域,抗体模拟结构域,单抗体结构域,多聚抗体,包含表位结合区的肽或蛋白水解片段。本发明中的术语“抗体”以最广泛含义使用,包括各种抗体和抗体模拟结构,包括但不限于单克隆抗体,多克隆抗体,多特异性抗体(例如双特异性抗体),人抗体,人源化抗体,去免疫化抗体,嵌合抗体,纳米抗体,抗体衍生物,抗体片段,抗运载蛋白,设计的锚蛋白重复序列(DARPins),亲和体,affilin,粘合素(affimer),affitine,阿尔法体(alphabody),阿维多聚体,fynomer,微小抗体(minibodies)和其他结合域,条件是它们显示对抗原理想的结合活性。这些抗体的抗原结合片段可用常规技术产生。这些片段的例子包括但不限于Fab、F(ab’)2、和Fv片段。也可考虑使用基因工程技术产生的抗体片段和衍生物。除非另外说明,术语“抗体”和“单克隆抗体”包括完整抗体及其抗原结合片段。“抗体片段”指除完整抗体以外的分子,所述分子包含完整抗体的部分,该部分结合与所述完整抗体结合的抗原。抗体片段的示例包括但不限于,Fv、Fab、Fab'、Fab'-SH、F(ab')2;双抗体;线性抗体;单链抗体分子(例如scFv);和抗体片段组成的多特异性抗体。VH和VL的Fv也称作“纳米抗体”。术语“模拟抗体”指不是抗体衍生物但能与抗原以抗体相同方式特异性结合的有机化合物或结合域。它们包括抗运载蛋白,设计的锚蛋白重复序列,亲和体,affilin,亲和素,affitine,阿尔法体,阿维多聚体,fynomer,微小抗体等。术语“嵌合”抗体指其中重链和/或轻链部分来源于一个特定来源或物种,而剩余的重链和/或轻链来源于不同的来源或物种的抗体。术语"全长抗体"、"完整抗体"和“全抗体”在本文中可互换使用,以表示具有与天然抗体结构基本类似的结构或具有包含如本文所述的Fc区的重链的抗体。“人抗体”是具有对应于人或人细胞产生,或衍生自使用人抗体库或其他编码人抗体的序列的非人来源的抗体的氨基酸序列的抗体。人抗体的定义特异性地排除了含有非人抗原结合残基的人源化抗体。在人中,抗体同种型是IgA,IgD,IgE,IgG和IgM。抗体“人源化”指嵌合抗体,其包含非人超变区(HVR)的氨基酸残基和来自剩余的人区域(FR:框架区)的氨基酸序列。在一些实施方式中,人源化抗体可包括基本至少一个完整的可变区,通常两个,其中所有或基本所有HVR(例如CDR)对应于非人抗体的相对部分,以及全部或几乎全部FR对应于人抗体的相对部分。人源化的抗体可任选地包含源自人抗体的抗体恒定区的至少一部分。抗体的“人源化形式”,例如非人抗体,指经过人源化的抗体。“去免疫化”的抗体是通过破坏HLA结合——T细胞刺激的基础要求——降低免疫原性的抗体。本文所用的术语“单克隆抗体”指获自一群基本同源的抗体的抗体,即,组成群体的每个抗体是相同的,和/或结合同一表位,除了可能的抗体变体,例如包含天然发生的突变或在单克隆抗体制备过程中产生的,这些变体通常以较低量存在。不同于通常包含针对不同决定簇(表位)的不同抗体的多克隆抗体制剂,单克隆抗体制剂中的各单克隆抗体均针对抗原上的单一决定簇。因此,修饰语“单克隆”指示该抗体获自基本均质的抗体群这一特点,而不应被解释为需要通过任何特定的方法来产生抗体。例如,待根据本发明使用的单克隆抗体可通过多种技术产生,包括但不限于,杂交瘤方法,基于重组DNA的方法,噬菌体展示方法,和使用含有人免疫球蛋白基因座的全部或部分的转基因动物的方法。在本发明的语境中,“结合MSF但不识别Fn1的抗体”包括能维持上面提到的特异性的对本发明抗体的修饰。这些改变包括例如,与效应分子例如化疗或细胞毒性剂和/或可检测报告部分的偶联。
双特异性抗体是大分子异双功能性交联物,其在一个分子内具有两个不同结合特异性。在该组中包括例如双特异性(bs)IgG,bs IgM-IgA,bs IgA-二聚物,bs(Fab’)2,bs(scFv)2,双抗体和bs双Fab Fc(Cao Y.和Suresh M.R.,Bioconjugate Chem.,1998,卷9,第635-644页)。
肽模拟物是指低分子量肽组分,其意指模拟天然肽组分,或者诱导相邻肽序列中特定结构形成的模板的结构(Kemp DS,Trends Biotechnol.,1990,第249-255页)。肽模拟物可以是例如衍生自CD3结构域。给定肽序列的方法学突变分析,即通过丙氨酸或谷氨酸扫描突变分析,允许鉴定对促凝血活性关键的肽残基。另一种改善某些肽序列活性的可能性是使用肽文库结合高通量筛选。
术语抗体还可以包括通过分析与结构-活性关系有关的数据获得的物质。这些化合物还可用作肽模拟物(Grassy G.等,Nature Biotechnol.,1998,卷16,第748-752页;Greer J.等,J.Med.Chem.,1994,卷37,第1035-1054页)。
术语抗体还可包括通过在宿主细胞中表达改变的编码免疫球蛋白的区域产生的蛋白质,例如“技术修饰的抗体”如合成抗体,嵌合或人源化抗体或其混合物,或抗体片段,其部分或完全缺乏恒定区,例如Fv、Fab、Fab’或F(ab)2等。在这些技术修饰的抗体中,例如一部分或多个部分的轻链和/或重链可以被取代。这些分子可以例如包括抗体,其由人源化重链和未修饰轻链(或嵌合轻链)组成,或相反。术语Fv,Fc,Fd,Fab,Fab’或F(ab)’2如现有技术所述使用(Harlow E.和Lane D.,于《抗体,实验室手册》(Antibodies,A LaboratoryManual),冷泉港实验室(Cold Spring Harbor Laboratory),1988)。
本发明还包含使用Fab片段或F(ab)'2片段,其衍生自单克隆抗体(mAb),针对MSF。优选地,异源框架区和恒定区选自人免疫球蛋白类型和同种型,例如IgG(亚型1-4),IgM,IgA和IgE。在免疫应答过程中,免疫球蛋白的类型转换可能发生,例如从IgM到IgG的转换;其中恒定区从例如交换成y。类型转换还可能以定向方式,通过基因工程方法发生("定向类型转换重组"),如现有技术已知的(Esser C.和Radbruch A.,Annu.Rev.Immunol.,1990,卷8,第717-735页)。然而,本发明的抗体不需要排他地包括免疫球蛋白的人序列。
在一个具体实施方式中,人源化抗体包含来自鼠单克隆抗体的互补决定区(CDR),其插在所选人抗体序列框架区中。然而也可使用人CDR区。优选人轻链和重链中的可变区技术上由一个或多个CDR交换改变。也可能使用全部6个CDR或少于6个CDR的不同组合。术语抗体还可以包括通过分析与结构-活性关系有关的数据获得的物质。这些化合物还可用作肽模拟物(Grassy G.等,Nature Biotechnol.,1998,卷16,第748-752页;Greer J.等,J.Med.Chem.,1994,卷37,第1035-1054页)。
本发明的抗体还包括那些结合特征已经通过直接突变、亲和成熟法、噬菌体展示改进的抗体。可通过本发明抗体任何CDR中的突变改变或改善亲和性或特异性。术语“可变区”或“可变结构域”指涉及抗体与抗原结合的抗体重链或轻链结构域。天然抗体的重链和轻链(分别为VH和VL)的可变域(或区)通常具有相似结构,每个结构域包含4个框架保守区(FR)和三个超变区(HVR见例如,Kindt等.《Kuby免疫学》(Kuby Immunology),第6版,W.H.Freeman and Co.,91页,2007)。.单个VH或VL结构域可足以赋予抗原结合特异性。此外,可以用来自与抗原结合的抗体的VH或VL结构域分离与特定抗原结合的抗体,来分别筛选互补VL或VH结构域文库(见例如Portolano等,J.Immunol.150:880-887,1993;Clarkson等,Nature352:624-628,1991)。
在另一个方面,抗体或其衍生物包含重链(VH)可变区序列和/或轻链(VL)可变区序列,其与如上所述SEQ ID NO:6或SEQ ID NO:8的氨基酸序列中各自包含的CDR具有至少80%,85%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%,或100%的序列相同性。在一些实施方式中,VH序列和/或VL序列与SEQ ID NO:6的aa 20-133或SEQ ID NO:8的aa.21-132分别具有至少80%,85%,90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%的相同性,与参比序列相比含有取代(例如保守取代),插入或缺失,然而包含该序列的抗-MSF抗体维持与表位结合的能力。抗体样结构域包括与抗体结构相关的结合蛋白,例如T细胞受体。本发明的抗体还包括功能等价物,其包括氨基酸序列与本发明抗体可变或超变区氨基酸序列基本相同的多肽。
在本发明中,“至少80%相同性”指相同性可以是与提到序列至少80%、87%或90%或95%或100%序列相同性。这应用于所有提到的%相同性。优选的,%相同性涉及提到序列的全长。
本发明的序列包括与所述序列具有至少70,优选至少80%,更优选至少90%相同性或同源性的氨基酸序列。相对于参照多肽序列的“氨基酸序列相同性百分数(%)”定义为,比对序列并导入缺口后(如果需要)以实现最大序列相同性百分比之后,候选序列中与参照多肽序列中氨基酸残基相同的氨基酸残基的百分比,且不考虑将任何保守性取代作为序列相同性的部分。以测定氨基酸序列相同性百分数为目的比对可以本领域技术范围内的不同方式实现,例如,使用公共渠道可获得的计算机软件如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。本领域技术人员能够确定用于比对序列的合适参数,包括使比较的序列实现全长最大对齐所需的任何算法。本发明的抗体可以例如具有以下解离常数(KD):<100nM,<10nM,<1nM,<0.1nM,<0.01nM,或<0.001nM或以下,例如从10-8M到10-13M,例如从10-9M到10-13M。重组和/或生物技术衍生物以及上述抗体的片段也包括在本发明内,条件是抗体的结合活性及其功能特异性被维持。上述抗体用作药物,优选用于治疗和/或预防癌症或炎症病状。可以用本发明的抗体治疗的疾病优选是肿瘤疾病,例如实体瘤(例如乳癌、肺癌、结直肠癌、胰腺癌如胰腺导管腺癌(PDAC)、胶质瘤、前列腺癌、甲状腺癌、卵巢癌、肝癌、神经母细胞瘤、黑色素瘤)和非实体瘤(例如白血病、多发性骨髓瘤和淋巴瘤、慢性骨髓增生性肿瘤)。
在本发明的语境中,除了癌症,炎症病状包括哮喘、过敏、脓毒症和感染性疾病;自身免疫病,例如类风湿性关节炎和自体炎症疾病,例如炎性肠病;慢性变性疾病,涉及组织重建和纤维化,例如特发性肺纤维化,肝硬化和慢性心脏衰竭。
在本发明的语境下,“癌症”或“肿瘤”包括原代和转移肿瘤,以及难治肿瘤,表达MSF的肿瘤,实体或非实体肿瘤。实体瘤的例子是:乳癌、肺癌、结直肠癌、胰腺癌例如胰腺导管腺癌、胶质瘤、淋巴瘤、前列腺癌、甲状腺癌、卵巢癌、肝癌、神经母细胞瘤、黑色素瘤。非实体瘤的例子是:白血病、多发性骨髓瘤和淋巴瘤、慢性骨髓增生性肿瘤。
本发明的还有一个方面是编码上述抗体或与上述核酸杂交的核酸,或由对应的简并序列组成。本发明范围包括编码上述抗体的表达载体,优选包含上述核酸。本发明范围内还有包含上述核酸或上述载体的宿主细胞。术语“宿主细胞”、“宿主细胞系”和“宿主细胞培养物”可互换使用,并且指已引入外源核酸的细胞,包括此类细胞的子代。宿主细胞包括“转化株”和“转化细胞”,其包括转化的原代细胞及其衍生的子代,不计步骤次数。子代的核酸含量与亲本细胞未必完全相同,并可包含突变。在本发明中,包括突变子代,其具有与在原始转化细胞中经筛选或选择的相同功能或生物活性。本发明的核酸可用于转化合适的哺乳动物宿主细胞。可用作表达宿主的哺乳动物细胞是熟知的,包括例如CHO和BHK细胞。原核宿主包括例如大肠杆菌,假单胞菌,杆菌等。本发明的抗体可与额外的氨基酸残基,例如促进分离的标签融合。本文所用术语“载体”指能够扩增与之相连的另一核酸的一种核酸分子。该术语包括自复制核酸结构形式的载体,以及进入宿主细胞(载体引入其中的细胞)基因组的载体。某些载体能够引导与之操作性连接的核酸的表达。目前这些载体被称作“表达载体”。可使用任何合适表达载体,例如原核克隆载体如大肠杆菌的质粒,例如colE1,pCR1,pBR322,pMB9,pUC。适用于哺乳动物细胞表达的表达载体包括SV-40、腺病毒、反转录病毒衍生的DNA序列的衍生物。用于本发明的表达载体包含至少一种表达控制序列,其与必须表达的DNA序列或片段可操作性连接。本发明的还有一个目的是治疗和/或预防血管生成相关疾病的方法,疾病优选肿瘤病状如黑色素瘤、胶质母细胞瘤、结直肠癌、乳癌、肾癌、卵巢癌、宫颈癌、非小细胞肺癌和/或转移,视网膜病变例如糖尿病性视网膜病,年龄相关的渗出性黄斑降解的神经血管生成,视网膜动脉阻塞引起的黄斑水肿,病理性近视导致的脉络膜神经血管生成,该方法包括对需要的患者施用治疗有效量的上述抗体或其合成或重组片段。本发明的另一个目的是包含至少上述抗体或其合成或重组片段,和药学上可接受的赋形剂的药学组合物,优选所述组合物用于肠胃外给药,优选静脉内使用。组合物包含有效量的抗体和/或其重组或合成抗原结合片段。药学组合物在该领域是常规的,可由本领域技术人员基于常规的一般知识制备。用于本文所述治疗的制剂可以例如包含上述抗体,其浓度为约0.1mg/ml到约100mg/ml,优选从0.1到10mg/ml,更优选从0.1到5mg/ml。在其他制剂中,抗体浓度可以更低,例如至少100pg/ml。本发明的抗体在一次或多次治疗中施给患者。根据疾病的类型和严重性,可施用约1-20mg/kg抗体剂量,例如一次或多次给药或连续输注。本发明的抗体可以与其他治疗剂联合施用,特别是与能中和涉及肿瘤生长或血管生成的受体的抗体联合施用。任何给药方法可以用于施用本发明的抗体,特别是例如给药可以是经口、静脉内、腹膜内、皮下或肌肉内。本发明的抗体可作为偶联物给药,其与受体特异性结合并释放毒性物质。在具体实施方式中,本发明的药物组合物可以单剂形式给药(例如片剂、胶囊、丸剂等)。对于药物用途,组合物可以是溶液,例如可注射溶液,乳液,悬液等形式。载剂可以是任何从药学上看适合的载剂。优选所用的载剂能提高分子进入靶细胞的进入效果。在本发明的药物组合物中,抗体可以与其他治疗剂结合,例如与肿瘤生成或血管生成相关的其他生长因子受体的拮抗剂,例如VEGFR-2,EGFR,PDGFR,受体激酶抑制剂,BRAF抑制剂,MEK抑制剂,免疫调节抗体,抗癌药例如:贝伐单抗,雷莫昔单抗,阿飞普西,舒尼替尼,帕唑帕尼,索拉非尼,卡博替尼,阿西替尼,雷戈非尼,尼达尼布,乐伐替尼,维罗非尼,达拉菲尼,曲美替尼,化疗药,例如甲基化剂(替莫唑胺,达卡巴嗪),铂化合物(顺铂、卡铂、沙利铂),紫杉烷(紫杉烷(paclitaxel),白蛋白结合型紫杉烷,多西它赛),氟化嘧啶(5-氟尿嘧啶、卡培他滨),拓扑异构酶I抑制剂(伊立替康,拓扑替康),聚(ADP-核糖酶)聚合酶抑制剂(PARP)(例如,奥拉帕尼)等。根据治疗要求选择药物组合物。这些本发明的药物组合物可以片剂、胶囊、口服制剂、粉末、颗粒、片剂、注射或输液的液体溶液,悬液,栓剂,吸入制剂施用。制剂参见以下书籍:Remington(《雷明顿:药物科学与实践》(“Remington:The Science andPractice of Pharmacy”),Lippincott Williams&Wilkins,2000)。本领域技术人员可选择给药形式,有效剂量,通过筛选合适的稀释剂、佐剂和/或赋形剂。术语“药物组合物”指此类形式的制剂:所述其中所含活性成分的生物学活性有效,并且不含对待接受该制剂的个体具有不可接受的毒性的其他成分。本发明的另一个方面是产生上述抗体或其合成或重组片段的方法,包括步骤:培养宿主细胞,从细胞培养物纯化抗体或其合成或重组片段。
