CN110636857B - 人红富铁激素的抗体及其用途 - Google Patents
人红富铁激素的抗体及其用途 Download PDFInfo
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Abstract
本文公开了对红富铁激素特异的抗体和包含所述抗体的测定。还公开了使用所述测定诊断或监测疾病的方法。
Description
相关申请的交叉引用
本申请要求2017年3月13日提交的美国临时专利申请62/470,853和2017年3月14日提交的美国临时专利申请62/471,195的权益,这些的美国临时专利申请的全部内容以引用方式并入本文。
技术领域
本发明涉及调节铁代谢的多肽的抗体及使用所述抗体的方法。
背景技术
红血细胞的生产是体内铁的非常主要的消耗者。50多年前就提出了响应红血细胞生产的需要而调节铁的激素的存在。
红富铁激素(erythroferrone,ERFE)是骨髓中的成红细胞响应于促红细胞生成素(EPO)而产生的一种激素。最近的动物研究已经表明,ERFE并不参与基线红细胞生成的调节,而是作为铁调素表达的应激性红细胞生成特异性调节剂。铁调素的高表达导致对饮食铁吸收的抑制,以及巨噬细胞和肝细胞中的铁螯合。通过抑制肝脏中的铁调素表达,ERFE有助于增加膳食铁吸收和出血后血量恢复所需的储存铁的再循环。此外,发现ERFE参与遗传性铁负荷性贫血(诸如β-地中海贫血)中的铁调素调节。ERFE有潜力作为评定血液病患者的红细胞生成的临床标志物。
迄今为止,还没有关于处于开发和/或验证中的人ERFE测定的报道。
发明概述
本文公开了特异于人红富铁激素(ERFE)的抗体和用于检测样品中ERFE多肽的存在和/或测量其量的测定。
在一些实施方式中,提供了一种红富铁激素(ERFE)结合抗体或其ERFE结合片段,所述抗体或其ERFE结合片段包含重链可变区(VH)和轻链可变区(VL),其中所述VH包含:
(i)与SEQ ID NO:18的氨基酸序列具有至少80%序列同一性的氨基酸序列,
(ii)与SEQ ID NO:28的氨基酸序列具有至少80%序列同一性的氨基酸序列,
(iii)与SEQ ID NO:38的氨基酸序列具有至少80%序列同一性的氨基酸序列,
(iv)与SEQ ID NO:48的氨基酸序列具有至少80%序列同一性的氨基酸序列,或
(v)与SEQ ID NO:58的氨基酸序列具有至少80%序列同一性的氨基酸序列,并且
并且所述VL包含:
(vi)与SEQ ID NO:23的氨基酸序列具有至少80%序列同一性的氨基酸序列;
(vii)与SEQ ID NO:33的氨基酸序列具有至少80%序列同一性的氨基酸序列,
(viii)与SEQ ID NO:43的氨基酸序列具有至少80%序列同一性的氨基酸序列,
(ix)与SEQ ID NO:53的氨基酸序列具有至少80%序列同一性的氨基酸序列,或
(x)与SEQ ID NO:63的氨基酸序列具有至少80%序列同一性的氨基酸序列。
在一些实施方式中,提供了ERFE结合抗体或其ERFE结合片段,其中所述抗体包含:
(i)具有SEQ ID NO:19至SEQ ID NO:21的氨基酸序列的重链CDR中的一个、两个或全部三个;
(ii)具有SEQ ID NO:24至SEQ ID NO:26的氨基酸序列的轻链CDR中的一个、两个或全部三个;
(iii)具有SEQ ID NO:29至SEQ ID NO:31的氨基酸序列的重链CDR中的一个、两个或全部三个;
(iv)具有SEQ ID NO:34至SEQ ID NO:36的氨基酸序列的轻链CDR中的一个、两个或全部三个;
(v)具有SEQ ID NO:39至SEQ ID NO:41的氨基酸序列的重链CDR中的一个、两个或全部三个,
(vi)具有SEQ ID NO:44至SEQ ID NO:46的氨基酸序列的轻链CDR中的一个、两个或全部三个,
(vii)具有SEQ ID NO:49至SEQ ID NO:51的氨基酸序列的重链CDR中的一个、两个或全部三个,
(viii)具有SEQ ID NO:54至SEQ ID NO:56的氨基酸序列的轻链CDR中的一个、两个或全部三个,
(ix)具有SEQ ID NO:59至SEQ ID NO:61的氨基酸序列的重链CDR中的一个、两个或全部三个,或
(x)具有SEQ ID NO:64至SEQ ID NO:66的氨基酸序列的轻链CDR中的一个、两个或全部三个。
在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含与SEQ ID NO:18的VH具有至少80%序列同一性的氨基酸序列和与SEQ ID NO:23的VL具有至少80%序列同一性的氨基酸序列。在一些实施方式中,VH具有与SEQ ID NO:18的氨基酸序列具有至少90%序列同一性的氨基酸序列。在一些实施方式中,VL具有与SEQ ID NO:23的氨基酸序列具有至少90%序列同一性的氨基酸序列。
在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:19至SEQ ID NO:21的氨基酸序列的重链CDR中的一个、两个或全部三个,以及具有SEQ ID NO:24至SEQ ID NO:26的氨基酸序列的轻链CDR中的一个、两个或全部三个。
在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含与SEQ ID NO:28的VH具有至少80%序列同一性的氨基酸序列或与SEQ ID NO:33的VL具有至少80%序列同一性的氨基酸序列。在一些实施方式中,VH具有与SEQ ID NO:28的氨基酸序列具有至少90%序列同一性的氨基酸序列。在一些实施方式中,VL具有与SEQ ID NO:33的氨基酸序列具有至少90%序列同一性的氨基酸序列。
在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:29至SEQ ID NO:31的氨基酸序列的重链CDR中的一个、两个或全部三个,以及具有SEQ ID NO:34至SEQ ID NO:36的氨基酸序列的轻链CDR中的一个、两个或全部三个。
在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含与SEQ ID NO:38的VH具有至少80%序列同一性的氨基酸序列和与SEQ ID NO:43的VL具有至少80%序列同一性的氨基酸序列。在一些实施方式中,VH具有与SEQ ID NO:38的氨基酸序列具有至少90%序列同一性的氨基酸序列。在一些实施方式中,VL具有与SEQ ID NO:43的氨基酸序列具有至少90%序列同一性的氨基酸序列。
在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:39至SEQ ID NO:41的氨基酸序列的重链CDR中的一个、两个或全部三个,以及具有SEQ ID NO:44至SEQ ID NO:46的氨基酸序列的轻链CDR中的一个、两个或全部三个。
在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含与SEQ ID NO:48的VH具有至少80%序列同一性的氨基酸序列和与SEQ ID NO:53的VL具有至少80%序列同一性的氨基酸序列。在一些实施方式中,VH具有与SEQ ID NO:48的氨基酸序列具有至少90%序列同一性的氨基酸序列。在一些实施方式中,VL具有与SEQ ID NO:53的氨基酸序列具有至少90%序列同一性的氨基酸序列。
在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:49至SEQ ID NO:51的氨基酸序列的重链CDR中的一个、两个或全部三个,以及具有SEQ ID NO:54至SEQ ID NO:56的氨基酸序列的轻链CDR中的一个、两个或全部三个。
在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含与SEQ ID NO:58的VH具有至少80%序列同一性的氨基酸序列或与SEQ ID NO:63的VL具有至少80%序列同一性的氨基酸序列。在一些实施方式中,VH具有与SEQ ID NO:58的氨基酸序列具有至少90%序列同一性的氨基酸序列。在一些实施方式中,VL具有与SEQ ID NO:63的氨基酸序列具有至少90%序列同一性的氨基酸序列。
在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:59至SEQ ID NO:61的氨基酸序列的重链CDR中的一个、两个或全部三个,以及具有SEQ ID NO:64至SEQ ID NO:66的氨基酸序列的轻链CDR中的一个、两个或全部三个。
在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含VH和VL,其中所述VH包含SEQ ID NO:18、SEQ ID NO:28、SEQ ID NO:38、SEQ ID NO:48或SEQ ID NO:58的氨基酸序列,并且所述VL包含SEQ ID NO:23、SEQ ID NO:33、SEQ ID NO:43、SEQ ID NO:53或SEQID NO:63的氨基酸序列。在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含SEQID NO:18、SEQ ID NO:28、SEQ ID NO:38、SEQ ID NO:48或SEQ ID NO:58的VH或SEQ ID NO:23、SEQ ID NO:33、SEQ ID NO:43、SEQ ID NO:53或SEQ ID NO:63的VL。
在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:19、SEQ ID NO:29、SEQ ID NO:39、SEQ ID NO:49或SEQ ID NO:59的氨基酸序列的CDRH1。在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:20、SEQ IDNO:30、SEQ ID NO:40、SEQ ID NO:50或SEQ ID NO:60的氨基酸序列的CDRH2。在一些实施方式中,ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:21、SEQ ID NO:31、SEQ ID NO:42、SEQ ID NO:52或SEQ ID NO:62的氨基酸序列的CDRH3。
在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:24、SEQ ID NO:34、SEQ ID NO:44、SEQ ID NO:54或SEQ ID NO:64的氨基酸序列的CDRL1。在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:25、SEQ IDNO:35、SEQ ID NO:45、SEQ ID NO:55或SEQ ID NO:65的氨基酸序列的CDRL2。在一些实施方式中,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:26、SEQ ID NO:36、SEQ IDNO:46、SEQ ID NO:56或SEQ ID NO:66的氨基酸序列的CDRL3。
在一些实施方式中,ERFE结合抗体或其ERFE结合片段是嵌合抗体、人源化抗体,或抗体片段。
本文还公开了用于检测样品中红富铁激素(ERFE)蛋白的存在和/或测量其量的测定,所述测定包括:使样品与第一抗体接触以形成第一抗体-ERFE复合物;然后检测与第一抗体-ERFE复合物结合的第二抗体的存在和/或测量其量,其中所述第一抗体和所述第二抗体不相同,从而确定样品中ERFE蛋白的存在和/或量。在一些实施方式中,第一抗体是捕获抗体,并且第二抗体是检测抗体。在一些实施方式中,测定包括ELISA测定。在一些实施方式中,样品是血清样品。在一些实施方式中,第一抗体特异性识别这样的ERFE多肽,所述ERFE多肽包含SEQ ID NO:1和/或SEQ ID NO:3至SEQ ID NO:16中的至少一者的序列、基本上由或由SEQ ID NO:1和/或SEQ ID NO:3至SEQ ID NO:16中的至少一者的序列组成。
在本文公开的测定的一些实施方式中,第一抗体选自单克隆抗体9B12、17A5、17E5、2D2、4C1、6H9、7H4、9C7、14B2和14D9,或其ERFE结合片段。在一些实施方式中,第一抗体选自本文公开的抗体。在一些实施方式中,第一抗体是4C1或其ERFE结合片段。
在本文公开的测定的一些实施方式中,第一抗体包被在固体支持物上。在一些实施方式中,固体支持物是ELISA板。
在本文公开的测定的一些实施方式中,检测步骤包括使第一抗体-ERFE多肽复合物与第二抗体接触,并且其中第二抗体被标记。在一些实施方式中,第二抗体是选自9B12、17A5、17E5、2D2、4C1、6H9、7H4、9C7、14B2和14D9的经标记的检测单克隆抗体。在一些实施方式中,第二抗体是选自权利要求1-39中任一项所述的抗体的经标记的检测抗体。在一些实施方式中,第二抗体是2D2。在一些实施方式中,标记是生物素。在一些实施方式中,标记是辣根过氧化物酶。
本文还公开了评定患有与ERFE或肌联素相关的疾患的受试者的红细胞生成的方法,所述方法包括对来自所述受试者的样品进行本文公开的测定。在一些实施方式中,所述疾患是地中海贫血。在一些实施方式中,所述疾患是心血管疾病。
本文还公开了在患有疾患的受试者中评定红细胞生成的方法,所述方法包括用本文公开的抗体检测来自受试者的样品中的红富铁激素。
本文还公开了一种用于夹心免疫测定的试剂盒,所述试剂盒包含捕获抗体和检测抗体,其中:
i)捕获抗体为17A5并且检测抗体为2D2、4C1或7H4;
ii)捕获抗体为2D2并且检测抗体为4C1、7H4,17A5或9B12;
iii)捕获抗体为4C1并且检测抗体为2D2、7H4、17A5或9B12;
iv)捕获抗体为7H4并且检测抗体为2D2、4C1、17A5、或9B12;
v)捕获抗体为9B12并且检测抗体为2D2、4C1、17A5或7H4。
在试剂盒的一些实施方式中,捕获抗体和检测抗体是不同的抗体。在一些实施方式中,捕获抗体与固体支持物缔合。在一些实施方式中,检测抗体与标记缔合。在一些实施方式中,标记是生物素。在一些实施方式中,标记是辣根过氧化物酶。在一些实施方式中,试剂盒还包含链霉亲和素-辣根过氧化物酶。在一些实施方式中,试剂盒还包含底物。在一些实施方式中,试剂盒还包含用于执行测定的说明书(instructions)。
附图说明
图1描绘了小鼠(SEQ ID NO:2)和人(SEQ ID NO:1)红富铁激素(ERFE)蛋白的比对。高亮显示的序列是SEQ ID NO:16。
图2A至图2B描绘了还原(泳道1)和非还原(泳道2)人重组ERFE的SDS-PAGE(图2A)和蛋白质印迹(图2B)。应注意,与多个条带相比还原ERFE的单个明显条带在蛋白质印迹上尤为明显,表明多聚体组成。泳道P表示阳性对照抗原(蛋白质印迹)。
图3A至图3F描绘了用六种单克隆抗体作为捕获抗体(以100ng/孔包被)和不同浓度的重组人ERFE(150ng/孔、75.00ng/孔、37.50ng/孔、18.75ng/孔;第一条形、第二条形、第三条形和第四条形)进行成对筛选:图3A:17E5;图3B:17A5;图3C:2D2;图3D:4C1;图3E:6H9;图3F:7H4)。测试了八种生物素化的检测抗体,以鉴定由六种捕获抗体捕获的不同浓度的ERFE的存在。
图4A至图4C描绘了用三种不同的包被抗体(7H4[图4A]、17A5[图4B],以及4C1[图4C])和四种不同的生物素化检测抗体(2D2、17A5、9B12和4C1)进行的抗hERFE夹心ELISA测定。不管使用哪种捕获抗体,一些检测抗体在测试的ERFE浓度范围内的斜率更大,尽管所有检测抗体的相关系数都是优异的。
图5A至图5B描绘了使用原型单克隆夹心ELISA(mAb 4C1作为捕获抗体和mAb 2D2作为检测抗体)产生的,以线性(图5A)和对数(图5B)曲线图示描绘的八点标准曲线。应注意,标准曲线较下部分的各点之间有很好的区别(图5B),从而给出在血清中测量的ERFE浓度的最佳分辨率。
图6描绘了血浆或血小板单采术(plasma-or platelet-apheresis)对人血清ERFE表达的影响(n=3名患者;实线、点线,或虚线)。血清ERFE在2天时升高,并保持高于基线水平14天,但所有患者在单采术后120天时恢复到基线ERFE水平。
图7描绘了X连锁性铁粒幼细胞性贫血患者(n=11,XLSA先证者)与其家族对照(n=15)相比的血清ERFE浓度。XLSA患者和对照的中值ERFE浓度分别为10.8ng/ml和0.1ng/ml。图例:****p<0.0001。
图8描绘了铁缺乏症患者和地中海贫血患者的ERFE。在对照(n=47)和铁缺乏(ID,n=22)供体以及α+-地中海贫血(n=15)、β+-地中海贫血(n=20)和β0-地中海贫血(n=27)患者中测量血清ERFE。对照中的中值ERFE为0.4ng/ml,而在ID,α+-地中海贫血、β+-地中海贫血和β0-地中海贫血患者的中值ERFE分别为0.7ng/ml、0.6ng/ml、1.4ng/ml和34.8ng/ml。图例:****p<0.0001,**p<0.005。
图9描绘了使用HRP标记的2D2或生物素化的2D2检测抗体在人血清样品(n=38)中测量的内源ERFE之间的关系。这表明与使用生物素化检测抗体相比,用HRP直接标记检测抗体给出了相当的血清ERFE浓度。
发明详述
本文公开了对红富铁激素(ERFE)具有特异性的抗体,使用所述抗体检测ERFE、诊断与ERFE相关的疾病并监测与ERFE相关的疾病的进展的方法。
红富铁激素是首个鉴定出的介导受试者体内红细胞产生以及铁的吸收和分布的“激素”。红富铁激素在受试者的骨髓中制造,并且当刺激红血细胞的产生时(例如在出血后或从贫血恢复时),其产生大大增加。红富铁激素调节铁的供应,以满足骨髓中红细胞产生的需求。特别地,发现红富铁激素作用于肝脏以抑制主要铁调节蛋白铁调素的产生。因此,在诸如β-地中海贫血的疾病中,红富铁激素的过量产生可导致铁超负荷,因此拮抗红富铁激素能够用于治疗β-地中海贫血。
在抑制铁调素表达的因子的寻找中发现了红富铁激素。铁调素是由肝脏合成的25个氨基酸的肽激素,是铁稳态的主要调节剂。铁调素通过与唯一的铁输出子铁转运蛋白结合而起作用,从而导致其泛素化、内化和溶酶体降解。当铁转运蛋白从细胞膜上消失时,饮食吸收被抑制并且再循环的铁被螯合在巨噬细胞中,从而减少了铁对红细胞生成的可用性。相比之下,低铁调素允许铁转运蛋白在将铁输出至血浆的细胞上保持活性,从而使更多的铁可用于血红蛋白合成。铁、炎症或ER应激刺激铁调素产生,而缺氧、铁缺乏和红细胞生成活性增强抑制铁调素产生。
出血或促红细胞生成素(EPO)施用后,铁调素被抑制。在出血、溶血或铁缺乏引起的贫血中,或在具有无效性红细胞生成的遗传性贫血中,铁调素被抑制。在具有无效性红细胞生成的疾病中,红细胞生成对铁调素的抑制效应尤为明显,在所述疾病中,红细胞前体大量扩增,但大部分在成红细胞阶段经历凋亡,而不是成熟为红细胞。
红富铁激素与一种主要由骨骼肌表达和分泌并参与脂肪酸代谢过程和运输的蛋白肌联素(CTRP15)相同。肌联素促进将脂质吸收到脂肪细胞和肝细胞中。肌联素是骨骼肌响应于葡萄糖或脂肪酸通量引起的细胞能量状态变化而分泌的代谢调节剂,并且在肥胖个体中可能失调。例如,在肥胖个体中,肌联素的表达和循环水平可降低。
红富铁激素同源物的氨基酸序列在脊椎动物进化过程中是非常保守的,因此小鼠和人蛋白质为约71%相同(图1),并且C末端的一半与斑马鱼同源物为约44%相同。结构域分析表明ERFE是与已知细胞因子仅具有中等相似性的TNFα超家族的成员。TNFα和RANK配体(RANKL)是最接近的蛋白。C末端区段的CLUSTAL比对表明TNF家族的人类成员和ERFE的人变体在信号序列上不同。
使用HHPredictB对整个蛋白质进行的结构建模表明,该蛋白质的N末端部分由以下组成:信号序列之后是具有胶原样区段的开放区域,并且C末端部分与TNFα/RANKL同源。与TNFα的相似性非常明显,因为与EFRE一样,TNFα抑制原代肝细胞培养物中的铁调素mRNA。与TNFα的相似性预示着ERFE形成多聚体的趋势。
为了促进ERFE的检测和表征,生成了一系列针对ERFE多肽和全长红富铁激素的人类形式中的抗原的抗体。另外,抗ERFE和/或ERFE蛋白的内部表位和N末端表位的抗体可以用于根据本公开的各种测定和治疗方法中。如本文所用的术语“蛋白质”或“蛋白”是指全长序列,并且“多肽”是指蛋白质序列的片段。
在一些实施方式中,ERFE蛋白包含以下序列、基本上由或由以下序列组成:与人ERFE的完整序列(MAPARRPAGARLLLVYAGLLAAAAAGLGSPEPGAPSRSRARREPPPGNELPRGPGESRAGPAARPPEPTAERAHSVDPRDAWMLFVRQSDKGVNGKKRSRGKAKKLKFGLPGPPGPPGPQGPPGPIIPPEALLKEFQLLLKGAVRQRERAEPEPCTCGPAGPVAASLAPVSATAGEDDDDVVGDVLALLAAPLAPGPRAPRVEAAFLCRLRRDALVERRALHELGVYYLPDAEGAFRRGPGLNLTSGQYRAPVAGFYALAATLHVALGEPPRRGPPRPRDHLRLLICIQSRCQRNASLEAIMGLESSSELFTISVNGVLYLQMGQWTSVFLDNASGCSLTVRSGSHFSAVLLGV;SEQ ID NO:1)具有约70%至约100%、约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%,或约100%序列同一性的序列。
在一些实施方式中,ERFE多肽包含以下序列、基本上由或由以下序列组成:与包含GLPGPPGPPGPQGPPGP(SEQ ID NO:3)、AHSVDPRDAWMLFV(SEQ ID NO:4)、AHSVDPRDAWMLFVXQSDKGXN(SEQ ID NO:5)、LLKEFQLLLKGAVRQRE(SEQ ID NO:6)、GPRAPRVEAAF(SEQ ID NO:7)、VXRRALHELGXYYLPX(SEQ ID NO:8)、GLNLTSGQY(SEQ ID NO:9)、APVAGFYALAATLHVAL(SEQ ID NO:10)、XMGLEXSSELFTISVNGVLYLQ(SEQ ID NO:11)、SSELFTISVNGVLYLQ(SEQ ID NO:12)、TSVFLDNASG(SEQ ID NO:13)、SLTVRSGSHFSA(SEQ IDNO:14)、SLTVRSGSHFSAXLLGX(SEQ ID NO:15),或EFQLLLKGAVRQRERAEPEPCTCGPAGPVAASLAPVSATAGEDDDDVVGDVLALLAAPLAPGPRAPRVEAAFLCRLRRDALVERRALHELGVYYLPDAEGAFRRGPGLNLTSGQYRAPVAGFYALAATLHVALGEPPRRGPPRPRDHLRLLICIQSRCQRNASLEAIMGLESSSELFTISVNGVLYLQMGQWTSVFLDNASGCSLTVRSGSHFSAVLLGV(SEQ ID NO:16)的ERFE片段具有具有约70%至约100%、约80%、约85%、约90%、约95%、约96%、约97%、约98%、约99%,或约100%序列同一性的序列,其中X是任何氨基酸。
在本文公开的一些实施方式中,抗ERFE抗体是单克隆抗体、嵌合抗体、人源化抗体,或其ERFE结合片段。如本文所公开,抗ERFE抗体与全长人ERFE蛋白(SEQ ID NO:1)和/或SEQ ID No.3至SEQ ID No.16的一者的多肽结合。在一些实施方式中,抗ERFE抗体不优先于人ERFE结合鼠ERFE(SEQ ID NO:2)。
在一些实施方式中,本文公开的抗ERFE抗体识别在SEQ ID No.1和SEQ ID No.3至SEQ ID No.16的一者或多者中公开的表位。在一些实施方式中,表位是由蛋白质的三维三级结构产生的构象表位。在一些实施方式中,表位由不连续的氨基酸组成。在一些实施方式中,表位包含抗原的糖基化部分。
术语“抗体”在本文中以最广义使用,并且涵盖各种抗体结构,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)和抗体片段,只要它们表现出所需的抗原结合活性即可。抗体广义上是指包含重(H)链和轻(L)链的任何免疫球蛋白(Ig)分子,或保留了Ig分子的基本表位结合特征的其任何功能片段、突变体、变体或衍生物。此类突变体、变体或衍生抗体形式是本领域已知的,其非限制性实施方式在下文讨论。如果抗体能够与分子特异性反应,则称所述抗体“能够结合”所述分子。如本文所用,术语“片段”在涉及抗体时应理解为是指抗原结合片段,诸如ERFE结合抗体片段。
如本文所用,术语“单克隆抗体”是指从作为独特的亲本细胞的克隆的相同的免疫细胞获得并从特定的单一编码序列表达(忽略可能在表达系统或细胞中出现的变异)的抗体。通常,单克隆抗体是单价的,因为它们与相同的表位结合。修饰语“单克隆”表示从克隆来源获得的抗体的特征,而不应解释为要求通过任何特定方法生产抗体。单克隆抗体可以来自任何哺乳动物物种,例如但不限于人类、小鼠、大鼠、鸡、兔、骆驼科动物等。
抗体的“抗原结合部分”或“抗原结合片段”(或简称为“抗体部分”或“抗体片段”)是指除完整抗体以外的这样的分子,所述分子包含完整抗体的一部分,所述部分与完整抗体结合的抗原结合(例如,保留与抗原特异性结合的能力的一个或多个抗体片段)。抗体片段的示例包括但不限于Fv、Fab、Fab'、Fab'-SH、F(ab')2、双体抗体、线性抗体、单链抗体分子(例如scFv)、仅重链抗体(HCAb),以及由抗体片段形成的多特异性抗体。木瓜蛋白酶对完整抗体的消化产生两个相同的抗原结合片段,称为“Fab”片段,每个“Fab”片段具有单一抗原结合位点;以及残留“Fc”片段,所述残留“Fc”片段的名称反映了其易于结晶的能力。胃蛋白酶处理产生F(ab')2片段,该F(ab')2片段具有两个抗原组合位点并且仍然能够与抗原交联。然而,除了通过蛋白水解消化产生的那些片段外,这些术语还可以应用于具有相同或相似性质的基因编码片段。已经显示抗体的抗原结合功能可以通过全长抗体的片段来执行。此类抗体实施方式也可以是双特异性(bispecific)、双重特异性(dual specific)或多特异性形式;与两种或更多种不同抗原特异性结合。术语抗体的“抗原结合部分”包括的结合片段的示例包括:(i)Fab片段,所述Fab片段是由VL、VH、CL和CH1结构域组成的单价片段;(ii)F(ab')2片段,所述F(ab')2片段是包含通过铰链区处的二硫桥连接的两个Fab片段的二价片段;(iii)Fd片段,所述Fd片段由VH和CH1结构域组成;(iv)Fv片段,所述Fv片段由抗体单臂的VL和VH结构域组成,(v)dAb片段(WO 90/05144A1,以引用方式并入本文),所述dAb片段包含单个可变结构域;以及(vi)分离的互补决定区(CDR)。此外,虽然Fv片段的两个结构域VL和VH由单独的基因编码,但它们可以使用重组方法通过合成接头接合,所述合成连接子使它们能够被制成单个蛋白质链,在所述单个蛋白质链中VL和VH区域配对以形成单价分子(称为单链Fv(scFv))。此类单链抗体还旨在包括在术语抗体的“抗原结合部分”内。也包括其他形式的单链抗体,诸如双体抗体。
术语“嵌合”抗体是指这样的抗体,在所述抗体中重链和/或轻链的一部分来源于一种具体来源或物种,并且所述重链和/或轻链的至少一个其他部分(包括重链和/或轻链的剩余部分)来源于不同的来源或物种。在某些实施方式中,CDR来源于鼠序列并且框架区来源于人序列。
抗体的“类别”是指其重链所具有的恒定结构域或恒定区的类型。人类抗体有五种主要类别:IgA、IgD、IgE、IgG和IgM,并且这些中的若干可以进一步分为亚类(同种型),例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。对应于不同类别的免疫球蛋白的重链恒定结构域分别称为α、δ、ε、γ和μ。
术语“双体抗体(diabodies)”是指具有两个抗原结合位点的抗体片段,所述片段包含在同一条多肽链(VH-VL)中与轻链可变结构域(VL)连接的重链可变结构域(VH)。通过使用太短以至于不允许同一条链上两个结构域之间配对的接头,所述结构域被迫与另一条链的互补结构域配对并产生两个抗原结合位点。双体抗体可以是二价和/或双特异性的。双体抗体更全面地描述于例如EP 404,097;WO 1993/01161;Hudson等人,Nat.Med.9:129-134(2003);和Hollinger等人,Proc.Natl.Acad.Sci.USA 90:6444-6448(1993)中。三体抗体和四体抗体也描述于Hudson等人,Nat.Med.9:129-134(2003)中。
术语“表位”或“抗原决定簇”包括能够特异性结合免疫球蛋白或T细胞受体的任何蛋白质或多肽决定簇。在某些实施方式中,表位决定簇包括分子的化学活性表面基团,诸如氨基酸、糖侧链、磷酰基或磺酰基,并且在某些实施方式中,可以具有特定的三维结构特征和/或特定的电荷特征。表位是抗原的被抗体结合的区域。在某些实施方式中,当抗体在蛋白质和/或大分子的复杂混合物中优先识别其靶抗原时,称所述抗体特异性结合所述抗原。
“Fab”片段含有重链和轻链可变结构域,并且还含有轻链的恒定结构域和重链的第一恒定结构域(CH1)。Fab'片段与Fab片段的区别在于在重链CH1结构域的羧基末端添加了一些残基,包括来自抗体铰链区的一个或多个半胱氨酸。Fab'-SH是其中恒定结构域的半胱氨酸残基带有游离硫醇基的Fab'在本文中的名称。F(ab')2抗体片段最初是作为其间具有铰链半胱氨酸的成对Fab'片段产生的。抗体片段的其他化学偶联也是已知的。
本文中的术语“Fc区”用于定义含有恒定区的至少一部分的免疫球蛋白重链C末端区域。该术语包括天然序列Fc区和变异Fc区。
“框架”或“FR”是指除互补决定区(CDR)残基之外的可变结构域残基。可变结构域的FR通常由以下四个FR结构域组成:FR1、FR2、FR3和FR4。因此,CDR序列和FR序列通常以以下次序出现在VH或VL序列中:FR1-CD1-FR2-CDR2-FR3-CDR3-FR4。
术语“全长抗体”、“完整抗体”和“整个抗体”在本文中可互换使用地指这样的抗体,所述抗体具有与天然抗体结构基本上相似的结构或具有含有如本文所定义的Fc区的重链。
“Fv”是指含有完整抗原结合位点的最小抗体片段。在一个实施方式中,双链Fv物质由一条重链可变结构域和一条轻链可变结构域的紧密、非共价缔合的二聚体组成。在单链Fv(scFv)物质中,一条重链可变结构域和一条轻链可变结构域可以通过柔性肽接头共价连接,使得轻链和重链可缔合成类似于双链Fv物质的“二聚”结构。以此配置,每个可变结构域的三个CDR相互作用以在VH-VL二聚体的表面上限定抗原结合位点。六个CDR共同向抗体赋予抗原结合特异性。然而,即使单个可变结构域(或仅包含三个抗原特异性CDR的Fv的一半)也具有识别和结合抗原的能力,尽管亲和力低于完整的结合位点。
“人抗体”是具有由人基因组编码或来源于人基因组的氨基酸序列的抗体。本公开的人抗体可包括不由人种系免疫球蛋白序列编码的氨基酸残基(例如,通过体外随机或位点特异性诱变或通过体内体细胞突变引入的突变),例如在CDR中。然而,如本文所用,术语“人抗体”不旨在包括这样的抗体,在所述抗体中来源于另一种哺乳动物物种(诸如小鼠)的种系的CDR序列已经移植到人框架序列上。
“人源化”抗体是指这样的抗体,所述抗体包含来自非人物种(例如,小鼠)的重链可变区序列和轻链可变区序列,但是其中VH和/或VL序列的至少一部分已被改变为更“类人的”,即与人种系可变序列更相似。一种类型的人源化抗体是CDR移植抗体,在所述CDR移植抗体中将非人CDR序列引入框架人VH和VL序列中以替代对应的人CDR序列。因此,人源化抗体可包含来自非人CDR的氨基酸残基和来自人FR的氨基酸残基。在某些实施方式中,人源化抗体将包含至少一个,通常两个可变结构域,其中所有或基本上所有的CDR对应于非人抗体(即,供体抗体)的CDR,并且所有或基本上所有的FR对应于人免疫球蛋白共有序列的FR。人源化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(例如,非人抗体)的“人源化形式”是指已经历人源化的抗体。在一些实施方式中,人源化抗体含有轻链以及至少重链可变结构域。抗体还可以包括重链的CH1、铰链、CH2、CH3和CH4区域。在一些实施方式中,人源化抗体仅含有人源化轻链。在一些实施方式中,人源化抗体仅含有人源化重链。在一些具体的实施方式中,人源化抗体仅含有轻链的人源化可变结构域和/或人源化重链。人源化抗体可以选自任何类别的免疫球蛋白,包括IgY、IgM、IgG、IgD、IgA和IgE,以及任何同种型,包括但不限于IgA1、IgA2、IgG1、IgG2、IgG3和IgG4。人源化抗体可以包含来自多于一种类别或同种型的序列,并且可以使用本领域众所周知的技术选择特定的恒定结构域以优化期望的效应子功能。人源化抗体的框架区和CDR区不必精确地对应于亲本序列,例如,可通过以下方式来诱变供体抗体CDR或共有框架:替换、插入和/或缺失至少一个氨基酸残基,以便使该位点处的CDR或框架残基不对应于供体抗体或共有框架。然而,在一个特定实施方式中,此类突变将不是广泛的。通常,至少50%、55%、60%、65%、70%、75%或80%,特别地至少85%,更特别地至少90%,以及特别地至少95%的人源化抗体残基将对应于亲本FR和CDR序列的那些残基。
术语“CDR移植抗体”是指这样的抗体,所述抗体包含来自一种物种的重链可变区序列和轻链可变区序列,但是其中VH和/或VL的一个或多个CDR区的序列被另一物种的CDR序列替代,诸如这样的抗体,所述抗体具有人重链和轻链可变区,其中一个或多个人CDR已被鼠CDR序列替代。
术语“可变区”或“可变结构域”是指参与抗体与抗原结合的抗体重链或轻链结构域。天然抗体的重链可变结构域和轻链可变结构域(分别为VH和VL)通常具有相似的结构,其中每个结构域均包含四个保守框架区(FR)和三个被称为互补决定区(CDR)的高变区。(参见例如,Kindt等人,Kuby Immunology,第6版,W.H.Freeman and Co.,第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,结合特定抗原的抗体可以使用来自与所述抗原结合的抗体的VH或VL结构域分离,以分别筛选互补VL或VH结构域的文库。
在某些实施方式中,抗ERFE抗体是9B12(ATCC登录号PTA-123882)、17A5(ATCC登录号PTA-123883)、2D2(ATCC登录号PTA-123879)、4C1(ATCC登录号PTA-123880)和7H4(ATCC登录号PTA-123881)中的一者,或含有来自这些抗体中的一者的一个或多个CDR的抗体或抗体片段。
本文公开的抗ERFE抗体包含2D2或其片段。在一些实施方式中,抗ERFE抗体或其片段包含VH和VL,其中VH包含SEQ ID NO:18的氨基酸序列并且VL包含SEQ ID NO:23的氨基酸序列。在一些实施方式中,抗ERFE抗体或其片段包含SEQ ID NO:18或SEQ ID NO:23的一者。在一些实施方式中,VH具有与SEQ ID NO:18的氨基酸序列具有至少90%序列同一性的氨基酸序列。在一些实施方式中,VL具有与SEQ ID NO:23的氨基酸序列具有至少90%序列同一性的氨基酸序列。在一些实施方式中,抗ERFE抗体或其片段包含具有SEQ ID NO:19至SEQID NO:21的氨基酸序列的重链CDR中的一个、两个或全部三个。在一些实施方式中,抗ERFE抗体或其片段包含具有SEQ ID NO:24至SEQ ID NO:26的氨基酸序列的轻链CDR中的一个、两个或全部三个。在一些实施方式中,抗体是本文公开的嵌合抗体、人源化抗体,或抗体片段。
本文公开的抗ERFE抗体包含4C1或其片段。在一些实施方式中,抗ERFE抗体或其片段包含VH和VL,其中VH包含SEQ ID NO:28的氨基酸序列并且VL包含SEQ ID NO:33的氨基酸序列。在一些实施方式中,抗ERFE抗体或其片段包含SEQ ID NO:28或SEQ ID NO:33的一者。在一些实施方式中,VH具有与SEQ ID NO:28的氨基酸序列具有至少90%序列同一性的氨基酸序列。在一些实施方式中,VL具有与SEQ ID NO:33的氨基酸序列具有至少90%序列同一性的氨基酸序列。在一些实施方式中,抗ERFE抗体或其片段包含具有SEQ ID NO:29至SEQID NO:31的氨基酸序列的重链CDR中的一个、两个或全部三个。在一些实施方式中,抗ERFE抗体或其片段包含具有SEQ ID NO:34至SEQ ID NO:36的氨基酸序列的轻链CDR中的一个、两个或全部三个。在一些实施方式中,抗体是本文公开的嵌合抗体、人源化抗体,或抗体片段。
本文公开的抗ERFE抗体包含7H4或其片段。在一些实施方式中,抗ERFE抗体或其片段包含VH和VL,其中VH包含SEQ ID NO:38的氨基酸序列并且VL包含SEQ ID NO:43的氨基酸序列。在一些实施方式中,抗ERFE抗体或其片段包含SEQ ID NO:38或SEQ ID NO:43的一者。在一些实施方式中,VH具有与SEQ ID NO:38的氨基酸序列具有至少90%序列同一性的氨基酸序列。在一些实施方式中,VL具有与SEQ ID NO:43的氨基酸序列具有至少90%序列同一性的氨基酸序列。在一些实施方式中,抗ERFE抗体或其片段包含具有SEQ ID NO:39至SEQID NO:41的氨基酸序列的重链CDR中的一个、两个或全部三个。在一些实施方式中,抗ERFE抗体或其片段包含具有SEQ ID NO:44至SEQ ID NO:46的氨基酸序列的轻链CDR中的一个、两个或全部三个。在一些实施方式中,抗体是本文公开的嵌合抗体、人源化抗体,或抗体片段。
本文公开的抗ERFE抗体包含9B12或其片段。在一些实施方式中,抗ERFE抗体或其片段包含VH和VL,其中VH包含SEQ ID NO:48的氨基酸序列并且VL包含SEQ ID NO:53的氨基酸序列。在一些实施方式中,抗ERFE抗体或其片段包含SEQ ID NO:48或SEQ ID NO:53的一者。在一些实施方式中,VH具有与SEQ ID NO:48的氨基酸序列具有至少90%序列同一性的氨基酸序列。在一些实施方式中,VL具有与SEQ ID NO:53的氨基酸序列具有至少90%序列同一性的氨基酸序列。在一些实施方式中,抗ERFE抗体或其片段包含具有SEQ ID NO:49至SEQ ID NO:51的氨基酸序列的重链CDR中的一个、两个或全部三个。在一些实施方式中,抗ERFE抗体或其片段包含具有SEQ ID NO:54至SEQ ID NO:56的氨基酸序列的轻链CDR中的一个、两个或全部三个。在一些实施方式中,抗体是本文公开的嵌合抗体、人源化抗体,或抗体片段。