在本发明的语境中,术语“包含”还包括术语“主要具有”或“主要由……组成”。在本发明中,本文所述的“蛋白质”还包括对应直向或同源基因编码的蛋白质,功能性变体,功能性衍生物,功能性片段或其类似物,同种型,其剪接变体。在本发明中,“功能性”意指,例如,“保持其活性”。本文所用的“片段”表示这样的多肽,其具有优选至少10个氨基酸,更优选地至少15个、至少17个氨基酸或至少20个氨基酸,甚至更优选地至少25个氨基酸或至少37或40个氨基酸,并且更优的至少50、或100、或150或200或250或300或350或400或450或500个氨基酸的长度。本文公开的“MSF片段”优选包含序列VSIPPRNLGY[SEQ ID NO:4的aa.648到aa.657)(SEQ ID NO:11))或其片段。
通过参考下图的非限制性实施例阐述本发明。
图1.MSF和纤连蛋白域结构的比较。MSF是通读机制从单拷贝纤连蛋白产生的hFn1的截短同种型。70kDa蛋白质与hFn1N-端直到外显子III-1a编码的氨基酸序列相同,且添加了独特的10氨基酸长的肽(VSIPPRNLGY(SEQ ID NO:11))[SEQ ID No:4(从aa.648到aa.657),NCBI登录号N.CAH60958.1])。[20]后适应的图。Fn1和MSF中的功能域:Hip1/Fib1:肝素和纤连蛋白结合域;Gel-BD:对明胶/胶原的结合域;细胞-BD:RGD-介导的与整合素的结合;Hep2:高亲和力肝素结合域;Fib2:C-末端纤连蛋白结合域;IGD基序:异亮氨酸-甘氨酸-天冬酰胺三肽基序介导促细胞运动活性。
图2:用于转染CHO细胞和表达重组人MSF的表达载体的示范性说明。人MSF的完整cDNA序列被亚克隆入存在于载体内的BamIII限制性位点。
图3:在来自表达rhMSF的CHO-3E6克隆的调理培养基上间接ELISA。用不同稀释度的来自CHO-3E6细胞(表达rhMSF)克隆的调理培养基涂覆塑料孔和用兔pAb揭示的结合的MSF。
图4:对免疫过的小鼠的血清进行滴定。几轮免疫接种后收集来自经免疫小鼠的血清,并用ELISA分析。不同稀释度的血清加到涂覆有PBS、人纤连蛋白1(hFn1)和His-MSF的多孔板中。与抗小鼠二抗一起孵育并加入显色底物后,记录450nm处的吸光度。报道的吸光度值指在多个孔中获得的平均值。
图5:间接ELISA首次筛选杂交瘤调理培养基。通过ELISA评估来自96孔板中培养的杂交瘤的调理培养基识别人MSF的能力。简单说,50微升各培养基被加到涂覆有MSFVSIPPRNLGY(SEQ ID NO:11)(SEQ ID No:4的aa 648到aa.657)独特十肽,或来自表达rhMSF的CHO-3E6细胞的调理培养基的多孔板中,如所示。与合适的二抗一起孵育并加入显色底物后,记录450nm处的吸光度。报道的吸光度值涉及单个孔。
图6:间接ELISA二次筛选杂交瘤调理培养基。所选的杂交瘤(来自首次筛选,见图5)亚克隆并在96孔细胞培养板中培养。然后用间接ELISA测试调理培养基,以检测识别人MSF的抗体。简单说,50微升杂交瘤培养基上清液被加到涂覆有MSF VSIPPRNLGY(SEQ IDNO:11)(SEQ ID No:4的aa 648到aa.657)独特十肽,或来自表达rhMSF的CHO-3E6细胞如所述的调理培养基的多孔板中,如所示。与合适的二抗一起孵育并加入显色底物后,记录450nm处的吸光度,如图5所述。阴性对照(缓冲液)在孔1A和1B(抗小鼠IgG)以及1E和1F(抗兔IgG);阳性对照(肽或来自CHO-3E6的上清液),在1C和1D(兔pAb)孔中。
图7:以0.5细胞/孔亚克隆后,筛选14个克隆(选自二次筛选)。用来自表达rhMSF的CHO-3ES的浓缩调理培养基(50μl/孔)或人hFn1(1μg/孔)涂覆96孔板。每个克隆在一式两份的孔中测试,数据表示成450nm处测定的平均OD±SD。
图8:ELISA滴定1G5.3单克隆抗体。微量滴定板孔用人rhMSF或hFn1(0.5μg/ml)涂覆,并用不同稀释度的Ig5.3(从10μg/ml到0.005ng/ml)在一式两份的孔中孵育。数据表示成450nm测定的OD(平均±SD)。
图9:重组人MSF的IAC纯化。色谱图记录为280nm处的紫外吸光度。在10%胶上,在变性和还原条件下跑IAC组分(输入、流穿、洗涤、洗脱)。代表性银染色凝胶如插图所示(13μl/泳道)。
图10:1G5.3抗体的人癌组织免疫染色。甲醛固定且石蜡包埋的人乳癌和肺癌组织切片用1G5.3染色。箭头表示阳性细胞。
图11:人癌组织的免疫荧光染色。用CD68和1G5.3对来自乳癌和肺癌的组织样品染色。用箭头标出对两个标志物阳性的细胞。
图12:1G5.3mAb的夹心ELISA。A)免疫亲和纯化的重组人MSF运行的标准曲线。B)来自CHO-3E6细胞的MSF水平(8.0μg/ml±3.1,平均±SEM,n=3).
图13:夹心ELISA中的hFn1尖峰效应。如图12所述,用1G5.3mAb包被96孔板。然后在存在或不存在hFn1(100μg/ml)的情况下加入缓冲液(PBS)或来自CHO-3E6的上清液,如所述揭示了结合的MSF。
图14:人血浆中的MSF水平。用基于1G5.3mAb的夹心ELISA测定了健康个体和癌症患者血液中的MSF水平。(*p=0.048,曼-惠特尼检验)。
图15:抗人MSF 1G5.3F(ab)’2片段的制备和表征。A)在Vivaspin 6 10kDa MWCO浓缩机上浓缩1G5.3抗体,相对于100mM柠檬酸钠pH 3.50,在HiTrapDesalting 5ml柱上交换缓冲液,然后用胃蛋白酶反应。显示了来自代表性SEC运行的280nm紫外吸光度(左轴和实线,监测蛋白质洗脱)和导电率(右轴和虚线,监测除盐)的放大图。B)缓冲液交换后的物质与胃蛋白酶一起孵育,然后加到HiTrap MabSelect 1ml柱上,用PBS平衡,用100mM柠檬酸钠(pH3.50)洗脱。报道了典型的色谱(280nm处的紫外吸光度,左轴和实线;导电率,右轴和虚线)。包含Fc片段的未结合(流过)物质被丢弃,保留含有F(ab)’2片段的洗脱液并进一步处理。C)来自B的洗脱液在Vivaspin 6 10kDa MWCO浓缩器上浓缩,在用PBS平衡的Superdex200 10/300GL柱上层析,并用PBS洗脱。用280nm处的紫外吸光度监测蛋白质分离(F(ab)’2,左轴和实线)。100μg等分试样的完整未处理1G5.3抗体以相同条件跑样(完整IgG,右轴和虚线)。显示了两种物质层析的重叠。D)完整1G5.3抗体的等分试样和对应的F(ab)’2片段(来自C中的SEC)在NuPAGE Novex Bis-Tris10%胶中以变性条件下,二硫苏糖醇存在与否的情况下(分别为+DTT和-DTT)分离。显示了考马斯蓝染色的凝胶。未还原的完整1G5.3和F(ab)’2分别迁移到150和110kDa处;还原条件下1G5.3分成60(重链)和25(轻链)kDa的两个条带,而F(ab)’2在25kDa显示一条条带。A到D中的数据代表了三个独立实验。
图16:与1G5.3 mAb和1G5.3-F(ab)’2片段一起产生的背景信号的比较。在包被有1G5.3或1G5.3-F(ab)’2抗体的孔中加入缓冲液,并如文中所述显色。(**p=0.022斯氏t检验)。
图17:用1G5.3-F(ab)’2片段包被获得的标准曲线。A)在包被了1G5.3-F(ab)’2的孔中孵育0.2–200ng/ml hrMSF。显示了来自许多独立实验的8根标准曲线的重叠。B)报道的是来自A)部分的8根独立曲线的平均所获得的标准曲线。动态线性范围的上下限(适合MSF定量)分别是0.4和25ng/ml。
图18:健康个体和PDAC病人中的MSF水平。用1G5.3-F(ab)'2作为捕获抗体通过夹心ELISA测定MSF。A)健康个体中MSF水平的分布(n=28)。B)将PDAC患者(n=33)的MSF水平与健康个体中的比较。(****P<0.0001,曼-惠特尼检验)。
图19:mAb7.1和1G5.3与rhMSF相互作用的斑点印迹分析。重组人MSF(rhMSF)用Bio-Dot仪器(Bio-Rad)吸附到硝基纤维素膜(200ng/孔)上。封闭未包被位点后,用来自mAb7.1杂交瘤培养物的调理培养基(未稀释上清液)或纯化的1G5.3单克隆抗体(250ng/ml)探测斑点。空白孔(不含rhMSF)用作阴性对照(Ctrl)。显示一个印迹代表两次独立实验的斑点。
图20:mAb7.1和1G5.3与biot-VSIPPRNLGY和rhMSF的相互作用的间接ELISA分析。A)biot-VSIPPRNLGY肽(SEQ ID NO:11)(跨越人MSF的C末端的aa648-657序列)捕获在包被NeutrAvidin的Maxisorb板上。加入来自mAb7.1杂交瘤培养物(未稀释)的调理培养基或纯化的1G5.3(10ng/ml),用合适的HRP-偶联二抗如材料和方法部分所述揭示结合抗体。B)用rhMSF包被Maxisorb板,与mAb7.1杂交瘤培养物或纯化的1G5.3一起孵育。如A所述揭示结合抗体。A和B中的结果都表达成450nm处的吸光度(A450nm,平均±SD)。仅含有NeutrAvidin(A中的NeutrAvidin)或PBS-/-(B中的PBS)的孔作为阴性对照。显示了两次独立实验之一的图,每次实验一式两份进行。
图21:mAb7.1和1G5.3与biot-VSIPPRNLGY(SEQ ID NO:11)以及rhMSF相互作用的剂量依赖性。A)biot-VSIPPRNLGY肽(SEQ ID No:11)捕获在包被有NeutrAcidin的Maxisorb板上,如图20所示。以指定浓度加入来自mAb7.1或1G5.3杂交瘤细胞培养物的调理培养基。用合适的HRP偶联二抗,如材料和方法中所述揭示结合抗体。用rhMSF包被Maxisorb板,与指定稀释度的来自mAb7.1或1G5.3杂交瘤细胞培养物的调理培养基一起孵育。如A所示揭示结合抗体。A和B中结果都表示成扣除来自空白孔的背景信号(即仅含NeutrAvidin或PBS-/-)后的450nm处的吸光度(A450nm,平均±SD)。显示了两次独立实验之一的图,每次实验一式两份进行。
实施例1
材料和方法
市售试剂和细胞系
人纤连蛋白1(hFn1)获自Calbiochem(默克公司(Merck),意大利米兰;目录号:341635)。低内毒素的胎牛血清(FCS)购自西格玛奥德里奇公司(Sigma Aldrich)(意大利米兰;目录号:F7524);用于细胞培养的RPMI-1640,达氏改良伊氏培养基(DMEM)和胰蛋白酶来自隆萨公司(LONZA)(Euroclone,意大利米兰;目录号分别是BE12-167F;BE12-733F和BE17-161E)。具有钙和镁的磷酸缓冲盐(PBS)(PBS+/+)来自Biosera(Biotecna,意大利米兰;目录号:XC-S2067),不含钙和镁的PBS(PBS-/-目录号:D8537)和遗传霉素(G418;目录号:G8168)来自西格玛奥德里奇公司(意大利米兰)。
对人MSF特异性的合成肽(SEQ ID No:4的aa 648-657)由PRIMM S.r.l.(Milan,Italy意大利米兰)合成。在10氨基酸长的肽(VSIPPRNLGYC[SEQ ID No:9])COOH-末端加上半胱氨酸残基。肽与匙孔血蓝蛋白(KLH)偶联(VSIPPRNLGYC-KLH)(SEQ ID NO:9)。
人MSF的长105个氨基酸的片段(His-MSF;MSF的C末端部分的残基553到657;分子量14.335kDa,SEQ ID No:10),包括C末端的特异性MSF十肽VSIPPRNLGY(SEQ ID NO:11)和N-末端的组氨酸标签,从PRIMM获得。表达载体pSG5(4,100bp)来自Stratagene(美国加利福尼亚州拉由拉(La Jolla));用于对可选择标记G418赋予抗性的pSV2neo获自ATCC(美国弗吉尼亚州马那萨斯(Manassas))。用2000(英杰公司(Invitrogen))转染CHO细胞。CHO(中国仓鼠卵巢)细胞和SP2/0骨髓瘤细胞获自ATCC(分别是目录号ATCC CCL-61和CRL 1581),在达氏改良伊氏培养基(DMEM)(补充有L-谷氨酰胺(隆萨公司,目录号:BE17-605E/U1)和10%(v/v)FCS)中培养。
人重组MSF的表达
重组人MSF(rhMSF)在CHO细胞中表达。人MSF的全长cDNA(2,192bp,登录号AJ535086.1,SEQ ID No:3)亚克隆入pSG5的BamH1位点(图2,pSG-MSF)。通过测序确定克隆的MSF的朝向。根据厂商的方案共转染CHO细胞与pSV2neo载体,赋予G418抗性。用800μg/mlG418筛选转染克隆,通过间接ELISA(见下文)使用兔多克隆抗血清(在兔中用MSF十肽接种产生)分析MSF产生。通过有限稀释进一步亚克隆阳性克隆之一,获得CHO-3E6细胞,其产生高水平的人重组MSF。
针对人重组MSF的抗体的产生和纯化
用合成的人MSF特异性的长10个氨基酸的肽免疫兔产生兔多克隆抗血清(pAb),其中在COOH末端加入一个半胱氨酸(SEQ ID No:9),其与作为运载体的KLH偶联(VSIPPRNLGYC-KLH)(SEQ ID NO:9)。腹膜内用300μg稀释于完全弗氏佐剂中的MSF特异性肽攻击兔。在第21、28和35天用稀释于不完全弗氏佐剂中的肽重复免疫。收集来自免疫兔的血液(40-50ml/兔),用ELISA针对免疫原(VSIPPRNLGYC-KLH)(SEQ ID NO:9)测试,然后用免疫亲和法在携带相同免疫原的CNBr-琼脂糖柱上纯化特异性抗体。