本文公开的抗ERFE抗体包含17A5或其片段。在一些实施方式中,抗ERFE抗体或其片段包含VH和VL,其中VH包含SEQ ID NO:58的氨基酸序列并且VL包含SEQ ID NO:63的氨基酸序列。在一些实施方式中,抗ERFE抗体或其片段包含SEQ ID NO:58或SEQ ID NO:63的一者。在一些实施方式中,VH具有与SEQ ID NO:58的氨基酸序列具有至少90%序列同一性的氨基酸序列。在一些实施方式中,VL具有与SEQ ID NO:63的氨基酸序列具有至少90%序列同一性的氨基酸序列。在一些实施方式中,抗ERFE抗体或其片段包含具有SEQ ID NO:59至SEQ ID NO:61的氨基酸序列的重链CDR中的一个、两个或全部三个。在一些实施方式中,抗ERFE抗体或其片段包含具有SEQ ID NO:64至SEQ ID NO:66的氨基酸序列的轻链CDR中的一个、两个或全部三个。在一些实施方式中,抗体是本文公开的嵌合抗体、人源化抗体,或抗体片段。
在一些实施方式中,抗ERFE抗体或其片段具有包含SEQ ID NO:19、SEQ ID NO:29、SEQ ID NO:39、SEQ ID NO:49或SEQ ID NO:59中一者的CDRH1。在一些实施方式中,抗ERFE抗体或其片段具有包含SEQ ID NO:20、SEQ ID NO:30、SEQ ID NO:40、SEQ ID NO:50或SEQID NO:60中一者的CDRH2。在一些实施方式中,抗ERFE抗体或其片段具有包含SEQ ID NO:21、SEQ ID NO:31、SEQ ID NO:42、SEQ ID NO:52或SEQ ID NO:62中一者的CDRH3。
在一些实施方式中,抗ERFE抗体或其片段具有包含SEQ ID NO:24、SEQ ID NO:34、SEQ ID NO:44、SEQ ID NO:54或SEQ ID NO:64中一者的CDRL1。在一些实施方式中,抗ERFE抗体或其片段具有包含SEQ ID NO:25、SEQ ID NO:35、SEQ ID NO:45、SEQ ID NO:55或SEQID NO:65中一者的CDRL2。在一些实施方式中,抗ERFE抗体或其片段具有包含SEQ ID NO:26、SEQ ID NO:36、SEQ ID NO:46、SEQ ID NO:56或SEQ ID NO:66中一者的CDRL3。
在一些实施方式中,提供了具有改善特性的抗ERFE抗体或其片段。例如,通过本文公开的抗体或片段的亲和力成熟来制备对ERFE具有改善的亲和力的抗ERFE抗体或其片段。
尽管CDR对于表位识别很重要,但是它们对于本文公开的抗体及其片段不是必需的。因此,提供了通过例如本文公开的抗体的亲和力成熟产生的具有改善性质的抗体和片段。
可以通过在侧接于一组特定CDR的可变区和恒定区序列内进行突变、缺失和/或插入而容易地产生多种多样的抗体和抗体片段,以及抗体模拟物。因此,例如,通过替换不同的重链,针对一组给定CDR的不同类别的抗体是可行的,由此例如可以产生IgG1-4、IgM、IgA1-2,、IgD、IgE抗体类型和同种型。类似地,可以通过将一组给定CDR嵌入完全合成的框架中来产生本公开范围内的人工抗体。
人源化抗体或经调适以不被其他哺乳动物排斥的抗体可以使用诸如表面再塑和CDR移植的几种技术来产生。在表面再塑技术中,将分子建模、统计分析和诱变组合以调节可变区的非CDR表面,使其类似于靶宿主已知抗体的表面。美国专利号5,639,641公开了用于抗体表面再塑的策略和方法,以及用于降低抗体在不同宿主内的免疫原性的其他方法,该美国专利的全部内容由此以引用方式并入。在CDR移植技术中,将鼠重链和轻链CDR移植到完整的人框架序列中。
本公开还涵盖本说明书中描述的抗体的功能等同物。功能等同物具有与抗体相当的结合特征,并且包括例如嵌合抗体、人源化抗体和单链抗体及其片段。产生此类功能等同物的方法公开于PCT申请WO 93/21319、欧洲专利申请号239,400;PCT申请WO 89/09622;欧洲专利申请338,745;和欧洲专利申请EP 332,424中,这些专利的相应全部内容以引用方式并入本文。功能等同物包括与本发明的抗体的可变区或高变区的氨基酸序列具有基本上相同的氨基酸序列的多肽。应用于氨基酸序列的“基本上相同”在本文中被定义为序列与另一氨基酸序列具有至少约90%,更优选至少约95%的序列同一性,按照通过根据Pearson和Lipman,Proc.Natl.Acad.Sci.USA85,2444-2448(1988)的FASTA搜索方法确定。功能等同物包括嵌合抗体、单链抗体片段,以及保持对ERFE的结合亲和力的其他抗体片段。
通过在抗体DNA中引入适当的核苷酸变化或通过肽合成来制备抗ERFE抗体的氨基酸序列变体也在本公开的范围内。此类变体包括例如对本文示例的抗体的氨基酸序列内的残基的缺失和/或插入和/或替换。进行缺失、插入和替换的任何组合以达成最终构建体,前提条件是最终构建体具有期望的特征。氨基酸变化还可改变人源化或变异抗体的翻译后过程,诸如改变糖基化位点的数目或位置。
一种用于鉴定作为优选诱变位置的特定抗体残基或区域的有用方法称为“丙氨酸扫描诱变”。鉴定出一个残基或一组靶残基(例如,带电荷的残基,诸如Arg、Asp、His、Lys,以及Glu),并替换成中性或带负电荷的氨基酸(最优选地丙氨酸或聚丙氨酸)以影响氨基酸与抗原的相互作用。然后通过在替换位点处或针对替换位点引入进一步或其他变异来改善那些对替换表现出功能敏感性的氨基酸位置。因此,虽然预先确定了用于引入氨基酸序列变异的位点,但是突变本身的性质无需预先确定。例如,为了分析给定位点处的突变的性能,在靶密码子或区域进行丙氨酸扫描或随机诱变,并对表达的抗体变体进行期望活性的筛选。
氨基酸序列插入包括长度从一个残基到含有一百个或更多个残基的多肽的氨基和/或羧基末端融合,以及单个或多个氨基酸残基的序列内插入。末端插入的示例包括具有N末端甲硫氨酰基残基的抗ERFE抗体或与表位标签融合的抗体。抗体分子的其他插入变体包括将延长抗体的血清半衰期的酶或多肽融合到抗体的N末端或C末端。
变体的另一种类型是氨基酸替换变体。这些变体在抗体分子中具有至少一个氨基酸残基被去除并且在其位置中插入了不同的残基。最感兴趣的替换诱变位点包括高变区,但也考虑FR改变。保守替换显示在表1的“优选替换”表头下。如果此类替换导致生物活性改变,则可以引入在表1中命名为“示例性替换”或者按照以下关于氨基酸类别进一步描述的更实质性改变,并筛选产物。
表1
对抗体的生物学特性的实质性修饰是通过以下方式实现的:选择在维持(a)取代区域中的多肽主链的结构(例如呈片状或螺旋构象),(b)靶位点处分子的电荷或疏水性,或(c)侧链的体积方面的效应显著不同的替换。天然残基基于常见的侧链特性分为以下各组:
(1)疏水性:正亮氨酸、Met、Ala、Val、Leu、Ile;
(2)中性亲水性:Cys、Ser、Thr;
(3)酸性:Asp、Glu;
(4)碱性:Asn、Gin、His、Lys、Arg;
(5)影响链取向的残基:Gly、Pro;以及
(6)芳香族:Trp、Tyr、Phe。
非保守替换将需要将这些类别中的一种类别的成员交换为另一种类别。
也可以通常用丝氨酸替换不参与维持抗ERFE抗体的适当构象的任何半胱氨酸残基,以改善分子的氧化稳定性并防止异常交联。相反,可将一个或多个半胱氨酸键添加至抗体以改善其稳定性(特别是当抗体是诸如Fv片段等抗体片段时)。
另一种类型的替换变体涉及替换亲本抗体(例如,人源化或人抗体)的一个或多个高变区残基。通常,选择用于进一步开发的所得变体将相对于产生它们的亲本抗体具有改善的生物学特性。产生此类替换变体的方便方式是使用噬菌体展示进行亲和力成熟。简而言之,几个高变区位点(例如,6-7个位点)经突变以产生每个位点处所有可能的氨基替换。如此产生的抗体变体以单价形式从丝状噬菌体颗粒展示为与包装在每个颗粒中的M13的基因IIII产物的融合体。然后如本文所公开的,对经噬菌体展示的变体进行针对它们的生物学活性(例如,结合亲和力)的筛选。为了鉴定用于修饰的候选高变区位点,可以执行丙氨酸扫描诱变以鉴定对抗原结合有显著贡献的高变区残基。替代地或另外,可为有益的是分析抗原-抗体复合物的晶体结构以鉴定抗体与人ERFE之间的接触点。根据本文详述的技术,此类接触残基和邻近残基是替换的候选者。一旦产生了此类变体,就对该组变体进行如本文所述的筛选,并且可以选择在一项或多项相关测定中具有优异特性的抗体用于进一步开发。
抗体的另一种氨基酸变体改变了抗体的原始糖基化模式。改变是指使抗体中发现的一个或多个碳水化合物部分缺失,和/或添加抗体中不存在的一个或多个糖基化位点。
抗体的糖基化通常是N-连接的或O-连接的。N-连接的是指碳水化合物部分附接至天冬酰胺残基的侧链。三肽序列天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸,其中X是除脯氨酸外的任何氨基酸,是将碳水化合物部分酶促附接至天冬酰胺侧链的识别序列。因此,多肽中这些三肽序列中任一者的存在产生潜在的糖基化位点。O-连接的糖基化是指糖N-乙酰半乳糖胺、半乳糖或木糖中的一者附接至羟基氨基酸,最通常为丝氨酸或苏氨酸,尽管也可以使用5-羟基脯氨酸或5-羟基赖氨酸。
通过改变氨基酸序列以使其含有上述三肽序列中的一个或多个,可以方便地实现将糖基化位点添加至抗体(对于N-连接的糖基化位点)。也可以通过对原始抗体的序列添加或替换为一个或多个丝氨酸或苏氨酸残基来进行改变(对于O-连接的糖基化位点)。
通过本领域已知的多种方法来制备编码抗ERFE抗体的氨基酸序列变体的核酸分子。这些方法包括但不限于从天然来源分离(在天然存在的氨基酸序列变体的情况下),或通过对先前制备的抗ERFE抗体的变异或非变异版本进行寡核苷酸介导的(或定点)诱变、PCR诱变和盒式诱变来制备。
考虑了抗ERFE抗体的其他修饰。例如,可期望在效应子功能方面对抗体进行修饰,例如以增强抗体在治疗疾病方面的功效。例如,可以将一个或多个半胱氨酸残基引入Fc区,从而允许在该区域中形成链间二硫键。
本文公开的抗体可以通过重组手段产生。因此,本文公开了编码抗体的核酸、包含编码抗体的核酸的表达载体,以及包含编码抗体的核酸的细胞。重组生产的方法在现有技术中是众所周知的,并且包括在原核和真核细胞中进行蛋白质表达,随后分离抗体,并通常纯化至药学上可接受的纯度。为了在宿主细胞中如上所述表达抗体,通过标准方法将编码抗体序列的核酸插入表达载体。在合适的原核或真核宿主细胞(如CHO细胞、NS0细胞、SP2/0细胞、HEK293细胞、COS细胞、PER.C6细胞、酵母或E.coli细胞)中执行表达,并从所述细胞中回收抗体(上清液或裂解后的细胞)。
因此,本文公开的某些实施方式包括制备抗ERFE抗体的方法,所述方法包括以下步骤:a)用至少一种包含编码抗体的核酸分子的表达载体转化宿主细胞;b)在允许抗体分子合成的条件下培养宿主细胞;以及c)从培养物中回收所述抗体分子。
通过常规的免疫球蛋白纯化方法,诸如蛋白A-琼脂糖凝胶、羟磷灰石层析、凝胶电泳、透析或亲和层析,将抗体与培养基适当地分离。
如本文所用,表述“细胞”、“细胞系”和“细胞培养物”可互换地使用,并且所有此类名称均包括子代。因此,词语“转化体”和“转化细胞”包括原代受试者细胞和来源于其的培养物,而与传代次数无关。还应理解,由于故意或无意的突变,所有子代的DNA物质可能不是精确相同的。包括具有与原始转化细胞中筛选的功能或生物学活性相同的功能或生物学活性的变异子代。在旨在使用不同的名称的情况下,将从上下文中明晰。
如本文所用的术语“转化”是指将载体/核酸转移到宿主细胞中的过程。如果将没有强大的细胞壁屏障的细胞用作宿主细胞,则可以例如通过磷酸钙沉淀法进行转染。然而,也可以使用诸如通过核注射或通过原生质体融合将DNA引入细胞中的其他方法。如果使用原核细胞或含有大量细胞壁构造的细胞,则例如一种转染方法是使用氯化钙进行钙处理。
如本文所用,“表达”是指将核酸转录成mRNA的过程和/或将经转录的mRNA(也称为转录物)随后翻译成肽、多肽或蛋白质的过程。转录物和编码的多肽统称为基因产物。如果多核苷酸来源于基因组DNA,则在真核细胞中表达可包括mRNA的剪接。
“载体”是核酸分子,尤其是自我复制的核酸分子,其将插入的核酸分子转移到宿主细胞内和/或之间。该术语包括主要起将DNA或RNA插入细胞中(例如,染色体整合)的功能的载体,主要起复制DNA或RNA的功能的载体的复制,以及作用为转录和/或翻译DNA或RNA的表达载体。还包括提供多于一种所述功能的载体。
“表达载体”是这样的多核苷酸,所述多核苷酸当被引入合适的宿主细胞中时,可以被转录并翻译成多肽。“表达系统”通常是指由可作用以产生期望表达产物的表达载体组成的合适宿主细胞。
如本文所用的术语“宿主细胞”表示可以经工程化以产生本文所公开的抗体的任何类型的细胞系统。在一个实施方式中,HEK293细胞和CHO细胞用作宿主细胞。
适用于原核生物的控制序列例如包括启动子、任选地操纵子序列,以及核糖体结合位点。已知真核细胞利用启动子、增强子和多腺苷酸化信号。
当核酸被放置为与另一核酸序列呈功能关系时,该核酸是“可操作地连接的”。例如,如果前序列或分泌前导序列的DNA表达为参与多肽分泌的前蛋白,则所述前序列或分泌前导序列的DNA与所述多肽的DNA可操作地连接;如果启动子或增强子影响编码序列的转录,则所述启动子或增强子与所述序列可操作地连接;或者如果核糖体结合位点经定位以促进翻译,则所述核糖体结合位点与编码序列可操作地连接。通常,“可操作地连接的”是指被连接的DNA序列是连续的,并且在分泌前导序列的情况下,是连续的并且在阅读框中。然而,增强子不必是连续的。类似地,在一些情况下,内含子可以存在于可操作地连接的核酸序列之间。连接通过在方便的限制性位点处进行连接来完成。如果不存在此类位点,则根据常规实践使用合成的寡核苷酸衔接子或接头。
本文还公开了编码抗ERFE抗体的分离核酸,包含所述核酸的载体和宿主细胞,以及用于产生所述抗体的重组技术。
为了重组产生抗体,可以将编码所述抗体的核酸分离,并插入到可复制载体中以进一步克隆(DNA扩增)或表达。在一些实施方式中,抗体可以通过同源重组产生,例如如在US 5,204,244中所述,其关于抗体产生的所有公开内容以引用方式特别地并入本文。使用常规程序(例如,通过使用能够与编码抗体的重链和轻链的基因特异性结合的寡核苷酸探针)容易地分离编码抗体的DNA并进行测序。许多载体可用。载体组分通常包括但不限于以下中的一种或多种:信号序列、复制起点、一个或多个标记基因、增强子元件、启动子,以及转录终止序列,例如如在US5,534,615中描述的,其关于蛋白质表达的所有公开内容以引用方式明确地并入本文。
用于克隆或表达本文的载体中的DNA的合适宿主细胞是上述原核生物、酵母,或更高等的真核细胞。用于此目的的合适原核生物包括真细菌,诸如革兰氏阴性或革兰氏阳性生物体,例如Enterobacteriaceae(诸如Escherichia,例如E.coli)、Enterobacter、Erwinia、Klebsiella、Proteus,Salmonella(例如,S.typhimurium)、Serratia(例如,S.marcescans)和Shigella,以及Bacilli(诸如B.subtilis和B.licheniformis)、Pseudomonas(诸如P.aeruginosa),以及Streptomyces。一种示例性的E.coli克隆宿主是E.coli 294(ATCC 31,446),但是其他菌株,诸如E.coli B、E.coli X1776(ATCC 31,537)和E.coli W3110(ATCC 27,325)也是合适的。这些示例是说明性的而不是限制性的。
除原核生物外,真核微生物,诸如丝状真菌或酵母,也是编码抗ERFE抗体的载体的合适克隆或表达宿主。Saccharomyces cerevisiae或普通面包酵母是低等真核宿主微生物中最常用的。然而,许多其他属、物种和菌株是普遍可得和在本文中可用的,诸如Schizosaccharomyces pombe;Kluyveromyces宿主,诸如K.lactis、K.fragilis(ATCC 12,424)、K.bulgaricus(ATCC 16,045)、K.wickeramii(ATCC 24,178)、K.waltii(ATCC 56,500)、K.drosophilarum(ATCC 36,906)、K.thermotolerans,以及K.marxianus;Yarrowia(EP 402,226);Pichia pastoris(EP183,070);Candida;Trichoderma reesia(EP 244,234);Neurospora crassa;Schwanniomyces,诸如S.occidentalis;以及丝状真菌,诸如Neurospora、Penicillium、Tolypocladium,以及Aspergillus宿主,诸如A.nidulans和A.niger。
用于表达糖基化抗ERFE抗体的合适宿主细胞来源于多细胞生物,包括无脊椎动物细胞,诸如植物细胞和昆虫细胞。已经鉴定出来自宿主的许多杆状病毒株和变体以及相应的允许昆虫宿主细胞,所述宿主为诸如Spodoptera frugiperda(毛虫)、Aedes aegypti(蚊子)、Aedes albopictus(蚊子)、Drosophila melanogaster(果蝇),以及Bombyx mori。用于转染的各种病毒株是可公开获得的,例如,Autographa californica NPV的L-1变体和B.mori NPV的Bm-5株,并且此类病毒可用作本文中根据本发明的病毒,特别是用于Spodoptera frugiperda细胞的转染。棉花、玉米、马铃薯、大豆、矮牵牛、番茄和烟草的植物细胞培养物也可以用作宿主。
然而,对脊椎动物细胞的兴趣最大,并且脊椎动物细胞在培养(组织培养)中的增殖已成为常规程序。有用的哺乳动物宿主细胞系的示例是通过SV40转化的猴肾CV1系(COS-7、ATCC CRL 1651);人胚胎肾细胞系(293细胞或经亚克隆以在悬浮培养中生长的293细胞);幼仓鼠肾细胞(BHK、ATCC CCL 10);中国仓鼠卵巢细胞/-DHFR(CHO);小鼠塞尔托利氏细胞(TM4);猴肾细胞(CV1ATCC CCL 70);非洲绿猴肾细胞(VERO-76、ATCC CRL-1587);人宫颈癌细胞(HELA、ATCC CCL 2);犬肾细胞(MDCK、ATCC CCL 34);布法罗大鼠肝细胞(BRL 3A、ATCC CRL 1442);人肺细胞(W138、ATCC CCL 75);人肝细胞(Hep G2、HB 8065);小鼠乳腺肿瘤(MMT 060562、ATCC CCL51);TRI细胞;MRC 5细胞;FS4细胞;以及人类肝癌细胞系(HepG2)。
用上述表达载体转化宿主细胞以进行抗ERFE抗体生产,并在经适当修饰的常规营养培养基中培养以诱导启动子、选择转化体或扩增编码期望序列的基因。
用于生产抗ERFE抗体的宿主细胞可以在多种培养基中培养。商业可用的培养基,诸如Ham's F10、基本必需培养基(MEM)、RPMI-1640和杜氏改良的伊格尔培养基(DMEM),都适合用于培养宿主细胞。此外,US4,767,704;US4,657,866;US4,927,762;US4,560,655;或US5,122,469;WO 90/03430;WO 87/00195;或US Re.30,985可用作宿主细胞的培养基。这些培养基中的任何一种都可以根据需要补充激素和/或其他生长因子(诸如胰岛素、转铁蛋白,或表皮生长因子)、盐(诸如氯化钠、钙、镁,以及磷酸盐)、缓冲剂(诸如HEPES)、核苷酸(诸如腺苷和胸苷)、抗生素(诸如GENTAMYCINTM)、微量元素(定义为通常以微摩尔范围的最终浓度存在的无机化合物),以及葡萄糖或等效能源。也可以以本领域技术人员已知的适当浓度包含任何其他必要的补充剂。培养条件,诸如温度、pH等,是先前与经选择用于表达的宿主细胞一起使用的那些条件,并且对于普通技术人员而言将是显而易见的。
当使用重组技术时,抗体可以在细胞内、在周质间隙中产生,或直接分泌到培养基中。如果抗体在细胞内产生,则作为第一步,例如通过离心或超滤去除为宿主细胞或裂解片段的微粒碎片。
可以使用例如羟基磷灰石层析、凝胶电泳、透析和亲和层析来纯化由细胞制备的抗体组合物,其中亲和层析是优选的纯化技术。蛋白A作为亲和配体的适用性取决于抗体中存在的任何免疫球蛋白Fc结构域的种类和同种型。蛋白A可用于纯化基于人γ1、γ2或γ4重链的抗体。建议将蛋白G用于所有小鼠同种型和人γ3。亲和配体所附接至的基质最通常是琼脂糖,但也可以使用其他基质。机械稳定的基质(诸如受控的孔玻璃或聚(苯乙烯二乙烯基)苯)允许实现比使用琼脂糖能够实现的更快的流速和更短的处理时间。如果抗体包含CH3结构域,则Bakerbond ABXTM树脂可用于纯化。取决于要回收的抗体,也可以使用其他蛋白质纯化技术,诸如离子交换柱上的分馏、乙醇沉淀、反相HPLC、硅胶上的层析、在肝素SEPHAROSETM上的层析、在阴离子或阳离子交换树脂上的色谱(诸如聚天冬氨酸柱)、层析聚焦、SDS-PAGE,以及硫酸铵沉淀。
在任何初步纯化步骤之后,可以使用洗脱缓冲液在约2.5-4.5之间的pH下对包含感兴趣的抗体和污染物的混合物进行低pH疏水相互作用层析,优选在低盐浓度(例如,约0-0.25M的盐)下执行。
在一些实施方式中,本文公开了用于检测样品中ERFE蛋白或多肽的存在和/或测量其量的测定,所述测定包括使样品与根据本公开的抗ERFE蛋白或多肽的抗体接触,然后检测结合抗体的存在和/或测量结合抗体的量。
如本文所用,术语“样品”是指可含有期望进行ERFE测定的ERFE的任何物质。样品可以是生物样品,诸如生物流体或生物组织。生物流体的示例包括血液、血清、血浆、唾液、痰、眼晶状体液、汗液、尿液、乳汁、腹水、粘液、滑液、腹膜液、经皮渗出液、咽部渗出液、支气管肺泡灌洗液、气管抽吸液、脑脊液、精液、宫颈粘液、阴道或尿道分泌物,羊水等。生物组织包含通常为特定类型的细胞及其细胞间物质的聚集体,所述聚集体形成人或动物的一种结构材料,包括结缔组织、上皮、肌肉和神经组织。样品可以以直接从来源获得的形式使用,或可以在预处理以改变其特性后使用。
在一些实施方式中,所述测定是免疫测定。示例性的非限制性免疫测定是酶联免疫吸附测定(ELISA)。在另一些实施方式中,免疫测定是免疫组织化学测定。免疫测定使用抗体对物质的特异性来测量所述物质,诸如分析物、蛋白质等。
在一个实施方式中,ELISA是夹心ELISA。在此类测定中,对该物质特异的捕获抗体与诸如微量滴定板的固体支持物缔合。使含有该物质的液体(或怀疑含有该物质,或需要确定不包含该物质的样品)与捕获抗体结合。然后加入同样对该物质特异的检测抗体,以检测与捕获抗体结合的物质。
在一些实施方式中,所述测定是免疫组织化学测定。免疫组织化学涉及通过利用抗体特异性结合生物组织中抗原的原理对组织切片中的抗原(蛋白质)进行选择性成像的过程。使抗体-抗原相互作用可视化可以以多种方式实现。在最常见的情况下,使用检测抗体,所述检测抗体允许检测与所述抗体结合的物质。
在一些实施方式中,检测抗体是标记的抗体。标记可包括放射性标记、酶标记、比色标记、荧光标记、化学发光标记,或本领域技术人员已知的其他标记。在一些实施方式中,标记是生物素。如果标记是生物素,则需要将包含亲和素或链霉亲和素的第二检测剂与酶、放射性同位素、比色剂或其他试剂缀合。在一个实施方式中,第二检测剂是链霉亲和素-辣根过氧化物酶。
在一些实施方式中,标记是酶标记,诸如过氧化物酶(例如,辣根过氧化物酶)、半乳糖苷酶(例如,β-D-半乳糖苷酶),或磷酸酶(例如,碱性磷酸酶)。对于酶标记,需要这样的底物,所述底物被酶切割以产生颜色、荧光或发光,所述颜色、荧光或发光采用分光光度法进行测量。过氧化物酶的示例性比色底物包括但不限于3,3',5,5'-四甲基联苯胺(TMB)、3,3',4,4'二氨基联苯胺(DAB)、4-氯-1-萘酚(4CN)、2,2'-连氮基-双[3-乙基苯并噻唑啉]磺酸(ABTS),以及邻苯二胺(OPD)。在一些实施方式中,当测定是ELISA时,底物是TMB,其产生在650nm的波长下测量的蓝色。可以通过添加酸或另一种终止剂来终止反应。使用硫酸终止溶液使TMB变黄,然后可以在450nm处读取颜色。磷酸酶的示例性比色底物包括但不限于5-溴-4-氯-3-吲哚基-磷酸/氮蓝四唑(BCIP/NBT)和对硝基苯基磷酸盐(p-NPP)。半乳糖苷酶的示例性比色底物包括但不限于5-十二烷酰氨基荧光素二-β-D-吡喃半乳糖苷(C12FDG)、9H-(1,3-二氯-9,9-二甲基吖啶-2-酮-7-基),以及β-D-吡喃半乳糖苷(DDAO半乳糖苷)。示例性荧光底物包括但不限于4-甲基伞形酮磷酸酯(4-MUP;对于磷酸酶而言),以及4-甲基伞形酮酰半乳糖苷(MUG;对于半乳糖苷酶而言)、荧光素二-β-D-吡喃半乳糖苷(FDG;对于半乳糖苷酶而言)、羟基苯乙酸(HPA;对于过氧化物酶而言),以及3-对羟基苯基丙酸(HPPA;对于过氧化物酶而言)。示例性的发光底物包括但不限于:鲁米诺、多酚(例如,焦棓酚、红倍酚(pupurogallin)、没食子酸,以及伞形酮)和吖啶酯,以及用于过氧化物酶的萤光素;用于磷酸酶的3-(2'-螺金刚烷)-4-甲基-4-(3'-磷酰氧基苯基-1,2-二氧杂环丁烷,二钠盐)(AMPPD);以及用于半乳糖苷酶的(3-(2'-螺金刚烷)-4-甲氧基-4-(3'-β-D-吡喃半乳糖基氧基苯基-1,2-二氧杂环丁烷(AMPGD)。
在一些实施方式中,标记是辣根过氧化物酶并且底物是TMB。
在一些实施方式中,标记是比色标记、荧光标记,或发光标记。示例性的比色标记包括但不限于纳米颗粒金。示例性的荧光标记包括但不限于溴化乙锭、荧光素及其衍生物、罗丹明及其衍生物、绿色荧光蛋白、德克萨斯红、喀斯喀特蓝(Cascade Blue)、俄勒冈绿、船坞蓝(Marina Blue)、atto标记、CFTM染料、Alexa Fluor,以及花青染料。示例性的发光标记包括但不限于萤光素和萤火虫萤光素酶。
适合用作捕获和检测抗体的抗体可以是单克隆或多克隆的,并且可以来源于许多物种。抗体的示例性物种包括人、兔、小鼠、大鼠、骆驼科动物、羊驼、鸡等。在一些实施方式中,捕获抗体和检测抗体均为小鼠单克隆抗体。在另一些实施方式中,捕获抗体和检测抗体是兔单克隆或多克隆抗体。同样在本公开范围内的是其中捕获抗体和检测抗体属于不同物种的测定,或者捕获抗体和检测抗体中的一种是多克隆抗体而一种是单克隆抗体的测定。
关于参考多肽序列的“氨基酸序列同一性百分比(%)”被定义为在比对序列并引入空位(如果需要的话)以实现最大序列同一性百分比,并且不考虑将任何保守取代作为序列同一性的一部分之后,候选序列中与参考多肽序列中的氨基酸残基相同的氨基酸残基的百分比。用于确定氨基酸序列同一性百分比的比对可以以本领域技术内的各种方式来实现,例如使用公开可得的计算机软件,诸如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。本领域技术人员可以确定用于比对序列的合适参数,包括在所比较的序列的全长上实现最大比对所需的任何算法。
还公开了使用抗体诊断或监测铁调素相关疾患、铁稳态疾病、与ERFE有关的疾患,和/或与肌联素有关的疾患的方法。
如本文所用,“铁调素相关疾患”是指由破坏铁稳态的铁调素水平异常(例如,相对于贫血或存储铁程度的铁调素过量或铁调素缺乏)引起的或与其相关的病症。铁稳态的破坏可继而导致继发性疾病,诸如贫血。急性或慢性炎症病症可导致铁调素表达上调,所述上调可导致循环铁水平降低,这可导致贫血或使现有贫血恶化。示例性的铁调素相关炎性疾病包括癌症性贫血、慢性疾病性贫血、炎症性贫血、化疗引起的贫血、慢性肾脏疾病(I期、II期、III期、IV期或V期)、终末期肾疾病、慢性肾衰竭、充血性心力衰竭、癌症、类风湿性关节炎、系统性红斑狼疮、克罗恩氏病、H.pylori感染或其他细菌感染、丙型肝炎、HIV和其他病毒性疾病、动脉硬化、动脉粥样硬化、肝硬化、胰腺炎、败血症、血管炎、铁缺乏、低色小红细胞性贫血、镰状细胞疾病,以及铁调素过量的病症。
如本文所用,短语“铁稳态疾病(或疾患)”是指受试者的铁水平需要调节的病症。其包括铁调素相关疾患;与铁调素水平升高无关但仍将受益于铁调素活性抑制的病症,诸如不是由铁调素引起的铁稳态破坏;铁吸收、循环、代谢或排泄异常导致正常铁血液水平或组织分布破坏的疾病;铁失调是另一种疾病或病症(诸如炎症、癌症或化疗)的结果的疾病;铁血液水平或组织分布异常导致的疾病或疾患;以及能够通过调节铁水平或分布来治疗的疾病或疾患。可导致铁调素过量的此类铁稳态疾病或疾患,铁调素相关疾患和炎性病症的非限制性示例包括非洲铁超负荷,铁难治性铁缺乏性贫血(IRIDA),α地中海贫血,阿尔茨海默氏病,贫血,癌症性贫血,慢性疾病性贫血,炎症性贫血,动脉硬化或动脉粥样硬化(包括冠状动脉疾病、脑血管疾病或外周闭塞性动脉疾病),共济失调,与铁有关的共济失调,转铁蛋白缺乏症,癌症,血浆铜蓝蛋白缺乏,化疗引起的贫血,慢性肾脏/肾疾病(I期、II期、III期、IV期或V期)(包括终末期肾疾病或慢性肾脏/肾衰竭),急性肾脏损伤(AKI),心肺旁路相关AKI,药物或毒素相关AKI,肝硬化,经典血色沉着病,胶原诱导的关节炎(CIA),铁调素过量(铁调素升高)的病症,先天性红细胞生成不良性贫血,充血性心力衰竭,克罗恩氏病,乳糜泻,炎性肠病(IBD),糖尿病,铁生物分布疾患,铁稳态疾患,铁代谢疾患,铁转运蛋白疾病,铁转运蛋白突变血色沉着病,叶酸缺乏,弗里德利希共济失调,索性脊髓病,Gracile综合征(Gracile syndrome),H.pylori感染或其他细菌感染,遗传性血色沉着病,获得性血色沉着病,转铁蛋白受体2突变导致的血色沉着病,血红蛋白病,肝炎,肝炎(Brock),丙型肝炎,肝细胞癌、HIV或其他病毒性疾病,亨廷顿氏病,高铁蛋白血症,低色小红细胞性贫血,血铁过少,胰岛素抵抗,缺铁性贫血,缺铁性疾患,铁超负荷疾患,铁调素过量的缺铁性病症,青少年血色沉着病(HFE2),多发性硬化症,转铁蛋白受体2、HFE、血幼素(hemojuvelin)、铁转运蛋白或其他铁代谢基因的突变,新生儿血色沉着病,与铁有关的神经退行性疾病,骨质减少,骨质疏松胰腺炎,泛酸激酶相关的神经变性,帕金森氏病,糙皮病,异食癖,卟啉症,迟发性皮肤卟啉症,假脑炎,肺含铁血黄素沉积,红血细胞疾患,类风湿性关节炎,败血症,铁粒幼红细胞性贫血,系统性红斑狼疮,地中海贫血,中间型地中海贫血,输血铁超负荷,肿瘤,血管炎,维生素B6缺乏症,维生素B12缺乏症,和/或威尔逊氏病。
与铁调节破坏有关的非炎性病症包括但不限于维生素B6缺乏症、维生素B12缺乏症、叶酸缺乏症、糙皮病、索性脊髓病、假脑炎、帕金森氏病、阿尔茨海默氏病、冠心病、骨质减少和骨质疏松症、血红蛋白病和红细胞代谢疾患,以及外周闭塞性动脉疾病。
如本文所用,短语“与ERFE有关的疾病(或疾患)”是指由ERFE水平异常(例如,ERFE过量或ERFE缺乏)引起或与之相关的病症。与ERFE有关的示例性疾病包括但不限于地中海贫血、镰状细胞疾病、铁止血疾病或疾患,以及铁调素相关疾患。
地中海贫血是以异常血红蛋白生产为特征的遗传性血液疾患。症状取决于类型并且可以从无症状至严重症状而异。有两种主要类型,α地中海贫血和β地中海贫血。α地中海贫血和β地中海贫血的严重程度取决于α球蛋白的四个基因或β球蛋白的两个基因有多少丢失。突变等位基因当部分功能是保守的时(蛋白质具有降低的功能,或者其功能正常但以减少的数量产生)被称为β+,或当不产生功能蛋白时被称为β0。
如本文所用,短语“与肌联素有关的疾病(或疾患)”是指由肌联素水平异常(例如,肌联素过量或肌联素缺乏)引起或与其相关的病症。与肌联素有关的示例性疾病包括但不限于铁止血疾病或疾患、铁调素相关疾患、心血管疾病或疾患、糖尿病、肥胖症,以及胰岛素抵抗。
如本文所用,术语“受试者”或“患者”或“个体”是指哺乳动物,并且包括但不限于家畜动物(例如,牛、绵羊、猫、狗,以及马)、灵长类动物(例如,人和非人灵长类动物,诸如猴)、兔,以及啮齿动物(例如,小鼠和大鼠)。在某些实施方式中,受试者是人类。
一些实施方式
实施方式1.一种红富铁激素(ERFE)结合抗体或其ERFE结合片段,所述ERFE结合抗体或其ERFE结合片段包含重链可变区(VH)和轻链可变区(VL),
其中所述VH包含:
(i)与SEQ ID NO:18的氨基酸序列具有至少80%序列同一性的氨基酸序列,
(ii)与SEQ ID NO:28的氨基酸序列具有至少80%序列同一性的氨基酸序列,
(iii)与SEQ ID NO:38的氨基酸序列具有至少80%序列同一性的氨基酸序列,
(iv)与SEQ ID NO:48的氨基酸序列具有至少80%序列同一性的氨基酸序列,或
(v)与SEQ ID NO:58的氨基酸序列具有至少80%序列同一性的氨基酸序列,并且
并且所述VL包含:
(vi)与SEQ ID NO:23的氨基酸序列具有至少80%序列同一性的氨基酸序列;
(vii)与SEQ ID NO:33的氨基酸序列具有至少80%序列同一性的氨基酸序列,
(viii)与SEQ ID NO:43的氨基酸序列具有至少80%序列同一性的氨基酸序列,
(ix)与SEQ ID NO:53的氨基酸序列具有至少80%序列同一性的氨基酸序列,或
(x)与SEQ ID NO:63的氨基酸序列具有至少80%序列同一性的氨基酸序列。
实施方式2.一种ERFE结合抗体或其ERFE结合片段,其中所述抗体包含:
(i)具有SEQ ID NO:19至SEQ ID NO:21的氨基酸序列的重链CDR中的一个、两个或全部三个;
(ii)具有SEQ ID NO:24至SEQ ID NO:26的氨基酸序列的轻链CDR中的一个、两个或全部三个;
(iii)具有SEQ ID NO:29至SEQ ID NO:31的氨基酸序列的重链CDR中的一个、两个或全部三个;
(iv)具有SEQ ID NO:34至SEQ ID NO:36的氨基酸序列的轻链CDR中的一个、两个或全部三个;
(v)具有SEQ ID NO:39至SEQ ID NO:41的氨基酸序列的重链CDR中的一个、两个或全部三个,
(vi)具有SEQ ID NO:44至SEQ ID NO:46的氨基酸序列的轻链CDR中的一个、两个或全部三个,
(vii)具有SEQ ID NO:49至SEQ ID NO:51的氨基酸序列的重链CDR中的一个、两个或全部三个,
(viii)具有SEQ ID NO:54至SEQ ID NO:56的氨基酸序列的轻链CDR中的一个、两个或全部三个,
(ix)具有SEQ ID NO:59至SEQ ID NO:61的氨基酸序列的重链CDR中的一个、两个或全部三个,或
(x)具有SEQ ID NO:64至SEQ ID NO:66的氨基酸序列的轻链CDR中的一个、两个或全部三个。
实施方式3.根据实施方式1所述的ERFE结合抗体或其ERFE结合片段,所述ERFE结合抗体或其ERFE结合片段包含与SEQ ID NO:18的VH具有至少80%序列同一性的氨基酸序列和与SEQ ID NO:23的VL具有至少80%序列同一性的氨基酸序列。
实施方式4.根据实施方式1或实施方式3所述的ERFE结合抗体或其ERFE结合片段,其中所述VH具有与SEQ ID NO:18的氨基酸序列具有至少90%序列同一性的氨基酸序列。
实施方式5.根据实施方式1或实施方式3所述的ERFE结合抗体或其ERFE结合片段,其中所述VL具有与SEQ ID NO:23的氨基酸序列具有至少90%序列同一性的氨基酸序列。
实施方式6.根据实施方式2所述的ERFE结合抗体或其ERFE结合片段,其中所述抗体包含具有SEQ ID NO:19至SEQ ID NO:21的氨基酸序列的重链CDR中的一个、两个或全部三个,以及具有SEQ ID NO:24至SEQ ID NO:26的氨基酸序列的轻链CDR中的一个、两个或全部三个。
实施方式7.根据实施方式1所述的ERFE结合抗体或其ERFE结合片段,所述ERFE结合抗体或其ERFE结合片段包含与SEQ ID NO:28的VH具有至少80%序列同一性的氨基酸序列或与SEQ ID NO:33的VL具有至少80%序列同一性的氨基酸序列。
实施方式8.根据实施方式1或实施方式7所述的ERFE结合抗体或其ERFE结合片段,其中所述VH具有与SEQ ID NO:28的氨基酸序列具有至少90%序列同一性的氨基酸序列。
实施方式9.根据实施方式1或实施方式7所述的ERFE结合抗体或其ERFE结合片段,其中所述VL具有与SEQ ID NO:33的氨基酸序列具有至少90%序列同一性的氨基酸序列。
实施方式10.根据实施方式2所述的ERFE结合抗体或其ERFE结合片段,其中所述抗体包含具有SEQ ID NO:29至SEQ ID NO:31的氨基酸序列的重链CDR中的一个、两个或全部三个,以及具有SEQ ID NO:34至SEQ ID NO:36的氨基酸序列的轻链CDR中的一个、两个或全部三个。
实施方式11.根据实施方式1所述的ERFE结合抗体或其ERFE结合片段,所述ERFE结合抗体或其ERFE结合片段包含与SEQ ID NO:38的VH具有至少80%序列同一性的氨基酸序列和与SEQ ID NO:43的VL具有至少80%序列同一性的氨基酸序列。
实施方式12.根据实施方式1或实施方式11所述的ERFE结合抗体或其ERFE结合片段,其中所述VH具有与SEQ ID NO:38的氨基酸序列具有至少90%序列同一性的氨基酸序列。
实施方式13.根据实施方式1或实施方式11所述的ERFE结合抗体或其ERFE结合片段,其中所述VL具有与SEQ ID NO:43的氨基酸序列具有至少90%序列同一性的氨基酸序列。
实施方式14.根据实施方式2所述的ERFE结合抗体或其ERFE结合片段,其中所述抗体包含具有SEQ ID NO:39至SEQ ID NO:41的氨基酸序列的重链CDR中的一个、两个或全部三个,以及具有SEQ ID NO:44至SEQ ID NO:46的氨基酸序列的轻链CDR中的一个、两个或全部三个。
实施方式15.根据实施方式1所述的ERFE结合抗体或其ERFE结合片段,所述ERFE结合抗体或其ERFE结合片段包含与SEQ ID NO:48的VH具有至少80%序列同一性的氨基酸序列和与SEQ ID NO:53的VL具有至少80%序列同一性的氨基酸序列。
实施方式16.根据实施方式1或实施方式15所述的ERFE结合抗体或其ERFE结合片段,其中所述VH具有与SEQ ID NO:48的氨基酸序列具有至少90%序列同一性的氨基酸序列。
实施方式17.根据实施方式1或实施方式15所述的ERFE结合抗体或其ERFE结合片段,其中所述VL具有与SEQ ID NO:53的氨基酸序列具有至少90%序列同一性的氨基酸序列。
实施方式18.根据实施方式2所述的ERFE结合抗体或其ERFE结合片段,其中所述抗体包含具有SEQ ID NO:49至SEQ ID NO:51的氨基酸序列的重链CDR中的一个、两个或全部三个,以及具有SEQ ID NO:54至SEQ ID NO:56的氨基酸序列的轻链CDR中的一个、两个或全部三个。
实施方式19.根据实施方式1所述的ERFE结合抗体或其ERFE结合片段,所述ERFE结合抗体或其ERFE结合片段包含与SEQ ID NO:58的VH具有至少80%序列同一性的氨基酸序列或与SEQ ID NO:63的VL具有至少80%序列同一性的氨基酸序列。
实施方式20.根据实施方式1或实施方式19所述的ERFE结合抗体或其ERFE结合片段,其中所述VH具有与SEQ ID NO:58的氨基酸序列具有至少90%序列同一性的氨基酸序列。
实施方式21.根据实施方式1或实施方式19所述的ERFE结合抗体或其ERFE结合片段,其中所述VL具有与SEQ ID NO:63的氨基酸序列具有至少90%序列同一性的氨基酸序列。
实施方式22.根据实施方式2所述的ERFE结合抗体或其ERFE结合片段,其中所述抗体包含具有SEQ ID NO:59至SEQ ID NO:61的氨基酸序列的重链CDR中的一个、两个或全部三个,以及具有SEQ ID NO:64至SEQ ID NO:66的氨基酸序列的轻链CDR中的一个、两个或全部三个。