免疫Balb/c小鼠(BALB/cAnNCrl,查尔斯河(Charles River),意大利,卡尔科(Calco))获得针对rhMSF的单克隆抗体。简单说,来自表达rhMSF的CHO-3E6细胞的200μl上清液在还原和变性条件下在Laemmli的不连续缓冲系统中,在10%聚丙烯酰胺凝胶上分离。凝胶用胶态考马斯(Bio-SafeTMCoomassie,目录号:161-0786,伯乐公司(Bio-Rad))染色,切下70kDa MSF条带,在PBS中粉碎。用悬液免疫8周龄Balb/c小鼠。程序重复三次,每次间隔3周。用纯化的His-MSF(20μg/小鼠)进行第四次攻击。用针对His-MSF和Fn1(用作阴性对照,见下)的间接ELISA分析抗体滴度。用聚乙烯Glycon1550(SERVA,意大利罗马)根据厂商的标准程序将来自响应小鼠的脾细胞与SP2/0骨髓瘤融合。细胞接种于96孔板中,并用HAT培养基(RPMI-1640培养基,含有10%FCS,100mg/mL链霉素,100IU/mL青霉素,100mM次黄嘌呤,16mM胸腺嘧啶和400mM氨基喋呤)筛选。2周后,用针对肽的间接ELISA筛选培养上清液的抗体反应性和特异性,用CHO-3E6的上清液作为人重组MSF来源。以5细胞/孔亚克隆来自4种不同阳性IgG生产孔的细胞(每个克隆两块96孔板)。用针对MSF十肽的间接ELISA和CHO-3E6细胞上清液所含的rhMSF进行第二次筛选。再次以0.5细胞/孔亚克隆两种不同IgG生产孔的细胞。通过针对包含在CHO-3E6细胞上清液中的rhMSF和Fn1的间接ELISA测试该亚克隆Ig的杂交瘤。发现总共14个杂交瘤能识别CHO-3E6培养上清液中含有的rhMSF,但不识别Fn1。选择杂交瘤1G5.3用于进一步开发。从蛋白质G-琼脂糖4Fast Flow柱(GE医疗公司(GEHealthcare),宾夕法尼亚州匹兹堡(Pittsburgh),目录号:17061801)根据厂商指示纯化现在命名为1G5.3的从1G5.3杂交瘤分泌的单克隆抗体。简单说,用PBS+/+平衡蛋白质G-琼脂糖柱(1ml柱体积),加载用相同缓冲液稀释的培养上清液。流穿再次加在柱上,过程重复3次。然后用0.1M甘氨酸-HCl(pH2.8)洗脱MSF特异性抗体,然后立即用1.5M Tris-HCl(pH8.8)缓冲。用小鼠单克隆抗体同种型测试试剂盒(伯乐公司,目录号:MMT1)测定1G5.3的同种型。使用兔mAb RM103(阿柏堪穆公司(Abcam),目录号:190484;抗小鼠κ轻链)和大鼠mAb JC5-1(阿柏堪穆公司,目录号:99622,抗小鼠λ轻链)通过Western印迹测定轻链类型。
1G5.3序列的测定
使用试剂(安碧公司(Ambion),目录号:15596-026)遵循技术手册从杂交瘤细胞分离总RNA。然后使用同种型特异性反义引物或通用引物,根据PrimeScriptTM第一链cDNA合成试剂盒(宝生物公司(Takara),目录号:6110A)的技术手册将总RNA逆转录成cDNA。根据GenScript的cDNA末端快速扩增(RACE)的标准操作程序(SOP)扩增VH、VL、CH和CL的抗体片段。分别将扩增的抗体片段克隆入标准克隆载体。进行集落PCR筛选具有正确尺寸的插入物的克隆。对于每个片段,对不少于五个具有正确尺寸的插入物的克隆进行测序。比对不同的克隆序列,提供共有序列。
F(ab)’2片段的制备
从1G5.3[1G5.3-F(ab)’2]通过酶处理产生F(ab)’2片段。8ml(8mg)等分试样的1G5.3单克隆抗体(1mg/ml于PBS溶液中)(西格玛奥德里奇公司,目录号:D1408)在Vivaspin6PES 10kDa MWCO浓缩器(赛多利斯斯泰帝公司(Sartorius Stedim),德国,哥廷根(Goettingen),目录号:VS0602)上浓缩到1ml,在HiTrap脱盐5ml柱(GE医疗公司,目录号:17-1408-01)上对100mM柠檬酸钠(pH 3.50)(默克密理博公司(Merck Millipore),德国,达姆施塔特(Darmstadt),目录号.106448)进行缓冲液交换,连续进行两次(500μl/次)。合并含蛋白质的组分(总体积4ml),通过280nm处的紫外吸光度测定抗体浓度,使用1.4的值作为小鼠IgG1在280nm处的消光系数(表示成0.1%(w/v)溶液在280nm处的吸光度)。
为了产生1G5.3-F(ab)’2片段,每mg抗体加入5μg胃蛋白酶(西格玛奥德里奇公司,目录号:P6887),得到的混合物在37℃孵育16小时。通过加入650μl 1M Tris-Cl,pH 8.80(默克密理博公司,目录号:108382)调节溶液pH至7.0,以封闭反应。然后将溶液加到HiTrapMabSelect蛋白质A1ml柱(GE医疗公司)上,用PBS平衡并用100mM柠檬酸钠(pH3.5)以1ml/分钟洗脱。合并含有F(ab)’2的组分(总体积4ml),用Vivaspin 6PES 10kDa MWCO浓缩器浓缩到600μl。在Superdex 20010/300GL柱(GE医疗公司)上层析浓缩的物质,该柱用PBS平衡,并以PBS以0.5ml/分钟速度洗脱。如上所述测定洗脱的组分中F(ab)’2片段,将SEC纯化的物质储存在-20℃备用。所有层析在Purifier FPLC系统(GE医疗公司)上进行;分别通过280nm处的紫外吸光度和导电率(mS/cm)监测蛋白质洗脱和盐分离。完整1G5.3抗体的3μg等分试样和对应的1G5.3-F(ab)’2片段(来自SEC)在NuPAGE Novex Bis-Tris 10%胶(赛默飞世尔科学公司(Thermo Fisher Scientific),马萨诸塞州沃尔瑟姆(Waltham))中以变性条件下,二硫苏糖醇存在与否的情况下分离。电泳后,用Bio-Safe考马斯染料(伯乐公司,加利福尼亚州赫拉克勒斯(Hercules))检测蛋白质。
人重组MSF的纯化
通过免疫亲和层析(IAC),从CHO-3E6的调理培养基中纯化人重组MSF。400ml调理培养基以2.5ml/分钟加到Purifier FPLC系统(GE医疗公司)中的共价偶联有1G5.3(2.8mg 1G5.3/ml亲和培养基)的5ml HiTrap NHS-激活的HP柱(GE医疗公司,宾夕法尼亚州匹兹堡)上,用缓冲液A(50mM Tris-HCl,150mM NaCl,pH 7.00)平衡。用缓冲液A,然后用缓冲液B(50mM Tris-HCl,500mM NaCl,pH7.00)以5ml/分钟充分洗涤1G5.3柱,用缓冲液C(3.5M MgCl2)洗脱结合的rhMSF,总体积为4ml。用Purifier FPLC系统上的分析级Superdex 200 10/300GL凝胶过滤系统(GE医疗公司)评估洗脱蛋白质的均一性,使用缓冲液B以0.5ml/分钟平衡和洗脱。另外,来自IAC的调理培养基(输入)、未结合物质(流穿)和洗脱的蛋白质(洗脱)的等分试样在NuPAGE Novex Bis-Tris 10%凝胶(赛默飞世尔科学公司,马萨诸塞州沃尔瑟姆)上在变性和还原条件下(即在二硫苏糖醇的存在下)解析。电泳后,用ProteoSilver Plus银染色试剂盒(西格玛奥德里奇公司,密苏里州圣路易斯(St.Louis))和Bio-Safe考马斯染料(伯乐公司,加利福尼亚州赫拉克勒斯)解析蛋白质,或将其转移到聚偏二氟乙烯(PVDF)膜上,用于随后使用抗人MSF或抗-hFn1兔多克隆抗体,然后用连接有抗兔IgG辣根过氧化物酶(HRP)的完全驴抗体(GE医疗公司)的免疫检测。用Immobilon western HRP底物(默克密理博公司,德国,达姆施塔特)对膜显色,在ChemidocMP系统(伯乐公司)上记录化学发光。整个纯化过程中,用Bradford蛋白质试验(伯乐公司)检测总蛋白质含量,用如下所述的“内部”ELISA MSF试验测定rhMSF特异性滴度。
对人肿瘤切片的免疫组化分析
切下石蜡包埋的人组织切片,并在37℃保存过夜。切片在Bioclear中脱蜡。在Decloaker室中,在DIVA缓冲液1X(生物医疗公司(Biocare Medical)目录号:DV2004)中进行抗原去掩蔽,在125℃进行3分钟,90℃进行5分钟。用Peroxidized-1(生物医疗公司,目录号:PX968)封闭内源过氧化物酶15分钟后,用Background Sniper溶液(生物医疗公司,目录号:BS966)封闭非特异性结合位点30分钟。然后用1G5.3(1/150-1/300)孵育人组织样品1小时,以鉴定MSF,或用小鼠单克隆抗人CD68(达科公司(Dako)目录号:MO876,克隆PG-M1,780μg/ml持续1小时)鉴定巨噬细胞。用CD68染色不需要抗原去掩蔽。在与兔抗小鼠MACH1聚合物-HRP(生物医疗公司,目录号:MIU539)孵育20分钟后揭示1G5.3或CD68的免疫染色。然后用3,3’-二氨基联苯胺四盐酸(生物医疗公司,目录号:DB801)显色反应。用苏木精溶液复染玻片3分钟。
间接ELISA
ELISA板(Nunc Maxisorb免疫平板目录号:446612)用His-MSF(1-0.5μg/孔),来自CHO-3E6(50μl)的上清液或hFn1(1μg/孔)(用15mM碳酸钠缓冲液(pH9.6)稀释)包被(4℃过夜)。包被后,用PBS+/+和0.05%(v/v)Tween 20(洗涤缓冲液)洗涤平板三次,室温与5%(w/v)脱脂牛奶(溶于洗涤缓冲液)孵育2小时封闭非特异性相互作用。用洗涤缓冲液洗涤孔三次,然后加入兔多克隆抗血清、来自抗MSF杂交瘤的上清液或稀释于洗涤缓冲液的纯化的1G5.3的等分试样,在室温孵育1小时。然后加入用辣根过氧化物酶标记的抗兔IgG或抗小鼠IgG(目录号分别为GENA934和GENA931,GE医疗公司)(1/2000,于洗涤缓冲液中),室温孵育1小时。用3,3′,5,5′-四甲基联苯胺(TMB;1StepTMULTRA TMB-ELISA,赛默飞科学公司(ThermoScientific),美国伊利诺伊州罗克福德(Rockford);目录号:34019)使反应显色,用2NH2SO4终止,然后用自动读板仪(Versamax微量滴定板读数器)读出450nm处的吸光度。一式三份分析每个样品,将结果报道成平均OD450±SD或SEM,如图中所示。在包被缓冲液的孔中加入抗MSF抗体获得基线。
夹心ELISA
为了测定生物液体中的MSF水平,开发了夹心ELISA。为此,ELISA平板和稀释于PBS-/-(pH7.0)的250ng/孔的1G5.3或500ng/孔的1G5.3-F(ab)’2片段4℃孵育过夜。包被后,用300μl洗涤缓冲液洗涤平板三次,然后用5%脱脂牛奶37℃封闭2小时。然后加入1/10稀释于含有2%胎牛血清白蛋白的洗涤缓冲液的100μl人血浆(获得使用同意书),室温孵育1小时。在同一平板中,用纯化重组人MSF产生标准曲线。洗涤后,平板与识别人hFn1的市售生物素化多克隆绵羊IgG(0.25μg/ml,于洗涤缓冲液中;R&D目录号:BAF1918)一起室温孵育1小时。最后,加入1/10000稀释于洗涤缓冲液的100μl过氧化物酶-链霉亲和素(BioSpa目录号:SB01-161),室温孵育1小时。然后洗涤平板,用100μl/孔生色底物TMB孵育,然后用2NH2SO4封闭。如上所述读出450nm的吸光度。根据重组MSF制作的标准曲线用线性回归计算血浆样品中的MSF浓度。
结果
本发明涉及人MSF作为炎性病变例如哮喘、过敏和癌症中所涉及的M2极化巨噬细胞的诊断和预后标志物的检测。为此,发明人开发了特异性识别rhMSF的单克隆抗体1G5.3。抗体1G5.3可通过ELISA鉴定rhMSF,可用于免疫亲和纯化rhMSF,在免疫组织化学中是有效的。最后也是最重要的,1G5.3mAb已高效用于开发测定生物液体中人MSF水平的特异性ELISA系统。该试验基于我们特别优越的特异性识别MSF的1G5.3抗体,抗体片段或其衍生物,以及基于使用全长人重组MSF作为标准。
人重组MSF的生产
从pSG-MSF转染的CHO细胞上清液纯化人重组MSF。通过间接ELISA分析了大约300个衍生自用pSG-MSF和pSVneo转染的CHO细胞的克隆,最初使用通过用偶联有KLH的MSF特异性肽免疫兔产生的pAb。仅6个克隆产生了理想水平的rhMSF,通过限制稀释进一步亚克隆。图3报道了间接ELISA的结果,显示克隆CHO-3E6收集的上清液的滴定曲线,其被选作重组蛋白来源用于进一步开发。
1G5.3 mAb的产生和表征。如材料和方法部分详述的,通过用rhMSF免疫小鼠,产生单克隆抗体1G5.3。通过间接ELISA,用His-MSF作为阳性对照,hFn1作为阴性对照分析免疫小鼠的血清。如图4所示,血清至少在本文所用的实验设置下识别人MSF(His-MSF)的100个氨基酸的片段,但不识别hFn1。
然后将来自响应小鼠的脾细胞与SP2/0骨髓瘤融合,铺在96孔板中。制备总共5块平板。2周后,用间接ELISA测试融合:来自5块96孔板的每个孔的100μl上清液分配到先前用作为重组MSF来源的CHO-3E6细胞上清液或用特异性MSF十肽包被的板孔中。图5报道了所分析的一块板的结果。从该最初筛选中,发明人选了四个孔(板1的G5和B8,板5的A5和D7),以5细胞/孔(每个克隆2块板)亚克隆。
用这些平板的上清液通过间接ELISA对肽和来自作为重组MSF来源的CHO-3E6细胞上清液进行二次筛选。图6报道了衍生自克隆G5的两块平板的筛选。从这次筛选中,发明人选择了两个克隆,板1的F7和板2的B8,以0.5细胞/孔亚克隆。获得10块平板,在包被有肽或来自作为rhMSF来源的CHO-3E6细胞上清液的微量滴定板上测试上清液。从该分析中,发明人选择14个克隆,命名为1G5.1、1G5.2、1G5.3……直到1G5.14。在6孔板中培养克隆,再次在CHO-3E6转染细胞上清液和hFn1中测试识别MSF的能力。如图7所示,这些克隆都不能识别hFn1,但能以不同效力识别MSF。选择克隆1G5.3用于进一步开发。
通过在蛋白质-G琼脂糖上亲和层析,从杂交瘤细胞培养上清液中纯化mAb1G5.3。杂交瘤1G5.3表达亚型1G1重链和κ轻链的分泌抗体。最后用ELISA分析纯化的抗体。图8显示了纯化的单克隆抗体1G5.3对包被有rhMSF或hFn1(都是500ng/孔)的板的滴定曲线结果。结果确证了mAb 1G5.3不识别人hFn1。
1G5.3的DNA和蛋白质序列
亚克隆两条链后,获得1G5.3的重链和轻链DNA序列。1G5.3的鼠重链DNA序列如SEQID NO:5所示,蛋白质序列如SEQ ID NO:6所示。1G5.3的轻链DNA序列如SEQ ID NO:7所示,蛋白质序列如SEQ ID NO:8所示。
mAb 1G5.3用于纯化rhMSF
可通过免疫亲和层析(IAC)高效纯化培养上清液中CHO-3E6细胞分泌的rhMSF。来自CHO-E6细胞的调理培养基(输入)通过如“材料和方法”所述平衡和洗脱的1G5.3柱。纯化过程的典型结果如图9所示。