实施方式23.一种ERFE结合抗体或其ERFE结合片段,所述ERFE结合抗体或其ERFE结合片段包含VH和VL,其中所述VH包含SEQ ID NO:18、SEQ ID NO:28、SEQ ID NO:38、SEQID NO:48或SEQ ID NO:58的氨基酸序列,并且所述VL包含SEQ ID NO:23、SEQ ID NO:33、SEQ ID NO:43、SEQ ID NO:53或SEQ ID NO:63的氨基酸序列。
实施方式24.一种ERFE结合抗体或其ERFE结合片段,所述ERFE结合抗体或其ERFE结合片段包含SEQ ID NO:18、SEQ ID NO:28、SEQ ID NO:38、SEQ ID NO:48或SEQ ID NO:58的VH或SEQ ID NO:23、SEQ ID NO:33、SEQ ID NO:43、SEQ ID NO:53或SEQ ID NO:63的VL。
实施方式25.一种ERFE结合抗体或其ERFE结合片段,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:19、SEQ ID NO:29、SEQ ID NO:39、SEQ ID NO:49或SEQ IDNO:59的氨基酸序列的CDRH1。
实施方式26.一种ERFE结合抗体或其ERFE结合片段,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:20、SEQ ID NO:30、SEQ ID NO:40、SEQ ID NO:50或SEQ IDNO:60的氨基酸序列的CDRH2。
实施方式27.一种ERFE结合抗体或其ERFE结合片段,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:21、SEQ ID NO:31、SEQ ID NO:42、SEQ ID NO:52或SEQ IDNO:62的氨基酸序列的CDRH3。
实施方式28.一种ERFE结合抗体或其ERFE结合片段,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:24、SEQ ID NO:34、SEQ ID NO:44、SEQ ID NO:54或SEQ IDNO:64的氨基酸序列的CDRL1。
实施方式29.一种ERFE结合抗体或其ERFE结合片段,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:25、SEQ ID NO:35、SEQ ID NO:45、SEQ ID NO:55或SEQ IDNO:65的氨基酸序列的CDRL2。
实施方式30.一种ERFE结合抗体或其ERFE结合片段,所述ERFE结合抗体或其ERFE结合片段包含具有SEQ ID NO:26、SEQ ID NO:36、SEQ ID NO:46、SEQ ID NO:56或SEQ IDNO:66的氨基酸序列的CDRL3。
实施方式31.根据实施方式1-30中一项所述的ERFE结合抗体或其ERFE结合片段,其中所述抗体是嵌合抗体、人源化抗体,或抗体片段。
实施方式32.一种用于检测样品中红富铁激素(ERFE)蛋白的存在和/或测量其量的测定,所述测定包括:使样品与第一抗体接触以形成第一抗体-ERFE复合物;以及然后检测与所述第一抗体-ERFE复合物结合的第二抗体的存在和/或测量其量,其中所述第一抗体和所述第二抗体不相同,从而确定所述样品中ERFE蛋白的存在和/或量。
实施方式33.根据实施方式32所述的测定,其中所述测定包括ELISA测定。
实施方式34.根据实施方式32所述的测定,其中所述样品是血清样品。
实施方式35.根据实施方式32所述的测定,其中所述第一抗体和第二抗体特异性识别这样的ERFE多肽,所述ERFE多肽包含以下序列、基本上由或由以下序列组成:SEQ IDNO:1和/或SEQ ID NO:3至SEQ ID NO:16中至少一者的序列。
实施方式36.根据实施方式32所述的测定,其中所述第一抗体选自单克隆抗体9B12、17A5、17E5、2D2、4C1、6H9、7H4、9C7、14B2和14D9,或其ERFE结合片段。
实施方式37.根据实施方式32所述的测定,其中所述第一抗体选自实施方式1-31中任一项所述的抗体。
实施方式38.根据实施方式32所述的测定,其中所述第一抗体是4C1或其ERFE结合片段。
实施方式39.根据实施方式32-38中任一项所述的测定,其中所述第一抗体包被在固体支持物上。
实施方式40.根据实施方式39所述的测定,其中所述固体支持物是ELISA板。
实施方式41.根据实施方式32所述的测定,其中所述检测步骤包括使第一抗体-ERFE多肽复合物与第二抗体接触,并且其中所述第二抗体被标记。
实施方式42.根据实施方式41所述的测定,其中所述第二抗体是选自9B12、17A5、17E5、2D2、4C1、6H9、7H4、9C7、14B2和14D9的经标记的检测单克隆抗体。
实施方式43.根据实施方式41所述的测定,其中所述第二抗体是选自权利要求1-39中任一项所述的抗体的经标记的检测抗体。
实施方式44.根据实施方式41所述的测定,其中所述第二抗体是2D2。
实施方式45.根据实施方式41所述的测定,其中所述标记是生物素。
实施方式46.根据实施方式41所述的测定,其中所述标记是辣根过氧化物酶。
实施方式47.一种评定患有与ERFE或肌联素相关的疾患的受试者的红细胞生成的方法,所述方法包括使来自所述受试者的样品进行实施方式32-46中任一项所述的测定。
实施方式48.根据实施方式47所述的方法,其中所述疾患是地中海贫血。
实施方式49.根据实施方式47所述的方法,其中所述疾患是心血管疾患。
实施方式50.一种在患有疾患的受试者中评定红细胞生成的方法,所述方法包括用根据实施方式1-31中任一项所述的抗体检测来自受试者的样品中的红富铁激素。
实施方式51.一种用于夹心免疫测定的试剂盒,所述试剂盒包含捕获抗体和检测抗体,其中:
i)捕获抗体为17A5并且检测抗体为2D2、4C1或7H4;
ii)捕获抗体为2D2并且检测抗体为4C1、7H4,17A5或9B12;
iii)捕获抗体为4C1并且检测抗体为2D2、7H4、17A5或9B12;
iv)捕获抗体为7H4并且检测抗体为2D2、4C1、17A5或9B12;
v)捕获抗体为9B12并且检测抗体为2D2、4C1、17A5或7H4;或者
vii)捕获和检测抗体各是根据权利要求14-44中任一项所述的抗体,其中所述捕获和检测抗体是不同的。
实施方式52.根据实施方式51所述的试剂盒,其中所述捕获抗体和所述检测抗体是不同的抗体。
实施方式53.根据实施方式51或52所述的试剂盒,其中所述捕获抗体与固体支持物缔合。
实施方式54.根据实施方式51-53中任一项所述的试剂盒,其中所述检测抗体与标记缔合。
实施方式55.根据实施方式54所述的试剂盒,其中所述标记是生物素。
实施方式56.根据实施方式54所述的试剂盒,其中所述标记是辣根过氧化物酶。
实施方式57.根据实施方式55所述的试剂盒,所述试剂盒还包含链霉亲和素-辣根过氧化物酶。
实施方式58.根据实施方式51-57中任一项所述的试剂盒,所述试剂盒还包含底物。
实施方式59.根据实施方式51-58中任一项所述的试剂盒,所述试剂盒还包含用于执行测定的说明书。
实施例
实施例1.用于临床评定无效性红细胞生成的血清红富铁激素的单克隆夹心ELISA
β-地中海贫血和其他常见遗传性和获得性铁负荷性贫血的标志是无效性红细胞生成(IE;受损的血液生产),所述无效性红细胞生成在铁超负荷的情况下导致衰弱性贫血。最近发现,红富铁激素(ERFE)是这样的激素,所述激素在发育中的红血细胞(RBC)中产生并且已被证明是铁调素的负调节剂,调节血浆铁水平的主要激素,并且在β地中海贫血患者中高度升高。
ERFE抗原的生产和纯化。用含有FLAG标签的克隆的ERFE瞬时转染培养的HEK细胞。在允许的条件下扩增转染的HEK细胞以进行ERFE表达,并且收集培养基上清液并合并以在抗FLAG柱中纯化。尽管抗原被抗ERFE mAb识别,但产率低。高效的HEK细胞系和用于ERFE的GenScript专有的克隆载体(Piscataway,NJ)提高了生产效率,产生了约5mg/L的纯化的ERFE。
ERFE mAb的等离子体共振评估。然后确定与ERFE抗原结合的抗体的特异性、亲和力和动力学。该方法使得能够选择ERFE的高亲和力mAb,并选择用于ERFE夹心ELISA的捕获和检测mAb的最佳对。使用ELISA以及ERFE包被的96孔板对所有单克隆抗体候选物进行初步筛选。因为表位可及性或其构象在固定在塑料上后可能会改变,因此将ERFE抗原以不同的浓度固定在ELISA板上。基于该测定选择在任一板上具有高滴度的杂交瘤上清液。对于表面等离子体共振分析,将高度纯化的抗体包被在Biacore传感器芯片上。为了确保以定向方式捕获抗体,使用了Fc特异性芯片(蛋白A/G传感器芯片CM5)。将表达和纯化的ERFE抗原以一定范围的浓度(nM至mM)注射,并在一定范围的缓冲条件下研究结合相互作用。作为对照,将BSA或非特异性抗体在相同条件下固定到参考表面上,以校正仪器和缓冲伪影(artifacts)。使用制造商提供的BIAevaluation 3.2版软件获得解离(koff)和缔合(kon)速率常数以及其他结合参数。
该实验也以相反的配置执行,其中芯片包被有ERFE抗原,并且注入了mAb溶液。将ERFE抗原通过-NH2或-COOH基团固定在芯片上,并使用相关蛋白作为对照。最后,使用鉴定出的有希望的候选对来测试抗体对与ERFE相互作用的能力。将一种抗体锚定在Fc芯片上,添加ERFE,并将另一种抗体浮置在芯片上。选择产生最高亲和力相互作用的抗体对。对照包括ERFE被其他相关或不相关蛋白替换的实验。
单克隆抗体生产。通过有限稀释鉴定出九种ERFE特异性小鼠单克隆杂交瘤,它们已被确认具有分泌合适量的ERFE特异性IgG抗体(约1μg IgG/ml TC培养基)的能力。将每种抗体的多个等分试样扩增并储存在液氮中。
通过夹心ELISA筛选合适的mAb对后,鉴定出抗ERFE抗体的子集。在组织培养瓶和10-100ml中空纤维生物反应器中评定所选杂交瘤的mAb生产效率,以确定这些生产条件是否影响测定性能。
为了进行体外生长研究,使用容纳在加湿、温度受控的CO2组织培养箱中的两个FiberCell Systems中空纤维生物反应器(Frederick,MD)在无血清培养基中培养mAb 2D2和4C1。将流速调节至25-50ml/min,以在30天内实现高毫克量的抗体。合并每天收获的生物反应器培养基中的单克隆抗体,并在5ml蛋白G柱上进行亲和纯化,并使用HiPrep 26/10脱盐柱(GE Healthcare,Uppsala,Sweden)进行针对PBS的脱盐。将96孔EIA板用纯化的捕获抗体包被过夜。将这些捕获mAb各自用每种以少量生物素标记的检测mAb进行测试,以通过ELISA获得同时结合活性。
还评定规模化的生物反应器生产,以确定杂交瘤培养基的组成和生产方法条件是否影响抗ERFE mAb的抗原抗体相互作用。比较通过不同方法或规模生产的mAb的技术指标。抗体生产条件可能对测定性能具有极小的影响。
开发用于生产ERFE mAb包被的微量滴定板的方法和材料.所有性能最佳的抗体均经过亲和纯化,并经过棋盘优化(checkerboard optimization),以确定用于将mAb被动吸附至96孔微量滴定板的最佳抗体浓度和条件。使用温度和湿度受控的培养箱将微量滴定板干燥过夜,将单个板热封在含有1克分子筛干燥剂小包的聚酯薄膜小袋中,并在4℃下保存。
已开发出用于ERFE的使用专有试剂的研究夹心ELISA。使用高pH值碳酸盐包被缓冲液,通过mAb的被动吸附对板进行包被和封闭。测试来自不同制造商的几种其他96孔微量滴定板形式,以确定产生最大的信噪比和最小孔间抗体结合变化(CV小于5%)的ERFE捕获mAb的最佳浓度和稀释度。
用于ERFE的临床测定的自动化和验证。现有的基于ERFE mAb的夹心ELISA是基线ERFE ELISA,将从所述基线ERFE ELISA验证临床测定。使用临床实验室改进修正案(Clinical Laboratory Improvement Amendments,CLIA)和美国病理学家学院(Collegeof American Pathologists,CAP)指南来在完全集成的Beckman FX平台上开发测定。Beckman平台配备有DTX-880检测器、BioTek平板清洗器和Cytomat 2C15培养箱以及平板/管尖栈(plate/tip hotel)。目前,夹心ELISA具有的卓越检测下限(LLOD)和定量下限(LLOQ)分别为0.1ng/ml和0.15ng/ml。自动化将增加研究ERFE夹心ELISA的动态范围,并允许在低pg/ml或低ng/ml范围内对ERFE的一致测量。测定间/测定内变异系数(CV)得到改善,并且信噪比得到改善。通过自动化Beckman FX ERFE测试中较低的LLOD/LLOQ度量,很容易看出ERFE测试灵敏度的变化。
测定开发始于从ERFE抗原制备的标准曲线,其最终浓度范围为0-50ng/ml、0-40ng/ml、0-30ng/ml、0-20ng/ml,或0-10ng/ml。由于基于mAb的诊断装置的一项期望特征是改善检测下限,因此进行研究以确保将样品充分稀释以落在线性检测范围内。通过在从一组患有无效性红细胞生成疾病的患者获得的血清中添加已知浓度的ERFE来检查测定选择性。
利用一组来自健康人类志愿者的292个首次血液供体的血清样品(具有正常实验室血红蛋白、铁蛋白、血清转铁蛋白受体和C反应蛋白水平的男性和女性均等分布)来建立自动化FX ERFE测试的参考范围。通过在同一天重复(n=6)测量血清样品来测试测定内精度,并确定变异系数(CV)。通过使用至少两名操作员在不同的三天执行测定来确定测定间的重复性并计算平均CV和中值CV。通过用由相同批次和不同批次的试剂制造的板重复实验来检查批内和批间测定变异性,以确保遵守测定验证研究所需的严格质量控制标准。
实施例2.重组人红富铁激素抗原的生产
发现人类ERFE之后,开发了原型夹心ELISA所必需的单克隆抗体。用人ERFE或带flag标签的ERFE转染HEK293F细胞,在5%CO2气氛中于37℃下培养72小时,收获上清液,并分别通过固定到蛋白G琼脂糖珠粒上的抗人ERFE多克隆抗体或抗Flag M2亲和层析来纯化抗原。通过ELISA、SDS-PAGE电泳和蛋白质印迹确认抗原活性和纯度,使用二辛可宁蛋白测定(BCA,Thermo Scientific,Rockford,IL)确定蛋白浓度,将等分试样于-80℃冷冻。初步研究表明了较差的产率,范围为每升组织培养上清液0.2-0.3mg的重组ERFE抗原。虽然抗原被抗ERFE mAb识别,但产率低。将高效的HEK细胞系和含有人ERFE或带flag标签的ERFE的GenScript专有的克隆载体(Piscataway,NJ)用于ERFE生产。GenScript表达试剂和方法产生约5mg/L的纯化ERFE。这种表达努力产生了1mg的总蛋白质,纯度为约70%(图2)。
实施例3.单克隆抗体和杂交瘤生产
通过在多个皮下部位处重复注射重组人红富铁激素(ERFE),来对雌性BALB/c小鼠(n=5只动物,6-8周龄)进行免疫。每4周监测血清滴度,选择每只对免疫反应强烈的小鼠,并使用淋巴结和脾脏的合并物执行融合。总共执行4次融合;每次融合接种十二个96孔板,将板在37℃下在5%CO2气氛中温育4天,从而得到可用于筛选的约4600个活杂交瘤集落。
通过用重组抗原包被96孔微孔板,向每个孔中添加100μl杂交瘤组织培养上清液来鉴定分泌人ERFE特异性抗体的杂交瘤,并通过添加辣根过氧化物酶标记的山羊抗小鼠IgG H+L链抗体来检测ERFE特异性抗体的存在。加入TMB(3,3',5,5'-四甲基联苯胺)后,使反应进行15min,用0.5N H2SO4终止,并测量吸光度(450nm)。总共鉴定出10种人ERFE特异性IgG杂交瘤(0.022%的命中率;9B12、17A5、17E5、2D2、4C1、6H9、7H4、9C7、14B2和14D9);同种型分析表明,九种ERFE特异性杂交瘤是IgG1(9B12、17A5、17E5、4C1、6H9、7H4、9C7、14B2和14D9),并且1种是IgG2a(2D2)。通过有限稀释将所有杂交瘤亚克隆,再次确认它们的同种型,并将每种杂交瘤的等分试样在液氮中冷冻。
鉴定出的杂交瘤以以下登录号保藏在美国典型培养物保藏中心的专利库中:
然后对来自杂交瘤9B12、17A5、2D2、4C1和7H4的抗体进行测序。根据制造商的说明书,使用试剂从杂交瘤细胞分离总RNA。然后使用同型特异性反义引物或通用引物,使用PrimeScriptTM第一链cDNA合成试剂盒,将总RNA逆转录为cDNA。使用GenScript,通过快速扩增cDNA末端(RACE),相应地扩增出抗体片段VH、VL、CH和CL。将扩增的抗体片段单独克隆到标准克隆载体中。执行菌落PCR以筛选具有正确大小的插入片段的克隆。每个片段测序不少于五个具有正确大小的插入片段的集落。比对不同克隆的序列,并在表2中提供共有序列。
表2
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开始研究以鉴定表现最佳的抗体对,以开发对人ERFE特异的单克隆抗体夹心ELISA。基于生物素化mAb对捕获的ERFE的结合特性,从液氮中复苏9个克隆,接种到6孔组织培养板中,使用含有10%胎牛血清的DMEM生长至汇合,并经数次扩增逐渐使其适应无血清培养基。适应后,将每种鼠杂交瘤扩增至T75然后T150组织培养瓶中,以产生约1升的培养上清液。使用1ml HiTrapTM蛋白G柱(GE Healthcare,Uppsala,Sweden)从上清液中纯化单克隆抗体(mAb),并将等分试样保存在-20℃下。使用EZ-连接磺基-NHS-LC-生物素化化学物(Thermo Scientific,Rockford,IL),用生物素标记每个mAb。将ELISA板用100ng/孔的未标记捕获mAb包被过夜,将重组人FLAG-ERFE(150ng/孔、75ng/孔、37.5ng/孔、18.75ng/孔)温育60min,洗涤以去除未结合的抗原,并将生物素化的mAb(150ng/孔)加入到每个孔中并温育另外一小时。通过加入链霉亲和素-HRP之后是TMB来检测抗体结合,反应进行15min,信号停止,并在450nm处测量吸光度。测试九种不同抗体作为捕获抗体,并测试八种生物素化的抗体作为检测抗体。测试七十二种不同的组合。初步分析表明,从选择用于成对比较的九种mAb中,多个抗体对能够捕获和检测出重组人ERFE(图3A至图3F)。
使用三种不同的包被抗体7H4、17A5和4C1以及四种不同的生物素化检测抗体2D2、17A5、9B12和4C1进行附加的抗ERFE夹心测定实验(图4A至图4C)。如图4所示,不管所测试的捕获抗体为何,由每种检测抗体产生的回归方程均显示出不同的斜率,表明每种检测抗体对被包被抗体捕获的ERFE具有不同的结合亲和力。该特性对夹心ELISA的开发很重要,因为越大的结合亲和力导致越灵敏的测定。此外,期望有更大的斜率,因为尽管事实上每个回归方程的相关系数都被认为是极好的(R2值范围为0.9944至0.9999),但抗原检测在所测试的ERFE浓度范围内是最佳的。综上所述,该方法根据经验确定了待考虑用于进一步测定开发的候选抗体对。
实施例4.单克隆夹心ELISA
在检测捕获抗体和检测抗体的所有可能组合的结合活性后,选择mAb4C1和2D2分别作为捕获抗体和检测抗体,以用于进一步的测定优化。将mAb 4C1干燥到96孔ELISA板上的初步“棋盘”研究,确定了8点标准曲线的最佳捕获抗体浓度和ERFE抗原,并用链霉亲和素-HRP定量了血清中ERFE的结合和检测。用八种ERFE浓度(10.0ng/ml、5.0ng/ml、2.5ng/ml、1.25ng/ml、0.63ng/ml、0.31ng/ml、0.16ng/ml、0.00ng/ml)构建标准曲线,产生的最大吸光度范围为2.0-2.2,背景信号小于0.05吸光度单位(图5)。该原型夹心ELISA的检测下限(LLOD)和定量下限(LLOQ)分别为0.15ng/ml和0.17ng/ml。
此外,在夹心测定中以两种形式的flag-hERFE评估测定,其中7H4作为捕获抗体并且生物素化的2D2作为检测抗体,这提供了相似的结果,从而进一步验证了测定。
使用该原型测定,通过测试来自110名具有正常铁状态(通过铁蛋白、血浆铁和转铁蛋白饱和度确定)的健康首次血液供体的血清来执行研究,以确定人ERFE的参考范围。正如在健康个体中所预期的,血清ERFE低(平均0.83ng/ml),并且范围是0.15至3.94ng/ml(5%和95%置信区间,表3)。
表3
用生物素或辣根过氧化物酶(HRP)标记的4C1捕获抗体和2D2检测抗体进行进一步测定。将2D2-生物素孔与链霉亲和素-HRP一起进一步温育,然后将所有孔与TMB反应。如图9所示,用生物素和HRP标记的检测抗体在它们的检测血清样品中ERFE的能力方面基本上等同。
实施例5.对ERFE进行临床评定以理解无效性红细胞生成
确定献血对人血清ERFE浓度的影响。三名供体在基线时进行血小板和血浆单采术,并且在基线时以及在单采术后120天以及在单采术后2-14天起至少五次获得血清。据估计,在单采程序过程中,每位患者损失了约30ml的红细胞。如预期的,每位患者在单采术后的头2天内血清ERFE从基线开始升高,并且在单采术后的14天中保持升高,但到单采术后120天,血清ERFE恢复至基线水平(图6)。
接下来,测试与无效性红细胞生成相关的血液疾患中血清ERFE浓度将升高的假设。从X连锁性铁粒幼细胞性贫血患者(XLSA先证者)及其15名家族成员(家族对照)中获得血清样本。XLSA先证者患者中有九名在ALAS2基因中存在点突变,并且两名具有α-珠蛋白重复。测量XLSA先证者和对照组中的血清ERFE,发现XLSA先证者组中的ERFE相对于家族对照而言显著升高(图7)。有趣的是,家族成员(对照)中的血清ERFE的浓度与首次健康血液供体相似。
进行了另一项研究以量化已知由于α-或β-球蛋白基因突变而表现出无效性红细胞生成,从而导致血红蛋白病和严重的铁超负荷的地中海贫血患者的血清ERFE浓度。从患有α+地中海贫血以及β+地中海贫血和β0-地中海贫血两者的患者获得血清,并将其与来自从一组铁缺乏症(ID)和对照患者获得的血清的ERFE水平进行比较。已发现β+地中海贫血和β0-地中海贫血患者的ERFE浓度均显著高于来自α+地中海贫血、ID和对照组的患者(图8)。另一个重要发现是β0-地中海贫血患者的血清ERFE浓度与β+地中海贫血患者相比显著更高。该发现表明,血清ERFE测量能够帮助将具有更严重的β0-地中海贫血性状的患者与表现出β+-地中海贫血性状或α+-地中海贫血性状的患者区分开(图8)。
除非另有说明,否则在说明书和权利要求中使用的表示成分的量、性质(诸如分子量)、反应条件等的所有数字应理解为在所有情况下均由术语“约”修饰。如本文所用,术语“约”和“大致”是指在10%至15%之内,优选在5%至10%之内。因此,除非有相反的指示,否则在说明书和所附权利要求书中列出的数值参数是近似值,所述近似值可以根据本发明寻求获得的所需性质而变化。无论如何并非试图限制权利要求书范围的等同物的原则的应用,每个数值参数应至少根据报告的有效位的数量并通过应用普通的舍入技术来解释。尽管阐述本发明广泛范围的数值范围和参数是近似值,但是具体实施例中列出的数值是尽可能精确报告的。然而,任何数值固有地含有必然由其各自相应的测试测量中存在的标准偏差引起的某些误差。
除非在此另外指明或者明显与上下文相矛盾,否则在描述本发明的上下文中(尤其是在以下权利要求的上下文中)不使用数量词修饰应被解释为涵盖单数和复数两者。本文中对值范围的描述仅旨在用作为引用落入该范围的每个单独值的速记方法。除非本文另有说明,否则每个单独的值被并入说明书中,如同其在本文中被单独引用一样。除非本文另有说明或明显与上下文相矛盾,否则本文所述的所有方法均可以任何合适的顺序进行。本文提供的任何和所有示例、或例示性语言(例如“例如”)的使用仅旨在更好地说明本发明,而不是对要求保护的本发明的范围构成限制。说明书中的任何语言都不应被解释为表示任何不要求保护的要素对于本发明的实践为必不可少的。
本文公开的本发明的替代要素或实施方式的分组不应解释为限制。每个组成员可以单独地或与该组中的其他成员或本文中找到的其他要素任意组合地被提及和要求保护。预期组中的一个或多个成员可以出于方便和/或可专利性的原因而被包括在组中或从组中删除。当发生任何此类包括或删除时,本说明书被视为包含经修改的组,从而满足对所附权利要求书中使用的所有马库什组的书面描述。
本文描述了本发明的某些实施方式,包括本发明人已知的用于实现本发明的最佳方式。当然,对于本领域普通技术人员来说,在阅读前面的描述后,这些描述的实施方式的变型将变得显而易见。本发明人希望技术人员适当地采用此类变型,并且本发明人希望以不同于本文具体描述的方式实践本发明。因此,本发明包括适用法律所允许的本文所附权利要求中所述主题的所有修改和等同物。此外,除非本文另有说明或明显与上下文相矛盾,否则本发明涵盖上述要素的所有可能变型的任何组合。
本文公开的具体实施方式可以在权利要求中使用由......组成或基本上由……组成的语言来进一步限制。当在权利要求中使用时,无论是原始提交还是按照修正添加,过渡术语“由...组成”不包括权利要求中未指定的任何要素、步骤或成分。过渡术语“基本上由......组成”将权利要求的范围限制于指定的材料或步骤,以及不会对基本和新颖特征产生实质性影响的那些材料或步骤。如此要求保护的本发明的实施方式在本文中被固有地或明确地描述和实现。
此外,在整个说明书中,已经对专利和印刷出版物进行了大量引用。上面引用的参考文献和印刷出版物中的每一者的全部内容均以引用方式单独地并入本文。
最后,应理解,本文公开的本发明的实施方式是对本发明原理的说明。可以采用的其他修改在本发明的范围内。因此,举例来说而非限制,可以根据本文的教导使用本发明的替代配置。因此,本发明不被限制为如精确地所示和所描述的。
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<110> 因全惜客生命科学有限公司
<120> 人红富铁激素的抗体及其用途
<130> 3800371-00028
<150> US62/470,853
<151> 2017-03-13
<150> US62/471,195
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<223> Xaa can be any naturally occurring amino acid
<400> 15
Ser Leu Thr Val Arg Ser Gly Ser His Phe Ser Ala Xaa Leu Leu Gly
1 5 10 15
Xaa
<210> 16
<211> 220
<212> PRT
<213> Homo sapiens
<400> 16
Glu Phe Gln Leu Leu Leu Lys Gly Ala Val Arg Gln Arg Glu Arg Ala
1 5 10 15
Glu Pro Glu Pro Cys Thr Cys Gly Pro Ala Gly Pro Val Ala Ala Ser
20 25 30
Leu Ala Pro Val Ser Ala Thr Ala Gly Glu Asp Asp Asp Asp Val Val
35 40 45
Gly Asp Val Leu Ala Leu Leu Ala Ala Pro Leu Ala Pro Gly Pro Arg
50 55 60
Ala Pro Arg Val Glu Ala Ala Phe Leu Cys Arg Leu Arg Arg Asp Ala
65 70 75 80
Leu Val Glu Arg Arg Ala Leu His Glu Leu Gly Val Tyr Tyr Leu Pro
85 90 95
Asp Ala Glu Gly Ala Phe Arg Arg Gly Pro Gly Leu Asn Leu Thr Ser
100 105 110
Gly Gln Tyr Arg Ala Pro Val Ala Gly Phe Tyr Ala Leu Ala Ala Thr
115 120 125
Leu His Val Ala Leu Gly Glu Pro Pro Arg Arg Gly Pro Pro Arg Pro
130 135 140
Arg Asp His Leu Arg Leu Leu Ile Cys Ile Gln Ser Arg Cys Gln Arg
145 150 155 160
Asn Ala Ser Leu Glu Ala Ile Met Gly Leu Glu Ser Ser Ser Glu Leu
165 170 175
Phe Thr Ile Ser Val Asn Gly Val Leu Tyr Leu Gln Met Gly Gln Trp
180 185 190
Thr Ser Val Phe Leu Asp Asn Ala Ser Gly Cys Ser Leu Thr Val Arg
195 200 205
Ser Gly Ser His Phe Ser Ala Val Leu Leu Gly Val
210 215 220
<210> 17
<211> 472
<212> PRT
<213> Mus musculus
<400> 17
Met Glu Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val Leu Ser Glu Val Gln Leu Gln Gln Phe Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Gly Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Asn Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Leu
50 55 60
Glu Trp Ile Gly Asp Phe Asn Pro Asn Tyr Asp Ser Ser Thr Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Gly Met Ile Leu Tyr Tyr Gly Asn Ser Gly Ser
115 120 125
Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys
130 135 140
Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr
145 150 155 160
Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro
165 170 175
Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val
180 185 190
His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser
195 200 205
Ser Val Thr Val Thr Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys
210 215 220
Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu
225 230 235 240
Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala
245 250 255
Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile
260 265 270
Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val
275 280 285
Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val
290 295 300
Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp
305 310 315 320
Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln
325 330 335
Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp
340 345 350
Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val
355 360 365
Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr
370 375 380
Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu
385 390 395 400
Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr
405 410 415
Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr
420 425 430
Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr
435 440 445
Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr Lys
450 455 460
Ser Phe Ser Arg Thr Pro Gly Lys
465 470
<210> 18
<211> 123
<212> PRT
<213> Mus musculus
<400> 18
Glu Val Gln Leu Gln Gln Phe Gly Pro Glu Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asn Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Asp Phe Asn Pro Asn Tyr Asp Ser Ser Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Met Ile Leu Tyr Tyr Gly Asn Ser Gly Ser Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 19
<211> 5
<212> PRT
<213> Mus musculus
<400> 19
Asp Tyr Asn Met Asp
1 5
<210> 20
<211> 17
<212> PRT
<213> Mus musculus
<400> 20
Asp Phe Asn Pro Asn Tyr Asp Ser Ser Thr Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 21
<211> 14
<212> PRT
<213> Mus musculus
<400> 21
Gly Met Ile Leu Tyr Tyr Gly Asn Ser Gly Ser Met Asp Tyr
1 5 10
<210> 22
<211> 234
<212> PRT
<213> Mus musculus
<400> 22
Met Lys Phe Pro Ser Gln Leu Leu Leu Phe Leu Leu Phe Arg Ile Thr
1 5 10 15
Gly Ile Met Cys Asp Ile Gln Met Thr Gln Ser Ser Ser Tyr Leu Ser
20 25 30
Val Ser Leu Gly Gly Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His
35 40 45
Ile Asn Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro
50 55 60
Arg Leu Leu Ile Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Lys Asp Tyr Thr Leu Thr Ile Ile
85 90 95
Ser Leu Gln Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp
100 105 110
Asn Thr Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
130 135 140
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
145 150 155 160
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
165 170 175
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
195 200 205
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
210 215 220
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 23
<211> 127
<212> PRT
<213> Mus musculus
<400> 23
Met Lys Phe Pro Ser Gln Leu Leu Leu Phe Leu Leu Phe Arg Ile Thr
1 5 10 15
Gly Ile Met Cys Asp Ile Gln Met Thr Gln Ser Ser Ser Tyr Leu Ser
20 25 30
Val Ser Leu Gly Gly Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His
35 40 45
Ile Asn Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro
50 55 60
Arg Leu Leu Ile Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Lys Asp Tyr Thr Leu Thr Ile Ile
85 90 95
Ser Leu Gln Thr Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp
100 105 110
Asn Thr Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
115 120 125
<210> 24
<211> 11
<212> PRT
<213> Mus musculus
<400> 24
Lys Ala Ser Asp His Ile Asn Asn Trp Leu Ala
1 5 10
<210> 25
<211> 7
<212> PRT
<213> Mus musculus
<400> 25
Gly Ala Thr Ser Leu Glu Thr
1 5
<210> 26