mAb1G5.3用于免疫组化分析
1G5.3在免疫组化分析中是有效的,识别人癌症组织中的MSF,如图10所示。蛋白质在癌细胞也在乳腺癌组织中的体细胞中,和肺癌组织的肺泡巨噬细胞中(如形态学判断)表达。用巨噬细胞标志物CD68的双免疫荧光染色证实了肺癌组织中肺泡巨噬细胞和乳腺癌标本的一部分巨噬细胞中的表达(图11)。
mAb 1G5.3用于开发测定生物液中MSF水平的免疫试验
为了开发测试生物液中MSF水平的免疫试验,发明人测试了1G5.3作为捕获抗体。为了产生标准曲线,用稀释于碳酸盐缓冲液中的250ng/孔mAb 1G5.3包被ELISA微量滴定板中的塑料孔。然后,封闭非特异性位点,将系列稀释的rhMSF(浓度范围为1.5-1000ng/ml)分散在一式两份的孔中。仅用缓冲液包被的孔作为阴性对照。如材料和方法部分详述进行ELISA,在过程终点,通过与针对hFn1的市售绵羊抗血清孵育揭示结合的MSF。图12A报道了根据该过程获得的典型标准曲线。最初,发明人用该试验测定CHO-3E6细胞培养上清液中的MSF水平。如图12B所示,来自CHO-3E6的上清液中MSF浓度约为8.0±3.1μg/ml(平均±SEM;三批不同的上清液)。
为了对此进行验证,尽管使用抗hFn1作为检测抗体,ELISA特异性识别人MSF,将多至100μg/ml纯化的hFn1加到试验中。如图13所示,hFn1在开发的夹心ELISA中不显示,而且加入hFn1不影响人MSF的识别。结果确认了1G5.3在识别和捕获人MSF,而不是hFn1中的特异性。发明人接着测试了该ELISA试验,以评估健康个体和癌症患者(获得其知情同意书)的血浆样品中的MSF含量。图14报道了所开发的夹心ELISA获得的结果。在健康个体和癌症病人的血浆中都可测量MSF。另外,如图14所示,患有癌症的患者相比健康个体具有更高水平的MSF(p=0.048,曼-惠特尼检验)。
1G5.3-F(ab)’2片段的产生
基于使用我们的mAb 1G5.3的夹心ELISA能有效在培养上清液和血浆样品中测定MSF水平。为了提高ELISA的特异性,发明人也测试了用胃蛋白酶处理纯化抗体后获得的1G5.3-F(ab)’2。为此,在Vivaspin 6浓缩机(10kDa MWCO)上浓缩1G5.3抗体,相对于100mM柠檬酸钠pH 3.50,在HiTrap Desalting 5ml柱上交换缓冲液,然后用胃蛋白酶反应。图15A显示了SEC分离蛋白后,胃蛋白酶处理前的典型概貌。经缓冲液交换的物质与胃蛋白酶一起孵育(37℃持续14小时),然后加到HiTrap MabSelect柱上,以分离Fc片段,从F(ab)’2片段回收未结合物质(流穿),用100mM柠檬酸钠从柱上洗脱(图15B)。随后用Vivaspin 6浓缩从柱上洗脱的F(ab)’2片段,在Superdex 200 10/300GL柱上层析,用PBS平衡和洗脱(图16C)。100μg等分试样的完整未处理1G5.3抗体以相同条件跑样(完整IgG,右轴和虚线,图15C)。完整1G5.3抗体和对应的F(ab)’2片段(来自C中的SEC)的等分试样在NuPAGE Novex Bis-Tris10%胶中以变性条件下,二硫苏糖醇存在与否的情况下(分别为+DTT和-DTT)分离。图15D报道了用考马斯染色的代表性凝胶。未还原的1G5.3和1G5.3F(ab)’2分别迁移到150和110kDa处;还原条件下1G5.3分成60(重链)和25(轻链)kDa的两个条带,而1G5.3-F(ab)’2在25kDa显示一条条带。
1G5.3-F(ab)’2片段用于开发测定生物液中MSF水平的免疫试验
然后在夹心ELISA中根据上述相同程序测试1G5.3-F(ab)’2片段。发明人最初比较了包被于塑料孔中的两种不同抗体获得的背景。如图16所示,用1G5.3-F(ab)’2包被背景显著减少(p=0.022;斯氏t检验)。这对于提高试验检测下限至关重要。为了确定用于标准曲线的rhMSF浓度的最佳范围,不同量的蛋白质(0.2-200ng/ml)在1G5.3-F(ab)’2包被的平板上孵育。rhMSF标准曲线的最佳范围结果是0.4-25mg/ml,这导致试验的灵敏度与基于1G5.3mAb(检测下限是1.5mg/ml)的设置有进步。图17A显示了所获得的标准曲线的可复制性,而图17B显示了产生的标准曲线。发明人然后测定了从健康供体和患有胰腺导管腺癌(PDAC)的患者(已获得告知同意书)收集的一系列血浆中的MSF水平。健康供体的中位MSF水平为11.11ng/ml(Q1-Q3:4.64-17.97;n=28;图18A),在PDAC病人中中位MSF水平是143.7ng/ml(Q1-Q3:111,6-176,8;n=33;图18B),与健康个体的水平有统计学意义的差异(p<0.0001曼-惠特尼检验)。总的说,本文显示的数据提示,1G5.3是识别MSF,一种与M2极化巨噬细胞有关的分子的特异性单克隆抗体。抗体及其衍生物可高效定量具有与巨噬细胞的M2极化相关的病理状态的个体生物液中的MSF水平。
临床应用
所开发的单克隆抗体可用于鉴定M2极化巨噬细胞(涉及不同炎症病状)和M2样肿瘤结合巨噬细胞。另外,抗体还可用于开发评估蛋白质循环水平的试验。MSF表达的分析可在癌症患者和其它人中具有诊断和预后价值。
实施例2
材料和方法
蛋白质和肽
如实施例1中所述在CHO细胞克隆中表达并纯化出rhMSF。由PRIMM S.r.l.(意大利米兰)合成对人MSF特异性的合成肽,其含有与N-端通过氨基己酸(Ahx)臂连接的生物素部分(biot-VSIPPRNLGY[biot-Ahx-VSIPPRNLGY](SEQ ID NO:11),aa 648-657)。
商业试剂
低内毒素的胎牛血清(FCS)购自西格玛奥德里奇公司(意大利米兰;目录号:F7524);达氏改良伊氏培养基(DMEM;)来自隆萨公司(Euroclone,意大利米兰;目录号:BE12-733F)。具有钙和镁的磷酸缓冲盐(PBS)(PBS+/+)来自Biosera(Biotecna,意大利米兰;目录号:XC-S2067),不含钙和镁的PBS(PBS-/-目录号:D8537)来自西格玛奥德里奇公司(意大利米兰)。所有其他化学品购自西格玛奥德里奇公司,都是可得到的最高纯度。
mAb7.1杂交瘤培养物
细胞在含有10%FCS的DMEM上生长。从约6-8x105细胞/ml培养物中收集含有分泌的抗体的调理培养基(上清液),2,000rpm离心除去细胞碎片,然后进行斑点印迹和ELISA分析。用间接ELISA和斑点印迹分析mAb7.1识别CHO-3E6细胞纯化获得的rhMSF或biot-VSIPPRNLGY(SEQ ID NO:11)肽的能力。在同一组试验中,用来自1G5.3杂交瘤的上清液或纯化的1G5.3mAb比较。
对rhMSF的间接ELISA
用rhMSF包被(4℃过夜(O/N))ELISA平板(Nunc Maxisorb免疫平板,目录号:446612)(200ng/孔,溶于15mM碳酸钠缓冲液,pH 9.60)。然后用含有0.05%(v/v)Tween 20的PBS+/+(洗涤缓冲液)洗涤平板三次,室温与5%(w/v)脱脂牛奶(溶于洗涤缓冲液)孵育2小时封闭未包被的位点。用洗涤缓冲液洗涤孔三次,然后加入100μl等分试样的来自mAb7.1杂交瘤的上清液(如说明,未稀释或用洗涤缓冲液稀释)或1G5.3杂交瘤培养物(如说明稀释于洗涤缓冲液),或纯化的1G5.3抗体(用洗涤缓冲液稀释;10ng/孔)。室温孵育1小时和额外洗涤后,加入100μl/孔偶联于辣根过氧化物酶(GE医疗公司,宾夕法尼亚州匹兹堡,目录号:GENA931)的抗小鼠IgG抗体(在洗涤缓冲液中1:2,000稀释),进一步室温孵育1小时。通过加入3,3′,5,5′-四甲基联苯胺(TMB;1StepTMULTRA TMB-ELISA,赛默飞科学公司,美国伊利诺伊州罗克福德;目录号:34019),然后加入2N H2SO4揭示结合的抗体。在VersaMax分光光度计(分子装置公司(Molecular Devices),加利福尼亚州森尼韦尔(Sunnyvale))上读板,结果表示成450nm的吸光度(A450nm)。对于每个使用的抗体稀释度,扣除空白孔的背景吸收(即不含MSF)。一式两份分析每个样品,将结果报道成平均±SD或SEM,如图中所示。
biot-VSIPPRNLGY(SEQ ID NO:11)肽上的间接ELISA
用PBS-/-中的NeutrAvidin蛋白包被(4℃过夜)Nunc Maxisorb免疫平板(1μg/孔;赛默飞科学公司,美国伊利诺伊州罗克福德;目录号:31000)。加入Biot-VSIPPRNLGY(SEQID NO:11)肽(100μl/孔,10μg/ml溶于含有0.05%(v/v)Tween 20的PBS+/+中,洗涤缓冲液),室温捕获在NeutrAvidin层上一小时,这允许肽实现N→C朝向,因此模拟了其在MSF蛋白存在下的拓扑学组织[19]。未涂覆的位点通过在室温下与溶于PBS+/+的2%(w/v)牛血清白蛋白(BSA,西格玛奥德里奇公司;目录号:A7030)孵育2小时进行封闭。用洗涤缓冲液洗涤孔三次,然后加入50μl等分试样的来自mAb7.1杂交瘤的上清液(如说明,用洗涤缓冲液未稀释或稀释)或1G5.3杂交瘤培养物(如说明稀释于洗涤缓冲液),或纯化的1G5.3抗体(用洗涤缓冲液稀释;10ng/孔)。如上所述揭示结合的抗体,结果表示成450nm处的吸光度(A450nm)。一式两份分析各样品,结果报道成平均值±SD。
斑点印迹分析
除了ELISA,用斑点印迹评估1G5.3和mAb7.1抗体与rhMSF的相互作用,根据厂商说明书通过真空阀门操作使用Bio-Dot设备(伯乐公司,美国加利福尼亚州赫拉克勒斯;目录号:1620115)。100μl等分试样的rhMSF(200ng/孔)溶于15mM碳酸钠缓冲液(pH 9.60),通过用100μl/孔20mM Tris-HCl,500mM NaCl,pH 7.50(TBS)预先湿润的0.45μm硝基纤维素膜。未包被的位点通过在室温下与2%(w/v)BSA的TBS溶液(TBS-BSA)孵育1小时进行封闭。用含有0.05%(v/v)Tween20(TBS-T)的200μl/孔TBS洗涤孔三次,然后加入100μl/孔来自mAb7.1杂交瘤培养物的上清液(用TBS-BSA1:2稀释)或纯化的1G5.3抗体(250ng/ml,溶于TBS-BSA)。室温孵育30分钟和额外洗涤后,加入100μl/孔偶联于辣根过氧化物酶的抗小鼠IgG抗体(在TBS-BSA中1:3,000稀释),进一步室温孵育30分钟。洗涤后,用PierceTMECL Western印迹底物(赛默飞科学公司;目录号:32106)揭示结合的抗体,在ChemiDoc MP系统(伯乐公司)上记录化学发光。用ImageLab软件(伯乐公司)分析获得的图像。
结果
在最初的实验中,发明人评估了mAb7.1(在产生抗体的杂交瘤细胞克隆培养的调理培养基中)和纯化的1G5.3在斑点印迹设置下对重组人MSF(rhMSF)的识别。如图19所示,两种抗体识别吸附的蛋白质,对空白孔有低非特异性结合。这和先前对mAb7.1在斑点印迹实验中的应用的报道一致[21,24,19]。另外,这些发现表明1G5.3抗体适用于斑点印迹分析。发明人因此将比较调查扩展到间接ELISA,使用包被了biot-VSIPPRNLGY(SEQ ID NO:11)肽(用于评估表位结合)或rhMSF的Maxisorb平板。如图20所示,纯化的1G5.3与biot-VSIPPRNLGY(SEQ ID NO:11)和rhMSF都结合,然而mAb7.1不能识别独特的MSF十肽和完整的蛋白质(rhMSF)(图20A和B)。在此值得注意在这些实验中使用的纯化1G5.3浓度低至10ng/ml,以排除灵敏度问题。为了进一步克服这一点,发明人比较了相同设置中系列稀释的来自1G5.3和mAb7.1杂交瘤的调理培养基,其从培养物中收集,具有类似的细胞计数和存活率。如图21所示,1G3.5杂交瘤的上清液证实对biot-VSIPPRNLGY肽(SEQ ID NO:11)(组图A)和重组MSF蛋白(组图B)的识别都是有效的。与此截然相反,mAb7.1杂交瘤的上清液两种分子都不能识别,尽管它已经比1G5.3有少得多的稀释(即浓度更高)。
结论
先前报道了抗体mAb7.1在斑点印迹设置中识别rhMSF[19,24],但对于该抗体在ELISA中的应用还没有数据。另外,基于现有的证据,该抗体的使用限于免疫组织化学过程[19,20,23]。发明人在此观察到mAb7.1在斑点印迹实验中结合rhMSF,但当biot-VSIPPRNLGY肽(即MSF的C-端独特尾部,SEQ ID NO:11)和rhMSF吸附在Maxisorb板的塑料孔中,在典型ELISA条件下不能对其识别。最重要的是,1G5.3抗体(调理培养基中或作为纯化分子)以剂量依赖形式识别biot-VSIPPRNLGY(SEQ ID NO:11)肽和rhMSF。另外,纯化的1G5.3在斑点印迹实验中特异性检测rhMSF,其将该抗体的应用范围扩大到了斑点印迹。这些结果表明,mAb7.1不适合ELISA应用,而1G5.3抗体在不同实验设置下具有独特的识别MSF的能力,最重要的是在设计用于病理条件的生物液中测定MSF水平的ELISA免疫试验中具有独特的识别MSF的能力。
序列
SEQ ID NO:1:纤连蛋白1的mRNA[智人],完整密码子(7753bp);GenBank登录号AB191261.1
SEQ ID NO:2:纤连蛋白1的蛋白质序列[智人](2265aa),GenBank登录号BAD52437.1
SEQ ID NO:3:迁移刺激因子的mRNA[智人](2192bp);GenBank登录号AJ535086.1
SEQ ID NO:4:迁移刺激因子的蛋白质序列[智人](657aa);GenBank n℃AH60958.1
1G5.3的DNA和蛋白质序列:
SEQ ID NO:5:1G5.3重链的DNA序列(1374bp)
SEQ ID No:6:1G5.3重链的蛋白质序列(457aa):
SEQ ID No:7:1G5.3轻链的DNA序列(720bp):
SEQ ID No:8:1G5.3轻链的蛋白质序列(239aa):
SEQ ID No:9:MSF特异性的十肽(SEQ ID No 4的aa 648-657),其中在COOH-末端加上半胱苷酸
VSIPPRNLGYC
SEQ ID No:10:His-MSF(SEQ ID No 4的aa 553-657加上His标签;123aa)
SEQ ID No:11:MSF特异性的十肽(SEQ ID No 4的aa 648-657)
VSIPPRNLGY
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序列表
<110> 博爱米拉索勒股份公司(Humanitas Mirasole S.p.A.)