<211> 9
<212> PRT
<213> Mus musculus
<400> 26
Gln Gln Tyr Trp Asn Thr Pro Arg Thr
1 5
<210> 27
<211> 466
<212> PRT
<213> Mus musculus
<400> 27
Met Ala Val Leu Gly Leu Leu Phe Cys Leu Val Thr Phe Pro Ser Cys
1 5 10 15
Val Leu Ser Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln
20 25 30
Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu
35 40 45
Thr Thr Tyr Ser Ile His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu
50 55 60
Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Ser Ile Asp Tyr Asn Ala
65 70 75 80
Ala Phe Ile Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Ser Gln
85 90 95
Val Phe Phe Lys Met Asn Ser Leu Gln Val Asn Asp Thr Ala Ile Tyr
100 105 110
Tyr Cys Ala Arg Asn Val Leu Thr Tyr Tyr Arg Tyr Asp Val Glu Ala
115 120 125
Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys
130 135 140
Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln
145 150 155 160
Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro
165 170 175
Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val
180 185 190
His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser
195 200 205
Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys
210 215 220
Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val
225 230 235 240
Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val
245 250 255
Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile
260 265 270
Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp
275 280 285
Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His
290 295 300
Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320
Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr
355 360 365
Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu
370 375 380
Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp
385 390 395 400
Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile
405 410 415
Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln
420 425 430
Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His
435 440 445
Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro
450 455 460
Gly Lys
465
<210> 28
<211> 123
<212> PRT
<213> Mus musculus
<400> 28
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr
20 25 30
Ser Ile His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Ser Ile Asp Tyr Asn Ala Ala Phe Ile
50 55 60
Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Val Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Asn Val Leu Thr Tyr Tyr Arg Tyr Asp Val Glu Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 29
<211> 5
<212> PRT
<213> Mus musculus
<400> 29
Thr Tyr Ser Ile His
1 5
<210> 30
<211> 16
<212> PRT
<213> Mus musculus
<400> 30
Val Ile Trp Ser Gly Gly Ser Ile Asp Tyr Asn Ala Ala Phe Ile Ser
1 5 10 15
<210> 31
<211> 15
<212> PRT
<213> Mus musculus
<400> 31
Asn Val Leu Thr Tyr Tyr Arg Tyr Asp Val Glu Ala Met Asp Tyr
1 5 10 15
<210> 32
<211> 234
<212> PRT
<213> Mus musculus
<400> 32
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser
20 25 30
Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln Gly
35 40 45
Ile Ser Asn Phe Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val
50 55 60
Lys Leu Leu Ile Tyr Tyr Thr Ser Asn Leu His Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Val Ser
85 90 95
Asn Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser
100 105 110
Glu Leu Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Val Ile Lys Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
130 135 140
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
145 150 155 160
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
165 170 175
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
195 200 205
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
210 215 220
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 33
<211> 114
<212> PRT
<213> Mus musculus
<400> 33
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln Gly Ile Ser Asn Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Asn Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Val Ser Asn Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Glu Leu Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Val Ile Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr
<210> 34
<211> 11
<212> PRT
<213> Mus musculus
<400> 34
Ser Ala Ser Gln Gly Ile Ser Asn Phe Leu Asn
1 5 10
<210> 35
<211> 7
<212> PRT
<213> Mus musculus
<400> 35
Tyr Thr Ser Asn Leu His Ser
1 5
<210> 36
<211> 9
<212> PRT
<213> Mus musculus
<400> 36
Gln Gln Tyr Ser Glu Leu Pro Phe Thr
1 5
<210> 37
<211> 465
<212> PRT
<213> Mus musculus
<400> 37
Met Glu Cys Asn Trp Ile Leu Pro Phe Ile Leu Ser Val Thr Ser Gly
1 5 10 15
Val Tyr Ser Glu Val Gln Leu Gln Gln Ser Gly Thr Val Val Ala Arg
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Thr Tyr Trp Met His Trp Val Lys Gln Trp Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Ser Asp Thr Thr Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Lys Leu Thr Ala Val Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Ser Leu Thr Asn Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Thr Arg Glu Asp Phe Tyr Asn Gly Tyr Asp Ala Glu Phe
115 120 125
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr
130 135 140
Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr
145 150 155 160
Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser
195 200 205
Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn
210 215 220
Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro
225 230 235 240
Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser
245 250 255
Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr
260 265 270
Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp
275 280 285
Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr
290 295 300
Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser
305 310 315 320
Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr
355 360 365
Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr
370 375 380
Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln
385 390 395 400
Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met
405 410 415
Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys
420 425 430
Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu
435 440 445
Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly
450 455 460
Lys
465
<210> 38
<211> 122
<212> PRT
<213> Mus musculus
<400> 38
Glu Val Gln Leu Gln Gln Ser Gly Thr Val Val Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr
20 25 30
Trp Met His Trp Val Lys Gln Trp Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Ser Asp Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Lys Leu Thr Ala Val Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Asn Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Glu Asp Phe Tyr Asn Gly Tyr Asp Ala Glu Phe Ala Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 39
<211> 5
<212> PRT
<213> Mus musculus
<400> 39
Thr Tyr Trp Met His
1 5
<210> 40
<211> 19
<212> PRT
<213> Mus musculus
<400> 40
Ala Ile Tyr Pro Gly Asn Ser Asp Thr Thr Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly Lys Ala
<210> 41
<211> 13
<212> PRT
<213> Mus musculus
<400> 41
Glu Asp Phe Tyr Asn Gly Tyr Asp Ala Glu Phe Ala Tyr
1 5 10
<210> 42
<211> 234
<212> PRT
<213> Mus musculus
<400> 42
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser
20 25 30
Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp
35 40 45
Ile Ser Asn Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val
50 55 60
Lys Leu Leu Ile Tyr Ser Thr Ser Lys Leu His Pro Gly Val Pro Pro
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser
85 90 95
Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Ser
100 105 110
Thr Leu Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
130 135 140
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
145 150 155 160
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
165 170 175
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
195 200 205
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
210 215 220
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 43
<211> 114
<212> PRT
<213> Mus musculus
<400> 43
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Ser Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Ser Thr Ser Lys Leu His Pro Gly Val Pro Pro Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Ser Thr Leu Leu Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr
<210> 44
<211> 11
<212> PRT
<213> Mus musculus
<400> 44
Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Ser
1 5 10
<210> 45
<211> 7
<212> PRT
<213> Mus musculus
<400> 45
Ser Thr Ser Lys Leu His Pro
1 5
<210> 46
<211> 9
<212> PRT