米兰大学(UniversitA degli Studi di Milano)
<120> 抗体及其用途
<130> PCT 138916
<150> IT 2017000104736
<151> 2018-09-19
<160> 21
<170> PatentIn version 3.5
<210> 1
<211> 7753
<212> DNA
<213> 智人(Homo sapiens)
<400> 1
gcccgcgccg gctgtgctgc acagggggag gagagggaac cccaggcgcg agcgggaaga 60
ggggacctgc agccacaact tctctggtcc tctgcatccc ttctgtccct ccacccgtcc 120
ccttccccac cctctggccc ccaccttctt ggaggcgaca acccccggga ggcattagaa 180
gggatttttc ccgcaggttg cgaagggaag caaacttggt ggcaacttgc ctcccggtgc 240
gggcgtctct cccccaccgt ctcaacatgc ttaggggtcc ggggcccggg ctgctgctgc 300
tggccgtcca gtgcctgggg acagcggtgc cctccacggg agcctcgaag agcaagaggc 360
aggctcagca aatggttcag ccccagtccc cggtggctgt cagtcaaagc aagcccggtt 420
gttatgacaa tggaaaacac tatcagataa atcaacagtg ggagcggacc tacctaggca 480
atgcgttggt ttgtacttgt tatggaggaa gccgaggttt taactgcgag agtaaacctg 540
aagctgaaga gacttgcttt gacaagtaca ctgggaacac ttaccgagtg ggtgacactt 600
atgagcgtcc taaagactcc atgatctggg actgtacctg catcggggct gggcgaggga 660
gaataagctg taccatcgca aaccgctgcc atgaaggggg tcagtcctac aagattggtg 720
acacctggag gagaccacat gagactggtg gttacatgtt agagtgtgtg tgtcttggta 780
atggaaaagg agaatggacc tgcaagccca tagctgagaa gtgttttgat catgctgctg 840
ggacttccta tgtggtcgga gaaacgtggg agaagcccta ccaaggctgg atgatggtag 900
attgtacttg cctgggagaa ggcagcggac gcatcacttg cacttctaga aatagatgca 960
acgatcagga cacaaggaca tcctatagaa ttggagacac ctggagcaag aaggataatc 1020
gaggaaacct gctccagtgc atctgcacag gcaacggccg aggagagtgg aagtgtgaga 1080
ggcacacctc tgtgcagacc acatcgagcg gatctggccc cttcaccgat gttcgtgcag 1140
ctgtttacca accgcagcct cacccccagc ctcctcccta tggccactgt gtcacagaca 1200
gtggtgtggt ctactctgtg gggatgcagt ggctgaagac acaaggaaat aagcaaatgc 1260
tttgcacgtg cctgggcaac ggagtcagct gccaagagac agctgtaacc cagacttacg 1320
gtggcaactc aaatggagag ccatgtgtct taccattcac ctacaatggc aggacgttct 1380
actcctgcac cacagaaggg cgacaggacg gacatctttg gtgcagcaca acttcgaatt 1440
atgagcagga ccagaaatac tctttctgca cagaccacac tgttttggtt cagactcgag 1500
gaggaaattc caatggtgcc ttgtgccact tccccttcct atacaacaac cacaattaca 1560
ctgattgcac ttctgagggc agaagagaca acatgaagtg gtgtgggacc acacagaact 1620
atgatgccga ccagaagttt gggttctgcc ccatggctgc ccacgaggaa atctgcacaa 1680
ccaatgaagg ggtcatgtac cgcattggag atcagtggga taagcagcat gacatgggtc 1740
acatgatgag gtgcacgtgt gttgggaatg gtcgtgggga atggacatgc attgcctact 1800
cgcagcttcg agatcagtgc attgttgatg acatcactta caatgtgaac gacacattcc 1860
acaagcgtca tgaagagggg cacatgctga actgtacatg cttcggtcag ggtcggggca 1920
ggtggaagtg tgatcccgtc gaccaatgcc aggattcaga gactgggacg ttttatcaaa 1980
ttggagattc atgggagaag tatgtgcatg gtgtcagata ccagtgctac tgctatggcc 2040
gtggcattgg ggagtggcat tgccaacctt tacagaccta tccaagctca agtggtcctg 2100
tcgaagtatt tatcactgag actccgagtc agcccaactc ccaccccatc cagtggaatg 2160
caccacagcc atctcacatt tccaagtaca ttctcaggtg gagacctaaa aattctgtag 2220
gccgttggaa ggaagctacc ataccaggcc acttaaactc ctacaccatc aaaggcctga 2280
agcctggtgt ggtatacgag ggccagctca tcagcatcca gcagtacggc caccaagaag 2340
tgactcgctt tgacttcacc accaccagca ccagcacacc tgtgaccagc aacaccgtga 2400
caggagagac gactcccttt tctcctcttg tggccacttc tgaatctgtg accgaaatca 2460
cagccagtag ctttgtggtc tcctgggtct cagcttccga caccgtgtcg ggattccggg 2520
tggaatatga gctgagtgag gagggagatg agccacagta cctggatctt ccaagcacag 2580
ccacttctgt gaacatccct gacctgcttc ctggccgaaa atacattgta aatgtctatc 2640
agatatctga ggatggggag cagagtttga tcctgtctac ttcacaaaca acagcgcctg 2700
atgcccctcc tgacccgact gtggaccaag ttgatgacac ctcaattgtt gttcgctgga 2760
gcagacccca ggctcccatc acagggtaca gaatagtcta ttcgccatca gtagaaggta 2820
gcagcacaga actcaacctt cctgaaactg caaactccgt caccctcagt gacttgcaac 2880
ctggtgttca gtataacatc actatctatg ctgtggaaga aaatcaagaa agtacacctg 2940
ttgtcattca acaagaaacc actggcaccc cacgctcaga tacagtgccc tctcccaggg 3000
acctgcagtt tgtggaagtg acagacgtga aggtcaccat catgtggaca ccgcctgaga 3060
gtgcagtgac cggctaccgt gtggatgtga tccccgtcaa cctgcctggc gagcacgggc 3120
agaggctgcc catcagcagg aacacctttg cagaagtcac cgggctgtcc cctggggtca 3180
cctattactt caaagtcttt gcagtgagcc atgggaggga gagcaagcct ctgactgctc 3240
aacagacaac caaactggat gctcccacta acctccagtt tgtcaatgaa actgattcta 3300
ctgtcctggt gagatggact ccacctcggg cccagataac aggataccga ctgaccgtgg 3360
gccttacccg aagaggccag cccaggcagt acaatgtggg tccctctgtc tccaagtacc 3420
ccctgaggaa tctgcagcct gcatctgagt acaccgtatc cctcgtggcc ataaagggca 3480
accaagagag ccccaaagcc actggagtct ttaccacact gcagcctggg agctctattc 3540
caccttacaa caccgaggtg actgagacca ccattgtgat cacatggacg cctgctccaa 3600
gaattggttt taagctgggt gtacgaccaa gccagggagg agaggcacca cgagaagtga 3660
cttcagactc aggaagcatc gttgtgtccg gcttgactcc aggagtagaa tacgtctaca 3720
ccatccaagt cctgagagat ggacaggaaa gagatgcgcc aattgtaaac aaagtggtga 3780
caccattgtc tccaccaaca aacttgcatc tggaggcaaa ccctgacact ggagtgctca 3840
cagtctcctg ggagaggagc accaccccag acattactgg ttatagaatt accacaaccc 3900
ctacaaacgg ccagcaggga aattctttgg aagaagtggt ccatgctgat cagagctcct 3960
gcacttttga taacctgagt cccggcctgg agtacaatgt cagtgtttac actgtcaagg 4020
atgacaagga aagtgtccct atctctgata ccatcatccc agctgttcct cctcccactg 4080
acctgcgatt caccaacatt ggtccagaca ccatgcgtgt cacctgggct ccacccccat 4140
ccattgattt aaccaacttc ctggtgcgtt actcacctgt gaaaaatgag gaagatgttg 4200
cagagttgtc aatttctcct tcagacaatg cagtggtctt aacaaatctc ctgcctggta 4260
cagaatatgt agtgagtgtc tccagtgtct acgaacaaca tgagagcaca cctcttagag 4320
gaagacagaa aacaggtctt gattccccaa ctggcattga cttttctgat attactgcca 4380
actcttttac tgtgcactgg attgctcctc gagccaccat cactggctac aggatccgcc 4440
atcatcccga gcacttcagt gggagacctc gagaagatcg ggtgccccac tctcggaatt 4500
ccatcaccct caccaacctc actccaggca cagagtatgt ggtcagcatc gttgctctta 4560
atggcagaga ggaaagtccc ttattgattg gccaacaatc aacagtttct gatgttccga 4620
gggacctgga agttgttgct gcgaccccca ccagcctact gatcagctgg gatgctcctg 4680
ctgtcacagt gagatattac aggatcactt acggagaaac aggaggaaat agccctgtcc 4740
aggagttcac tgtgcctggg agcaagtcta cagctaccat cagcggcctt aaacctggag 4800
ttgattatac catcactgtg tatgctgtca ctggccgtgg agacagcccc gcaagcagca 4860
agccaatttc cattaattac cgaacagaaa ttgacaaacc atcccagatg caagtgaccg 4920
atgttcagga caacagcatt agtgtcaagt ggctgccttc aagttcccct gttactggtt 4980
acagagtaac caccactccc aaaaatggac caggaccaac aaaaactaaa actgcaggtc 5040
cagatcaaac agaaatgact attgaaggct tgcagcccac agtggagtat gtggttagtg 5100
tctatgctca gaatccaagc ggagagagtc agcctctggt tcagactgca gtaaccacta 5160
ttcctgcacc aactgacctg aagttcactc aggtcacacc cacaagcctg agcgcccagt 5220
ggacaccacc caatgttcag ctcactggat atcgagtgcg ggtgaccccc aaggagaaga 5280
ccggaccaat gaaagaaatc aaccttgctc ctgacagctc atccgtggtt gtatcaggac 5340
ttatggtggc caccaaatat gaagtgagtg tctatgctct taaggacact ttgacaagca 5400
gaccagctca gggagttgtc accactctgg agaatgtcag cccaccaaga agggctcgtg 5460
tgacagatgc tactgagacc accatcacca ttagctggag aaccaagact gagacgatca 5520
ctggcttcca agttgatgcc gttccagcca atggccagac tccaatccag agaaccatca 5580
agccagatgt cagaagctac accatcacag gtttacaacc aggcactgac tacaagatct 5640
acctgtacac cttgaatgac aatgctcgga gctcccctgt ggtcatcgac gcctccactg 5700
ccattgatgc accatccaac ctgcgtttcc tggccaccac acccaattcc ttgctggtat 5760
catggcagcc gccacgtgcc aggattaccg gctacatcat caagtatgag aagcctgggt 5820
ctcctcccag agaagtggtc cctcggcccc gccctggtgt cacagaggct actattactg 5880
gcctggaacc gggaaccgaa tatacaattt atgtcattgc cctgaagaat aatcagaaga 5940
gcgagcccct gattggaagg aaaaagacag acgagcttcc ccaactggta acccttccac 6000
accccaatct tcatggacca gagatcttgg atgttccttc cacagttcaa aagacccctt 6060
tcgtcaccca ccctgggtat gacactggaa atggtattca gcttcctggc acttctggtc 6120
agcaacccag tgttgggcaa caaatgatct ttgaggaaca tggttttagg cggaccacac 6180
cgcccacaac ggccaccccc ataaggcata ggccaagacc atacccgccg aatgtaggac 6240
aagaagctct ctctcagaca accatctcat gggccccatt ccaggacact tctgagtaca 6300
tcatttcatg tcatcctgtt ggcactgatg aagaaccctt acagttcagg gttcctggaa 6360
cttctaccag tgccactctg acaggcctca ccagaggtgc cacctacaac atcatagtgg 6420
aggcactgaa agaccagcag aggcataagg ttcgggaaga ggttgttacc gtgggcaact 6480
ctgtcaacga aggcttgaac caacctacgg atgactcgtg ctttgacccc tacacagttt 6540
cccattatgc cgttggagat gagtgggaac gaatgtctga atcaggcttt aaactgttgt 6600
gccagtgctt aggctttgga agtggtcatt tcagatgtga ttcatctaga tggtgccatg 6660
acaatggtgt gaactacaag attggagaga agtgggaccg tcagggagaa aatggccaga 6720
tgatgagctg cacatgtctt gggaacggaa aaggagaatt caagtgtgac cctcatgagg 6780
caacgtgtta cgatgatggg aagacatacc acgtaggaga acagtggcag aaggaatatc 6840
tcggtgccat ttgctcctgc acatgctttg gaggccagcg gggctggcgc tgtgacaact 6900
gccgcagacc tgggggtgaa cccagtcccg aaggcactac tggccagtcc tacaaccagt 6960
attctcagag ataccatcag agaacaaaca ctaatgttaa ttgcccaatt gagtgcttca 7020
tgcctttaga tgtacaggct gacagagaag attcccgaga gtaaatcatc tttccaatcc 7080
agaggaacaa gcatgtctct ctgccaagat ccatctaaac tggagtgatg ttagcagacc 7140
cagcttagag ttcttctttc tttcttaagc cctttgctct ggaggaagtt ctccagcttc 7200
agctcaactc acagcttctc caagcatcac cctgggagtt tcctgagggt tttctcataa 7260
atgagggctg cacattgcct gttctgcttc gaagtattca ataccgctca gtattttaaa 7320
tgaagtgatt ctaagatttg gtttgggatc aataggaaag catatgcagc caaccaagat 7380
gcaaatgttt tgaaatgata tgaccaaaat tttaagtagg aaagtcaccc aaacacttct 7440
gctttcactt aagtgtctgg cccgcaatac tgtaggaaca agcatgatct tgttactgtg 7500
atattttaaa tatccacagt actcactttt tccaaatgat cctagtaatt gcctagaaat 7560
atctttctct tacctgttat ttatcaattt ttcccagtat ttttatacgg aaaaaattgt 7620
attgaaaaca cttagtatgc agttgataag aggaatttgg tataattatg gtgggtgatt 7680
attttttata ctgtatgtgc caaagcttta ctactgtgga aagacaactg ttttaataaa 7740
agatttacat tcc 7753
<210> 2
<211> 2265
<212> PRT
<213> 智人(Homo sapiens)
<400> 2
Met Leu Arg Gly Pro Gly Pro Gly Leu Leu Leu Leu Ala Val Gln Cys
1 5 10 15
Leu Gly Thr Ala Val Pro Ser Thr Gly Ala Ser Lys Ser Lys Arg Gln
20 25 30
Ala Gln Gln Met Val Gln Pro Gln Ser Pro Val Ala Val Ser Gln Ser
35 40 45
Lys Pro Gly Cys Tyr Asp Asn Gly Lys His Tyr Gln Ile Asn Gln Gln
50 55 60
Trp Glu Arg Thr Tyr Leu Gly Asn Ala Leu Val Cys Thr Cys Tyr Gly
65 70 75 80
Gly Ser Arg Gly Phe Asn Cys Glu Ser Lys Pro Glu Ala Glu Glu Thr
85 90 95
Cys Phe Asp Lys Tyr Thr Gly Asn Thr Tyr Arg Val Gly Asp Thr Tyr
100 105 110
Glu Arg Pro Lys Asp Ser Met Ile Trp Asp Cys Thr Cys Ile Gly Ala
115 120 125
Gly Arg Gly Arg Ile Ser Cys Thr Ile Ala Asn Arg Cys His Glu Gly
130 135 140
Gly Gln Ser Tyr Lys Ile Gly Asp Thr Trp Arg Arg Pro His Glu Thr
145 150 155 160
Gly Gly Tyr Met Leu Glu Cys Val Cys Leu Gly Asn Gly Lys Gly Glu
165 170 175
Trp Thr Cys Lys Pro Ile Ala Glu Lys Cys Phe Asp His Ala Ala Gly
180 185 190
Thr Ser Tyr Val Val Gly Glu Thr Trp Glu Lys Pro Tyr Gln Gly Trp
195 200 205
Met Met Val Asp Cys Thr Cys Leu Gly Glu Gly Ser Gly Arg Ile Thr
210 215 220
Cys Thr Ser Arg Asn Arg Cys Asn Asp Gln Asp Thr Arg Thr Ser Tyr
225 230 235 240
Arg Ile Gly Asp Thr Trp Ser Lys Lys Asp Asn Arg Gly Asn Leu Leu
245 250 255
Gln Cys Ile Cys Thr Gly Asn Gly Arg Gly Glu Trp Lys Cys Glu Arg
260 265 270
His Thr Ser Val Gln Thr Thr Ser Ser Gly Ser Gly Pro Phe Thr Asp
275 280 285
Val Arg Ala Ala Val Tyr Gln Pro Gln Pro His Pro Gln Pro Pro Pro
290 295 300
Tyr Gly His Cys Val Thr Asp Ser Gly Val Val Tyr Ser Val Gly Met
305 310 315 320
Gln Trp Leu Lys Thr Gln Gly Asn Lys Gln Met Leu Cys Thr Cys Leu
325 330 335
Gly Asn Gly Val Ser Cys Gln Glu Thr Ala Val Thr Gln Thr Tyr Gly
340 345 350
Gly Asn Ser Asn Gly Glu Pro Cys Val Leu Pro Phe Thr Tyr Asn Gly
355 360 365
Arg Thr Phe Tyr Ser Cys Thr Thr Glu Gly Arg Gln Asp Gly His Leu
370 375 380
Trp Cys Ser Thr Thr Ser Asn Tyr Glu Gln Asp Gln Lys Tyr Ser Phe
385 390 395 400
Cys Thr Asp His Thr Val Leu Val Gln Thr Arg Gly Gly Asn Ser Asn
405 410 415
Gly Ala Leu Cys His Phe Pro Phe Leu Tyr Asn Asn His Asn Tyr Thr
420 425 430
Asp Cys Thr Ser Glu Gly Arg Arg Asp Asn Met Lys Trp Cys Gly Thr
435 440 445
Thr Gln Asn Tyr Asp Ala Asp Gln Lys Phe Gly Phe Cys Pro Met Ala
450 455 460
Ala His Glu Glu Ile Cys Thr Thr Asn Glu Gly Val Met Tyr Arg Ile
465 470 475 480
Gly Asp Gln Trp Asp Lys Gln His Asp Met Gly His Met Met Arg Cys
485 490 495
Thr Cys Val Gly Asn Gly Arg Gly Glu Trp Thr Cys Ile Ala Tyr Ser
500 505 510
Gln Leu Arg Asp Gln Cys Ile Val Asp Asp Ile Thr Tyr Asn Val Asn
515 520 525
Asp Thr Phe His Lys Arg His Glu Glu Gly His Met Leu Asn Cys Thr
530 535 540
Cys Phe Gly Gln Gly Arg Gly Arg Trp Lys Cys Asp Pro Val Asp Gln
545 550 555 560
Cys Gln Asp Ser Glu Thr Gly Thr Phe Tyr Gln Ile Gly Asp Ser Trp
565 570 575
Glu Lys Tyr Val His Gly Val Arg Tyr Gln Cys Tyr Cys Tyr Gly Arg
580 585 590
Gly Ile Gly Glu Trp His Cys Gln Pro Leu Gln Thr Tyr Pro Ser Ser
595 600 605
Ser Gly Pro Val Glu Val Phe Ile Thr Glu Thr Pro Ser Gln Pro Asn
610 615 620
Ser His Pro Ile Gln Trp Asn Ala Pro Gln Pro Ser His Ile Ser Lys
625 630 635 640
Tyr Ile Leu Arg Trp Arg Pro Lys Asn Ser Val Gly Arg Trp Lys Glu
645 650 655
Ala Thr Ile Pro Gly His Leu Asn Ser Tyr Thr Ile Lys Gly Leu Lys
660 665 670
Pro Gly Val Val Tyr Glu Gly Gln Leu Ile Ser Ile Gln Gln Tyr Gly
675 680 685
His Gln Glu Val Thr Arg Phe Asp Phe Thr Thr Thr Ser Thr Ser Thr
690 695 700
Pro Val Thr Ser Asn Thr Val Thr Gly Glu Thr Thr Pro Phe Ser Pro
705 710 715 720
Leu Val Ala Thr Ser Glu Ser Val Thr Glu Ile Thr Ala Ser Ser Phe
725 730 735
Val Val Ser Trp Val Ser Ala Ser Asp Thr Val Ser Gly Phe Arg Val
740 745 750
Glu Tyr Glu Leu Ser Glu Glu Gly Asp Glu Pro Gln Tyr Leu Asp Leu
755 760 765
Pro Ser Thr Ala Thr Ser Val Asn Ile Pro Asp Leu Leu Pro Gly Arg
770 775 780
Lys Tyr Ile Val Asn Val Tyr Gln Ile Ser Glu Asp Gly Glu Gln Ser
785 790 795 800
Leu Ile Leu Ser Thr Ser Gln Thr Thr Ala Pro Asp Ala Pro Pro Asp
805 810 815
Pro Thr Val Asp Gln Val Asp Asp Thr Ser Ile Val Val Arg Trp Ser
820 825 830
Arg Pro Gln Ala Pro Ile Thr Gly Tyr Arg Ile Val Tyr Ser Pro Ser
835 840 845
Val Glu Gly Ser Ser Thr Glu Leu Asn Leu Pro Glu Thr Ala Asn Ser
850 855 860
Val Thr Leu Ser Asp Leu Gln Pro Gly Val Gln Tyr Asn Ile Thr Ile
865 870 875 880
Tyr Ala Val Glu Glu Asn Gln Glu Ser Thr Pro Val Val Ile Gln Gln
885 890 895
Glu Thr Thr Gly Thr Pro Arg Ser Asp Thr Val Pro Ser Pro Arg Asp
900 905 910
Leu Gln Phe Val Glu Val Thr Asp Val Lys Val Thr Ile Met Trp Thr
915 920 925
Pro Pro Glu Ser Ala Val Thr Gly Tyr Arg Val Asp Val Ile Pro Val
930 935 940
Asn Leu Pro Gly Glu His Gly Gln Arg Leu Pro Ile Ser Arg Asn Thr
945 950 955 960
Phe Ala Glu Val Thr Gly Leu Ser Pro Gly Val Thr Tyr Tyr Phe Lys
965 970 975
Val Phe Ala Val Ser His Gly Arg Glu Ser Lys Pro Leu Thr Ala Gln
980 985 990
Gln Thr Thr Lys Leu Asp Ala Pro Thr Asn Leu Gln Phe Val Asn Glu
995 1000 1005
Thr Asp Ser Thr Val Leu Val Arg Trp Thr Pro Pro Arg Ala Gln
1010 1015 1020
Ile Thr Gly Tyr Arg Leu Thr Val Gly Leu Thr Arg Arg Gly Gln
1025 1030 1035
Pro Arg Gln Tyr Asn Val Gly Pro Ser Val Ser Lys Tyr Pro Leu
1040 1045 1050
Arg Asn Leu Gln Pro Ala Ser Glu Tyr Thr Val Ser Leu Val Ala
1055 1060 1065
Ile Lys Gly Asn Gln Glu Ser Pro Lys Ala Thr Gly Val Phe Thr
1070 1075 1080
Thr Leu Gln Pro Gly Ser Ser Ile Pro Pro Tyr Asn Thr Glu Val
1085 1090 1095
Thr Glu Thr Thr Ile Val Ile Thr Trp Thr Pro Ala Pro Arg Ile
1100 1105 1110
Gly Phe Lys Leu Gly Val Arg Pro Ser Gln Gly Gly Glu Ala Pro
1115 1120 1125
Arg Glu Val Thr Ser Asp Ser Gly Ser Ile Val Val Ser Gly Leu
1130 1135 1140
Thr Pro Gly Val Glu Tyr Val Tyr Thr Ile Gln Val Leu Arg Asp
1145 1150 1155
Gly Gln Glu Arg Asp Ala Pro Ile Val Asn Lys Val Val Thr Pro
1160 1165 1170
Leu Ser Pro Pro Thr Asn Leu His Leu Glu Ala Asn Pro Asp Thr
1175 1180 1185
Gly Val Leu Thr Val Ser Trp Glu Arg Ser Thr Thr Pro Asp Ile
1190 1195 1200
Thr Gly Tyr Arg Ile Thr Thr Thr Pro Thr Asn Gly Gln Gln Gly
1205 1210 1215
Asn Ser Leu Glu Glu Val Val His Ala Asp Gln Ser Ser Cys Thr
1220 1225 1230
Phe Asp Asn Leu Ser Pro Gly Leu Glu Tyr Asn Val Ser Val Tyr
1235 1240 1245
Thr Val Lys Asp Asp Lys Glu Ser Val Pro Ile Ser Asp Thr Ile
1250 1255 1260
Ile Pro Ala Val Pro Pro Pro Thr Asp Leu Arg Phe Thr Asn Ile
1265 1270 1275
Gly Pro Asp Thr Met Arg Val Thr Trp Ala Pro Pro Pro Ser Ile
1280 1285 1290
Asp Leu Thr Asn Phe Leu Val Arg Tyr Ser Pro Val Lys Asn Glu
1295 1300 1305
Glu Asp Val Ala Glu Leu Ser Ile Ser Pro Ser Asp Asn Ala Val
1310 1315 1320
Val Leu Thr Asn Leu Leu Pro Gly Thr Glu Tyr Val Val Ser Val
1325 1330 1335
Ser Ser Val Tyr Glu Gln His Glu Ser Thr Pro Leu Arg Gly Arg
1340 1345 1350
Gln Lys Thr Gly Leu Asp Ser Pro Thr Gly Ile Asp Phe Ser Asp
1355 1360 1365
Ile Thr Ala Asn Ser Phe Thr Val His Trp Ile Ala Pro Arg Ala
1370 1375 1380
Thr Ile Thr Gly Tyr Arg Ile Arg His His Pro Glu His Phe Ser
1385 1390 1395
Gly Arg Pro Arg Glu Asp Arg Val Pro His Ser Arg Asn Ser Ile
1400 1405 1410
Thr Leu Thr Asn Leu Thr Pro Gly Thr Glu Tyr Val Val Ser Ile
1415 1420 1425
Val Ala Leu Asn Gly Arg Glu Glu Ser Pro Leu Leu Ile Gly Gln
1430 1435 1440
Gln Ser Thr Val Ser Asp Val Pro Arg Asp Leu Glu Val Val Ala
1445 1450 1455
Ala Thr Pro Thr Ser Leu Leu Ile Ser Trp Asp Ala Pro Ala Val
1460 1465 1470
Thr Val Arg Tyr Tyr Arg Ile Thr Tyr Gly Glu Thr Gly Gly Asn
1475 1480 1485
Ser Pro Val Gln Glu Phe Thr Val Pro Gly Ser Lys Ser Thr Ala
1490 1495 1500
Thr Ile Ser Gly Leu Lys Pro Gly Val Asp Tyr Thr Ile Thr Val
1505 1510 1515
Tyr Ala Val Thr Gly Arg Gly Asp Ser Pro Ala Ser Ser Lys Pro
1520 1525 1530
Ile Ser Ile Asn Tyr Arg Thr Glu Ile Asp Lys Pro Ser Gln Met
1535 1540 1545
Gln Val Thr Asp Val Gln Asp Asn Ser Ile Ser Val Lys Trp Leu
1550 1555 1560
Pro Ser Ser Ser Pro Val Thr Gly Tyr Arg Val Thr Thr Thr Pro
1565 1570 1575
Lys Asn Gly Pro Gly Pro Thr Lys Thr Lys Thr Ala Gly Pro Asp
1580 1585 1590
Gln Thr Glu Met Thr Ile Glu Gly Leu Gln Pro Thr Val Glu Tyr
1595 1600 1605
Val Val Ser Val Tyr Ala Gln Asn Pro Ser Gly Glu Ser Gln Pro
1610 1615 1620
Leu Val Gln Thr Ala Val Thr Thr Ile Pro Ala Pro Thr Asp Leu
1625 1630 1635
Lys Phe Thr Gln Val Thr Pro Thr Ser Leu Ser Ala Gln Trp Thr
1640 1645 1650
Pro Pro Asn Val Gln Leu Thr Gly Tyr Arg Val Arg Val Thr Pro
1655 1660 1665
Lys Glu Lys Thr Gly Pro Met Lys Glu Ile Asn Leu Ala Pro Asp
1670 1675 1680
Ser Ser Ser Val Val Val Ser Gly Leu Met Val Ala Thr Lys Tyr
1685 1690 1695
Glu Val Ser Val Tyr Ala Leu Lys Asp Thr Leu Thr Ser Arg Pro
1700 1705 1710
Ala Gln Gly Val Val Thr Thr Leu Glu Asn Val Ser Pro Pro Arg
1715 1720 1725
Arg Ala Arg Val Thr Asp Ala Thr Glu Thr Thr Ile Thr Ile Ser
1730 1735 1740
Trp Arg Thr Lys Thr Glu Thr Ile Thr Gly Phe Gln Val Asp Ala
1745 1750 1755
Val Pro Ala Asn Gly Gln Thr Pro Ile Gln Arg Thr Ile Lys Pro
1760 1765 1770
Asp Val Arg Ser Tyr Thr Ile Thr Gly Leu Gln Pro Gly Thr Asp
1775 1780 1785
Tyr Lys Ile Tyr Leu Tyr Thr Leu Asn Asp Asn Ala Arg Ser Ser
1790 1795 1800
Pro Val Val Ile Asp Ala Ser Thr Ala Ile Asp Ala Pro Ser Asn
1805 1810 1815
Leu Arg Phe Leu Ala Thr Thr Pro Asn Ser Leu Leu Val Ser Trp
1820 1825 1830
Gln Pro Pro Arg Ala Arg Ile Thr Gly Tyr Ile Ile Lys Tyr Glu
1835 1840 1845
Lys Pro Gly Ser Pro Pro Arg Glu Val Val Pro Arg Pro Arg Pro
1850 1855 1860
Gly Val Thr Glu Ala Thr Ile Thr Gly Leu Glu Pro Gly Thr Glu
1865 1870 1875
Tyr Thr Ile Tyr Val Ile Ala Leu Lys Asn Asn Gln Lys Ser Glu
1880 1885 1890
Pro Leu Ile Gly Arg Lys Lys Thr Asp Glu Leu Pro Gln Leu Val
1895 1900 1905
Thr Leu Pro His Pro Asn Leu His Gly Pro Glu Ile Leu Asp Val
1910 1915 1920
Pro Ser Thr Val Gln Lys Thr Pro Phe Val Thr His Pro Gly Tyr
1925 1930 1935
Asp Thr Gly Asn Gly Ile Gln Leu Pro Gly Thr Ser Gly Gln Gln
1940 1945 1950
Pro Ser Val Gly Gln Gln Met Ile Phe Glu Glu His Gly Phe Arg
1955 1960 1965
Arg Thr Thr Pro Pro Thr Thr Ala Thr Pro Ile Arg His Arg Pro
1970 1975 1980
Arg Pro Tyr Pro Pro Asn Val Gly Gln Glu Ala Leu Ser Gln Thr
1985 1990 1995
Thr Ile Ser Trp Ala Pro Phe Gln Asp Thr Ser Glu Tyr Ile Ile
2000 2005 2010
Ser Cys His Pro Val Gly Thr Asp Glu Glu Pro Leu Gln Phe Arg
2015 2020 2025
Val Pro Gly Thr Ser Thr Ser Ala Thr Leu Thr Gly Leu Thr Arg
2030 2035 2040
Gly Ala Thr Tyr Asn Ile Ile Val Glu Ala Leu Lys Asp Gln Gln
2045 2050 2055
Arg His Lys Val Arg Glu Glu Val Val Thr Val Gly Asn Ser Val
2060 2065 2070
Asn Glu Gly Leu Asn Gln Pro Thr Asp Asp Ser Cys Phe Asp Pro
2075 2080 2085
Tyr Thr Val Ser His Tyr Ala Val Gly Asp Glu Trp Glu Arg Met
2090 2095 2100
Ser Glu Ser Gly Phe Lys Leu Leu Cys Gln Cys Leu Gly Phe Gly
2105 2110 2115
Ser Gly His Phe Arg Cys Asp Ser Ser Arg Trp Cys His Asp Asn
2120 2125 2130
Gly Val Asn Tyr Lys Ile Gly Glu Lys Trp Asp Arg Gln Gly Glu
2135 2140 2145
Asn Gly Gln Met Met Ser Cys Thr Cys Leu Gly Asn Gly Lys Gly
2150 2155 2160
Glu Phe Lys Cys Asp Pro His Glu Ala Thr Cys Tyr Asp Asp Gly
2165 2170 2175
Lys Thr Tyr His Val Gly Glu Gln Trp Gln Lys Glu Tyr Leu Gly
2180 2185 2190
Ala Ile Cys Ser Cys Thr Cys Phe Gly Gly Gln Arg Gly Trp Arg
2195 2200 2205
Cys Asp Asn Cys Arg Arg Pro Gly Gly Glu Pro Ser Pro Glu Gly
2210 2215 2220
Thr Thr Gly Gln Ser Tyr Asn Gln Tyr Ser Gln Arg Tyr His Gln
2225 2230 2235
Arg Thr Asn Thr Asn Val Asn Cys Pro Ile Glu Cys Phe Met Pro
2240 2245 2250
Leu Asp Val Gln Ala Asp Arg Glu Asp Ser Arg Glu
2255 2260 2265
<210> 3
<211> 2192
<212> DNA
<213> 智人(Homo sapiens)
<400> 3
caaacttggt ggcaacttgc ctcccggtgc gggcgtctct cccccaccgt ctcaacatgc 60
ttaggggtcc ggggcccggg ctgctgctgc tggccgtcca gtgcctgggg acagcggtgc 120
cctccacggg agcctcgaag agcaagaggc aggctcagca aatggttcag ccccagtccc 180
cggtggctgt cagtcaaagc aagcccggtt gttatgacaa tggaaaacac tatcagataa 240
atcaacagtg ggagcggacc tacctaggca atgcgttggt ttgtacttgt tatggaggaa 300
gccgaggttt taactgcgag agtaaacctg aagctgaaga gacttgcttt gacaagtaca 360
ctgggaacac ttaccgagtg ggtgacactt atgagcgtcc taaagactcc atgatctggg 420
actgtacctg catcggggct gggcgaggga gaataagctg taccatcgca aaccgctgcc 480
atgaaggggg tcagtcctac aagattggtg acacctggag gagaccacat gagactggtg 540
gttacatgtt agagtgtgtg tgtcttggta atggaaaagg agaatggacc tgcaagccca 600
tagctgagaa gtgttttgat catgctgctg ggacttccta tgtggtcgga gaaacgtggg 660
agaagcccta ccaaggctgg atgatggtag attgtacttg cctgggagaa ggcagcggac 720
gcatcacttg cacttctaga aatagatgca acgatcagga cacaaggaca tcctatagaa 780
ttggagacac ctggcgcaag aaggataatc gaggaaacct gctccagtgc atctgcacag 840
gcaacggccg aggagagtgg aagtgtgaga ggcacacctc tgtgcagacc acatcgagcg 900
gatctggccc cttcaccgat gttcgtgcag ctgtttacca accgcagcct cacccccagc 960
ctcctcccta tggccactgt gtcacagaca gtggtgtggt ctactctgtg gggatgcagt 1020
ggctgaagac acaaggaaat aagcaaatgc tttgcacgtg cctgggcaac ggagtcagct 1080
gccaagagac agctgtaacc cagacttacg gtggcaactc aaatggagag ccatgtgtct 1140
taccattcac ctacaatggc aggacgttct actcctgcac cacagaaggg cgacaggacg 1200
gacatctttg gtgcagcaca acttcgaatt atgagcagga ccagaaatac tctttctgca 1260
cagaccacac tgttttggtt cagactcgag gaggaaattc caatggtgcc ttgtgccact 1320
tccccttcct atacaacaac cacaattaca ctgattgcac ttctgagggc agaagagaca 1380
acatgaagtg gtgtgggacc acacagaact atgatgccga ccagaagttt gggttctgcc 1440
ccatggctgc ccacgaggaa atctgcacaa ccaatgaagg ggtcatgtac cgcattggag 1500
atcagtggga taagcagcat gacatgggtc acatgatgag gtgcacgtgt gttgggaatg 1560
gtcgtgggga atggacatgc attgcctact cgcagcttcg agatcagtgc attgttgatg 1620
acatcactta caatgtgaac gacacattcc acaagcgtca tgaagagggg cacatgctga 1680
actgtacatg cttcggtcag ggtcggggca ggtggaagtg tgatcccgtc gaccaatgcc 1740
aggattcaga gactgggacg ttttatcaaa ttggagattc atgggagaag tatgtgcatg 1800
gtgtcagata ccagtgctac tgctatggcc gtggcattgg ggagtggcat tgccaacctt 1860
tacagaccta tccaagctca agtggtcctg tcgaagtatt tatcactgag actccgagtc 1920
agcccaactc ccaccccatc cagtggaatg caccacagcc atctcacatt tccaagtaca 1980
ttctcaggtg gagacctgtg agtatcccac ccagaaacct tggatactga gtctcctaat 2040
cttatcaatt ctgatggttt ctttttttcc cagcttttga gccaacaact ctgattaact 2100
attcctatag catttactat atttgtttag tgaacaaaca atatgtggtc aattaaattg 2160
acttgtagac tgaaaaaaaa aaaaaaaaaa aa 2192
<210> 4
<211> 657
<212> PRT
<213> 智人(Homo sapiens)
<400> 4
Met Leu Arg Gly Pro Gly Pro Gly Leu Leu Leu Leu Ala Val Gln Cys
1 5 10 15
Leu Gly Thr Ala Val Pro Ser Thr Gly Ala Ser Lys Ser Lys Arg Gln
20 25 30
Ala Gln Gln Met Val Gln Pro Gln Ser Pro Val Ala Val Ser Gln Ser
35 40 45
Lys Pro Gly Cys Tyr Asp Asn Gly Lys His Tyr Gln Ile Asn Gln Gln
50 55 60
Trp Glu Arg Thr Tyr Leu Gly Asn Ala Leu Val Cys Thr Cys Tyr Gly
65 70 75 80
Gly Ser Arg Gly Phe Asn Cys Glu Ser Lys Pro Glu Ala Glu Glu Thr
85 90 95
Cys Phe Asp Lys Tyr Thr Gly Asn Thr Tyr Arg Val Gly Asp Thr Tyr
100 105 110
Glu Arg Pro Lys Asp Ser Met Ile Trp Asp Cys Thr Cys Ile Gly Ala
115 120 125
Gly Arg Gly Arg Ile Ser Cys Thr Ile Ala Asn Arg Cys His Glu Gly
130 135 140
Gly Gln Ser Tyr Lys Ile Gly Asp Thr Trp Arg Arg Pro His Glu Thr
145 150 155 160
Gly Gly Tyr Met Leu Glu Cys Val Cys Leu Gly Asn Gly Lys Gly Glu
165 170 175
Trp Thr Cys Lys Pro Ile Ala Glu Lys Cys Phe Asp His Ala Ala Gly
180 185 190
Thr Ser Tyr Val Val Gly Glu Thr Trp Glu Lys Pro Tyr Gln Gly Trp
195 200 205
Met Met Val Asp Cys Thr Cys Leu Gly Glu Gly Ser Gly Arg Ile Thr
210 215 220
Cys Thr Ser Arg Asn Arg Cys Asn Asp Gln Asp Thr Arg Thr Ser Tyr
225 230 235 240
Arg Ile Gly Asp Thr Trp Arg Lys Lys Asp Asn Arg Gly Asn Leu Leu
245 250 255
Gln Cys Ile Cys Thr Gly Asn Gly Arg Gly Glu Trp Lys Cys Glu Arg
260 265 270
His Thr Ser Val Gln Thr Thr Ser Ser Gly Ser Gly Pro Phe Thr Asp
275 280 285
Val Arg Ala Ala Val Tyr Gln Pro Gln Pro His Pro Gln Pro Pro Pro
290 295 300
Tyr Gly His Cys Val Thr Asp Ser Gly Val Val Tyr Ser Val Gly Met
305 310 315 320
Gln Trp Leu Lys Thr Gln Gly Asn Lys Gln Met Leu Cys Thr Cys Leu
325 330 335
Gly Asn Gly Val Ser Cys Gln Glu Thr Ala Val Thr Gln Thr Tyr Gly
340 345 350
Gly Asn Ser Asn Gly Glu Pro Cys Val Leu Pro Phe Thr Tyr Asn Gly
355 360 365
Arg Thr Phe Tyr Ser Cys Thr Thr Glu Gly Arg Gln Asp Gly His Leu
370 375 380
Trp Cys Ser Thr Thr Ser Asn Tyr Glu Gln Asp Gln Lys Tyr Ser Phe
385 390 395 400
Cys Thr Asp His Thr Val Leu Val Gln Thr Arg Gly Gly Asn Ser Asn
405 410 415
Gly Ala Leu Cys His Phe Pro Phe Leu Tyr Asn Asn His Asn Tyr Thr
420 425 430
Asp Cys Thr Ser Glu Gly Arg Arg Asp Asn Met Lys Trp Cys Gly Thr
435 440 445
Thr Gln Asn Tyr Asp Ala Asp Gln Lys Phe Gly Phe Cys Pro Met Ala
450 455 460
Ala His Glu Glu Ile Cys Thr Thr Asn Glu Gly Val Met Tyr Arg Ile
465 470 475 480
Gly Asp Gln Trp Asp Lys Gln His Asp Met Gly His Met Met Arg Cys
485 490 495
Thr Cys Val Gly Asn Gly Arg Gly Glu Trp Thr Cys Ile Ala Tyr Ser
500 505 510
Gln Leu Arg Asp Gln Cys Ile Val Asp Asp Ile Thr Tyr Asn Val Asn
515 520 525
Asp Thr Phe His Lys Arg His Glu Glu Gly His Met Leu Asn Cys Thr
530 535 540
Cys Phe Gly Gln Gly Arg Gly Arg Trp Lys Cys Asp Pro Val Asp Gln
545 550 555 560
Cys Gln Asp Ser Glu Thr Gly Thr Phe Tyr Gln Ile Gly Asp Ser Trp
565 570 575
Glu Lys Tyr Val His Gly Val Arg Tyr Gln Cys Tyr Cys Tyr Gly Arg
580 585 590
Gly Ile Gly Glu Trp His Cys Gln Pro Leu Gln Thr Tyr Pro Ser Ser
595 600 605
Ser Gly Pro Val Glu Val Phe Ile Thr Glu Thr Pro Ser Gln Pro Asn
610 615 620
Ser His Pro Ile Gln Trp Asn Ala Pro Gln Pro Ser His Ile Ser Lys
625 630 635 640
Tyr Ile Leu Arg Trp Arg Pro Val Ser Ile Pro Pro Arg Asn Leu Gly
645 650 655
Tyr
<210> 5
<211> 1374
<212> DNA
<213> 人工序列
<220>
<223> 1G5.3重链的DNA序列
<400> 5
atgtacttgg gactgaactg tgtattcata gtttttctct taaaaggtgt ccagagtgaa 60
gtgaaaattg aggagtctgg aggaggcttg gtgcaacctg gaggatccat gaaactctcc 120
tgtgttgcct ctggattcac tttcagtaac gactggatga actgggtccg ccagtctcca 180
gagaaggggc ttgagtgggt tgctgaaatt agaatgaaat ctgataatta tgcaacatat 240
tatgcggagt ctgtgaaagg gaggttcacc atctcaagag atgattccaa aaatagtgtc 300
tacctgcaaa tgaacaattt aagagctgaa gacaatggca tttattactg taccagttgg 360
gactactggg gccaaggcac cactctcaca gtctcctcag ccaaaacgac acccccatct 420
gtctatccac tggcccctgg atctgctgcc caaactaact ccatggtgac cctgggatgc 480
ctggtcaagg gctatttccc tgagccagtg acagtgacct ggaactctgg atccctgtcc 540
agcggtgtgc acaccttccc agctgtcctg cagtctgacc tctacactct gagcagctca 600
gtgactgtcc cctccagcac ctggcccagc gagaccgtca cctgcaacgt tgcccacccg 660
gccagcagca ccaaggtgga caagaaaatt gtgcccaggg attgtggttg taagccttgc 720
atatgtacag tcccagaagt atcatctgtc ttcatcttcc ccccaaagcc caaggatgtg 780
ctcaccatta ctctgactcc taaggtcacg tgtgttgtgg tagacatcag caaggatgat 840
cccgaggtcc agttcagctg gtttgtagat gatgtggagg tgcacacagc tcagacgcaa 900
ccccgggagg agcagttcaa cagcactttc cgctcagtca gtgaacttcc catcatgcac 960
caggactggc tcaatggcaa ggagttcaaa tgcagggtca acagtgcagc tttccctgcc 1020
cccatcgaga aaaccatctc caaaaccaaa ggcagaccga aggctccaca ggtgtacacc 1080
attccacctc ccaaggagca gatggccaag gataaagtca gtctgacctg catgataaca 1140
gacttcttcc ctgaagacat tactgtggag tggcagtgga atgggcagcc agcggagaac 1200
tacaagaaca ctcagcccat catggacaca gatggctctt acttcgtcta cagcaagctc 1260
aatgtgcaga agagcaactg ggaggcagga aatactttca cctgctctgt gttacatgag 1320
ggcctgcaca accaccatac tgagaagagc ctctcccact ctcctggtaa atga 1374
<210> 6
<211> 457
<212> PRT
<213> 人工序列
<220>
<223> 1G5.3重链的蛋白质序列
<400> 6
Met Tyr Leu Gly Leu Asn Cys Val Phe Ile Val Phe Leu Leu Lys Gly
1 5 10 15
Val Gln Ser Glu Val Lys Ile Glu Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe
35 40 45
Ser Asn Asp Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu
50 55 60
Glu Trp Val Ala Glu Ile Arg Met Lys Ser Asp Asn Tyr Ala Thr Tyr
65 70 75 80
Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser
85 90 95
Lys Asn Ser Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Asn
100 105 110
Gly Ile Tyr Tyr Cys Thr Ser Trp Asp Tyr Trp Gly Gln Gly Thr Thr
115 120 125
Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu
130 135 140
Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys
145 150 155 160
Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser
165 170 175
Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
180 185 190
Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp
195 200 205
Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr
210 215 220
Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys
225 230 235 240
Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys
245 250 255
Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val
260 265 270
Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe
275 280 285
Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu
290 295 300
Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His
305 310 315 320
Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala
325 330 335
Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg
340 345 350
Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met
355 360 365
Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro
370 375 380
Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn
385 390 395 400
Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val
405 410 415
Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr
420 425 430
Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu
435 440 445
Lys Ser Leu Ser His Ser Pro Gly Lys
450 455
<210> 7
<211> 720
<212> DNA
<213> 人工序列
<220>
<223> 1G5.3轻链的DNA序列
<400> 7
atggattcac aggcccaggt tcttatattg ctgctgctat gggtatctgg tacctgtggg 60
gacattgtga tgtcacagtc tccatcctcc ctggctgtgt caacaggaga gaaggtcact 120
atgaactgca gatccagtca ctatctgctc aacagtagaa cccgaaagaa cttcttgtct 180
tggtaccaac agaaaccagg acagtctcct caactgctga tctactgggc atccactagg 240
tattctgggg tccctgatcg cttcacaggc agtggatctg ggacagattt cactctcacc 300
atcagcagtg tgcaggctga agacctggca gtttattact gcaaacaatc ttataatctt 360
cacacgttcg gaggggggac caagttggaa ataaagcggg ctgatgctgc accaactgta 420
tccatcttcc caccatccag tgagcagtta acatctggag gtgcctcagt cgtgtgcttc 480
ttgaacaact tctaccccaa agacatcaat gtcaagtgga agattgatgg cagtgaacga 540
caaaatggcg tcctgaacag ttggactgat caggacagca aagacagcac ctacagcatg 600
agcagcaccc tcacgttgac caaggacgag tatgaacgac ataacagcta tacctgtgag 660
gccactcaca agacatcaac ttcacccatt gtcaagagct tcaacaggaa tgagtgttag 720
<210> 8
<211> 239
<212> PRT
<213> 人工序列
<220>
<223> 1G5.3轻链的蛋白质序列
<400> 8
Met Asp Ser Gln Ala Gln Val Leu Ile Leu Leu Leu Leu Trp Val Ser
1 5 10 15
Gly Thr Cys Gly Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala
20 25 30
Val Ser Thr Gly Glu Lys Val Thr Met Asn Cys Arg Ser Ser His Tyr
35 40 45
Leu Leu Asn Ser Arg Thr Arg Lys Asn Phe Leu Ser Trp Tyr Gln Gln
50 55 60
Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Trp Ala Ser Thr Arg
65 70 75 80
Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr
100 105 110
Tyr Cys Lys Gln Ser Tyr Asn Leu His Thr Phe Gly Gly Gly Thr Lys
115 120 125
Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro
130 135 140
Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe
145 150 155 160
Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp
165 170 175
Gly Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp
180 185 190
Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys
195 200 205
Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys
210 215 220
Thr Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 9
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 9
Val Ser Ile Pro Pro Arg Asn Leu Gly Tyr Cys
1 5 10
<210> 10
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> His-MSF
<400> 10
Met Gly Ser Asp Lys Ile His His His His His His His His His His
1 5 10 15
Gly Val Trp Lys Cys Asp Pro Val Asp Gln Cys Gln Asp Ser Glu Thr
20 25 30
Gly Thr Phe Tyr Gln Ile Gly Asp Ser Trp Glu Lys Tyr Val His Gly
35 40 45
Val Arg Tyr Gln Cys Tyr Cys Tyr Gly Arg Gly Ile Gly Glu Trp His
50 55 60
Cys Gln Pro Leu Gln Thr Tyr Pro Ser Ser Ser Gly Pro Val Glu Val
65 70 75 80
Phe Ile Thr Glu Thr Pro Ser Gln Pro Asn Ser His Pro Ile Gln Trp
85 90 95
Asn Ala Pro Gln Pro Ser His Ile Ser Lys Tyr Ile Leu Arg Trp Arg
100 105 110
Pro Val Ser Ile Pro Pro Arg Asn Leu Gly Tyr
115 120
<210> 11
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 11
Val Ser Ile Pro Pro Arg Asn Leu Gly Tyr
1 5 10
<210> 12
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> CDRH3
<400> 12
Trp Asp Tyr
1
<210> 13
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> CDRH2
<400> 13
Glu Ile Arg Met Lys Ser Asp Asn Tyr Ala Thr Tyr Tyr Ala Glu Ser
1 5 10 15
Val Lys Gly
<210> 14
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> CDRH1
<400> 14
Asn Asp Trp Met Asn
1 5
<210> 15
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDRL3
<400> 15
Gln Ser Tyr Asn Leu His Thr
1 5
<210> 16
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDRL2
<400> 16
Trp Ala Ser Thr Arg Tyr Ser
1 5
<210> 17
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDRL1
<400> 17
Arg Ser Ser His Tyr Leu Leu Asn Ser Arg Thr Arg Lys Asn Phe Leu
1 5 10 15
Ser
<210> 18
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 重链可变区
<400> 18
Glu Val Lys Ile Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Asp
20 25 30
Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Glu Ile Arg Met Lys Ser Asp Asn Tyr Ala Thr Tyr Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Asn Gly Ile Tyr
85 90 95
Tyr Cys Thr Ser Trp Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
100 105 110
Ser Ser
<210> 19
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 轻链可变区
<400> 19
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Thr Gly
1 5 10 15
Glu Lys Val Thr Met Asn Cys Arg Ser Ser His Tyr Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Phe Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Gln Leu Leu Ile Tyr Trp Ala Ser Thr Arg Tyr Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Tyr Asn Leu His Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 20
<211> 342
<212> DNA
<213> 人工序列
<220>
<223> 编码抗体的核酸分子
<400> 20
gaagtgaaaa ttgaggagtc tggaggaggc ttggtgcaac ctggaggatc catgaaactc 60
tcctgtgttg cctctggatt cactttcagt aacgactgga tgaactgggt ccgccagtct 120
ccagagaagg ggcttgagtg ggttgctgaa attagaatga aatctgataa ttatgcaaca 180
tattatgcgg agtctgtgaa agggaggttc accatctcaa gagatgattc caaaaatagt 240
gtctacctgc aaatgaacaa tttaagagct gaagacaatg gcatttatta ctgtaccagt 300
tgggactact ggggccaagg caccactctc acagtctcct ca 342
<210> 21
<211> 336
<212> DNA
<213> 人工序列
<220>
<223> 编码抗体的核酸分子
<400> 21
gacattgtga tgtcacagtc tccatcctcc ctggctgtgt caacaggaga gaaggtcact 60
atgaactgca gatccagtca ctatctgctc aacagtagaa cccgaaagaa cttcttgtct 120
tggtaccaac agaaaccagg acagtctcct caactgctga tctactgggc atccactagg 180
tattctgggg tccctgatcg cttcacaggc agtggatctg ggacagattt cactctcacc 240
atcagcagtg tgcaggctga agacctggca gtttattact gcaaacaatc ttataatctt 300
cacacgttcg gaggggggac caagttggaa ataaag 336
Claims (33)
1.一种能识别和结合人迁移刺激因子(MSF)中序列VSIPPRNLGY(SEQ ID NO:11)所包含表位,而不能识别和结合人纤连蛋白1(hFn1)的抗体。
2.如权利要求1所述的抗体,其中表位由人迁移刺激因子(MSF)的序列VSIPPRNLGY(SEQID NO:11)组成。
3.如权利要求1或2所述的抗体,特征是其是利用序列VSIPPRNLGY(SEQ ID NO:11)的肽获得和/或所述抗体选自IgG、IgM、IgA和IgE抗体。
4.如前述权利要求中任一项所述的抗体,其能在免疫试验,优选酶联免疫吸附试验(ELISA)中识别和结合MSF。
5.如前述权利要求中任一项所述的抗体,包含:
-重链的互补决定区3(CDRH3),与氨基酸序列WDY(SEQ ID NO:12)具有至少80%相同性,和/或
-轻链的互补决定区3(CDRL3),与氨基酸序列QSYNLHT(SEQ ID NO:15)具有至少80%相同性。
6.如前述权利要求中任一项所述的抗体,包含:
-重链的互补决定区3(CDRH3),包含序列SEQ.ID No.12,和/或
-轻链的互补决定区3(CDRL3),包含序列SEQ.ID No.15。
7.如前述权利要求中任一项所述的抗体,包含:
-重链的互补决定区3(CDRH3),与氨基酸序列WDY(SEQ ID NO:12)具有至少80%相同性,优选所述CDRH3包含SEQ ID NO.12,和/或
-重链的互补决定区2(CDRH2),与氨基酸序列EIRMKSDNYATYYAESVKG(SEQ ID NO:13)具有至少80%相同性,优选所述CDRH2包含SEQ ID NO.13,和/或
-重链的互补决定区1(CDRH1),与氨基酸序列NDWMN(SEQ ID NO:14)具有至少80%相同性,优选所述CDRH1包含SEQ ID NO.14,和/或
-轻链的互补决定区3(CDRL3),与氨基酸序列QSYNLHT(SEQ ID NO:15)具有至少80%相同性,优选所述CDRL3包含SEQ ID NO.15,和/或
-轻链的互补决定区2(CDRL2),与氨基酸序列WASTRYS(SEQ ID NO:16)具有至少80%相同性,优选所述CDRL2包含SEQ ID NO.16,和/或
-轻链的互补决定区1(CDRL1),与氨基酸序列RSSHYLLNSRTRKNFLS(SEQ ID NO:17)具有至少80%相同性,优选所述CDRL1包含SEQ ID NO.17。
8.如前述权利要求中任一项所述的抗体,其包含重链可变区,其包含与以下氨基酸序列具有至少80%相同性的序列:EVKIEESGGGLVQPGGSMKLSCVASGFTFSNDWMNWVRQSPEKGLEWV
AEIRMKSDNYATYYAESVKGRFTISRDDSKNSVYLQMNNLRAEDNGIYYCTSWDYWGQGTTLTVSS(SEQ IDNO:18)和/或
轻链可变区,其包含与以下氨基酸序列具有至少80%相同性的序列:DIVMSQSPSSLAVSTGEKVTMNCRSSHYLLNSRTRKNFLSWYQQKPG
QSPQLLIYWASTRYSGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCKQSYNLHTFGGGTKLEIK(SEQ IDNO:19)。
9.如前述权利要求中任一项所述的抗体,包含:
-重链可变区,包含以下氨基酸序列:
EVKIEESGGGLVQPGGSMKLSCVASGFTFSNDWMNWVRQSPEKGLEWV
AEIRMKSDNYATYYAESVKGRFTISRDDSKNSVYLQMNNLRAEDNGIYYCTSWDYWGQGTTLTVSS(SEQ IDNO:18)和/或
-轻链可变区,包含以下氨基酸序列:
DIVMSQSPSSLAVSTGEKVTMNCRSSHYLLNSRTRKNFLSWYQQKPG
QSPQLLIYWASTRYSGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCKQSYNLHTFGGGTKLEIK(SEQ IDNO:19),
优选包含主要由SEQ ID No.6的氨基酸序列组成的重链和/或主要由SEQ IDNo.8的氨基酸序列组成的轻链。
10.能够识别和结合前述权利要求所述的抗体识别的表位,且不识别和结合人纤连蛋白1(hFn1)的抗体。
11.如前述权利要求中任一项所述的抗体,其中所述抗体选自以下:单克隆抗体、嵌合抗体、人源化抗体、去免疫化抗体、全人抗体、单链抗体、双特异性抗体、双抗体、scFv、Fab、F(ab)’2及其二聚、寡聚或多聚物。
12.一种选择性检测和/或测定蛋白质MSF或其片段的体外或离体方法,包括步骤:在从个体获得的分离的生物样品中检测MSF或其片段,通过能识别和结合人迁移刺激因子(MSF)的序列VSIPPRNLGY(SEQ ID NO:11)中包含的表位,而不识别和结合人纤连蛋白1(hFn1)的配体,优选所述配体是抗体,更优选所述抗体是权利要求1-11中任一项所述的抗体。
13.一种在个体内对癌症或炎症病状,优选哮喘或过敏评估风险和/或诊断和/或预后和/或监测进展和/或监测治疗处理的效果和/或筛选治疗处理的体外或离体方法,包括步骤:
a)在获自个体的分离生物样品中检测或测定蛋白质MSF或其片段,或编码所述蛋白质或其片段的多核苷酸的量或活性,和
b)与合适的对照进行比较。
14.如权利要求13所述的体外或离体方法,其中检测和/或测定蛋白质MSF或其片段的量是通过特异性配体,其能够识别和结合包含在人迁移刺激因子(MSF)序列(VSIPPRNLGY)(SEQ ID NO:11)中的表位,且不识别和结合人纤连蛋白1(hFn1)。
15.如权利要求14所述的体外或离体方法,其中所述配体是抗体,更优选地所述抗体是权利要求1-11中任一项所述的抗体。
16.权利要求15所述的体外或离体方法,包括步骤:
a)生物样品与权利要求1-11所述的抗体接触并孵育,从而如MSF存在形成MSF-抗体复合物;
b)将生物样品与MSF-抗体复合物分离;
c)用抗体的检测手段选择性检测与抗体结合的MSF和/或对与抗体结合的MSF定量;
d)将c)中获得的结果与对照结果比较。
17.如权利要求15或16所述的体外或离体方法,其中抗体固定在固相支持物上,优选固定的抗体包被在板上。
18.如权利要求16或17所述的体外或离体方法,其中检测手段是可检测抗体,其可被直接检测,可任选地其中可检测抗体由荧光试剂放大,更可任选的是其中可检测抗体生物素化,检测手段是亲和素或链霉亲和素-过氧化物酶和3,3’,5,5’-四甲基联苯胺,更可任选的是其中可检测抗体与过氧化物酶偶联,检测手段是3,3’,5,5’-四甲基联苯胺,更可任选的是其中可检测抗体与碱性磷酸酶偶联,检测手段是对硝基苯基磷酸盐和/或4-甲基伞形基磷酸盐。
19.如权利要求12-18中任一项所述的体外或离体方法,其中蛋白质MSF或其片段量的所述检测和/或测定通过免疫试验,优选通过ELISA试验进行。
20.如权利要求1-11中任一项所述的抗体的用途,用于在分离的生物样品中检测和/或定量蛋白质MSF或其片段,优选其中MSF或其片段的检测能确定M2极化巨噬细胞和/或M2样肿瘤相关巨噬细胞在个体中的存在。
21.如权利要求1-11中任一项所述的抗体的医药用途。
22.能调节MSF表达和/或功能的分子,用于预防和/或治疗癌症或炎症病状,优选哮喘或过敏,其中所述分子优选能选择性耗竭M2极化巨噬细胞和/或M2样肿瘤相关巨噬细胞,所述分子优选是权利要求1-11中任一项所述的抗体。
23.一种药物组合物,包含至少一种如权利要求1-11中任一项所述的抗体和药物学上可接受的赋形剂,优选所述组合物用于胃肠外给药,优选静脉内给药。
24.编码如权利要求1-11中任一项所述的抗体的核酸分子,优选包含主要由以下组成的核苷酸序列:
GAAGTGAAAATTGAGGAGTCTGGAGGAGGCTTGGTGCAACCTGGAGGATCCATGAAACTCTCCTGTGTTGCCTCTGGATTCACTTTCAGTAACGACTGGATGAACTGGGTCCGCCAGTCTCCAGAGAAGGGGCTTGAGTGGGTTGCTGAAATTAGAATGAAATCTGATAATTATGCAACATATTATGCGGAGTCTGTGAAAGGGAGGTTCACCATCTCAAGAGATGATTCCAAAAATAGTGTCTACCTGCAAATGAACAATTTAAGAGCTGAAGACAATGGCATTTATTACTGTACCAGTTGGGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA(SEQ ID NO:20)和/或
GACATTGTGATGTCACAGTCTCCATCCTCCCTGGCTGTGTCAACAGGAGAGAAGGTCACTATGAACTGCAGATCCAGTCACTATCTGCTCAACAGTAGAACCCGAAAGAACTTCTTGTCTTGGTACCAACAGAAACCAGGACAGTCTCCTCAACTGCTGATCTACTGGGCATCCACTAGGTATTCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTGTGCAGGCTGAAGACCTGGCAGTTTATTACTGCAAACAATCTTATAATCTTCACACGTTCGGAGGGGGGACCAAGTTGGAAATAAAG(SEQ ID NO:21)。
25.一种表达载体,其编码权利要求1-11所述的抗体,优选包含权利要求24所述的核酸。
26.一种宿主细胞,其包含如权利要求24所述的核酸或如权利要求25所述的表达载体。
27.检测和/或定量生物样品中的蛋白质MSF或其片段的试剂盒,其包含权利要求1-11中任一项所述的抗体和可任选的复合物抗原-抗体的检测和/或定量手段。
28.如权利要求27所述的试剂盒,其还包含固定抗体的固相支持物。
29.如权利要求28所述的试剂盒,其中所述固相支持物是微量滴定板。
30.如权利要求27-29所述的试剂盒的用途,用于进行权利要求12-19中任一项所述的方法。
31.如权利要求27-29所述的试剂盒,用于在个体生物样品中对癌症或炎症病状进行诊断和/或预测发生的风险和/或预后和/或监测进展和/或监测治疗处理的效力和/或筛选治疗处理方法。
32.如权利要求30-31所述的试剂盒,其中所述方法是免疫试验,优选ELISA。
33.如权利要求30或31或32所述的试剂盒,其中所述方法检测和/或定量生物样品中的人MSF。
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PCT/EP2018/075363 WO2019057780A1 (en) | 2017-09-19 | 2018-09-19 | ANTIBODIES AGAINST THE HUMAN MIGRATION STIMULATION FACTOR (MSF) AND USES THEREOF |
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GRAZIELLA SOLINAS ET AL: "Tumor-Conditioned Macrophages Secrete Migration-Stimulating Factor: A New Marker for M2-Polarization , Influencing Tumor Cell Motility", 《THE JOURNAL OF IMMUNOLOGY》 * |
SETH L. SCHOR ET AL: "Migration-Stimulating Factor: A Genetically Truncated Onco-Fetal Fibronectin Isoform Expressed by Carcinoma and Tumor-Associated Stromal Cells", 《CANCER RESEARCH》 * |
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