<213> Mus musculus
<400> 46
Gln Gln Gly Ser Thr Leu Leu Arg Thr
1 5
<210> 47
<211> 462
<212> PRT
<213> Mus musculus
<400> 47
Met Gly Trp Ser Arg Ile Phe Leu Phe Leu Leu Ser Ile Ile Ala Gly
1 5 10 15
Val His Cys Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Arg Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Tyr Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Ala Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Phe Phe Cys Ala Arg Glu Gly Ile Thr Thr Asn Ala Leu Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro
130 135 140
Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met
145 150 155 160
Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr
165 170 175
Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro
180 185 190
Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val
195 200 205
Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His
210 215 220
Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys
225 230 235 240
Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe
245 250 255
Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro
260 265 270
Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val
275 280 285
Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr
290 295 300
Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu
305 310 315 320
Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys
325 330 335
Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser
340 345 350
Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro
355 360 365
Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile
370 375 380
Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly
385 390 395 400
Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp
405 410 415
Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp
420 425 430
Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His
435 440 445
Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
450 455 460
<210> 48
<211> 115
<212> PRT
<213> Mus musculus
<400> 48
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Arg Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Ala Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Phe Phe Cys
85 90 95
Ala Arg Glu Gly Ile Thr Thr Asn Ala Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val
115
<210> 49
<211> 5
<212> PRT
<213> Mus musculus
<400> 49
Ser Tyr Tyr Ile His
1 5
<210> 50
<211> 17
<212> PRT
<213> Mus musculus
<400> 50
Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 51
<211> 10
<212> PRT
<213> Mus musculus
<400> 51
Glu Gly Ile Thr Thr Asn Ala Leu Asp Tyr
1 5 10
<210> 52
<211> 233
<212> PRT
<213> Mus musculus
<400> 52
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Phe Cys Phe Gln
1 5 10 15
Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser
20 25 30
Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp
35 40 45
Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val
50 55 60
Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Tyr Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Asn Gly Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser
85 90 95
Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly His
100 105 110
Thr Leu Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala
115 120 125
Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu
130 135 140
Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro
145 150 155 160
Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn
165 170 175
Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr
180 185 190
Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His
195 200 205
Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile
210 215 220
Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 53
<211> 106
<212> PRT
<213> Mus musculus
<400> 53
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Asn Gly Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly His Thr Leu Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 54
<211> 11
<212> PRT
<213> Mus musculus
<400> 54
Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 55
<211> 7
<212> PRT
<213> Mus musculus
<400> 55
Tyr Thr Ser Arg Leu Tyr Ser
1 5
<210> 56
<211> 8
<212> PRT
<213> Mus musculus
<400> 56
Gln Gln Gly His Thr Leu Trp Thr
1 5
<210> 57
<211> 462
<212> PRT
<213> Mus musculus
<400> 57
Met Gly Trp Ser Ser Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ser Val Leu Val Arg
20 25 30
Pro Gly Ala Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Trp Met His Trp Ala Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Glu Ile His Pro Lys Ser Gly Asp Thr Asn His Asn
65 70 75 80
Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Asn
85 90 95
Thr Ala Tyr Val Asp Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Gly Ile Thr Thr Val Gly Phe Asp Leu Trp
115 120 125
Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro
130 135 140
Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met
145 150 155 160
Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr
165 170 175
Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro
180 185 190
Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val
195 200 205
Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His
210 215 220
Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys
225 230 235 240
Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe
245 250 255
Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro
260 265 270
Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val
275 280 285
Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr
290 295 300
Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu
305 310 315 320
Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys
325 330 335
Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser
340 345 350
Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro
355 360 365
Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile
370 375 380
Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly
385 390 395 400
Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp
405 410 415
Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp
420 425 430
Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His
435 440 445
Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
450 455 460
<210> 58
<211> 119
<212> PRT
<213> Mus musculus
<400> 58
Gln Val Gln Leu Gln Gln Pro Gly Ser Val Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Ala Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile His Pro Lys Ser Gly Asp Thr Asn His Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Val Asp Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Thr Thr Val Gly Phe Asp Leu Trp Gly Ala Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 59
<211> 5
<212> PRT
<213> Mus musculus
<400> 59
Ser Tyr Trp Met His
1 5
<210> 60
<211> 17
<212> PRT
<213> Mus musculus
<400> 60
Glu Ile His Pro Lys Ser Gly Asp Thr Asn His Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 61
<211> 10
<212> PRT
<213> Mus musculus
<400> 61
Glu Gly Ile Thr Thr Val Gly Phe Asp Leu
1 5 10
<210> 62
<211> 235
<212> PRT
<213> Mus musculus
<400> 62
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Ile Ser Arg Gly Gln Ile Val Leu Thr Gln Ser Pro Ala Ile
20 25 30
Met Ser Ala Ser Pro Gly Gln Lys Val Thr Leu Thr Cys Ser Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met Asn Trp Val Gln Gln Lys Ser Gly Thr Ser
50 55 60
Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile
85 90 95
Ser Ser Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser His Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
115 120 125
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
130 135 140
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
145 150 155 160
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
165 170 175
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
195 200 205
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
210 215 220
Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 63
<211> 106
<212> PRT
<213> Mus musculus
<400> 63
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Gln Lys Val Thr Leu Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Val Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser His Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 64
<211> 10
<212> PRT
<213> Mus musculus
<400> 64
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn
1 5 10
<210> 65
<211> 7
<212> PRT
<213> Mus musculus
<400> 65
Asp Thr Ser Lys Leu Ala Ser
1 5
<210> 66
<211> 9
<212> PRT
<213> Mus musculus
<400> 66
Gln Gln Trp Ser Ser His Pro Tyr Thr
1 5
Claims (16)
1. 一种红富铁激素(ERFE)结合抗体或其ERFE结合片段,所述ERFE结合抗体或其ERFE结合片段包含重链可变区(VH)和轻链可变区(VL),其中:
(a)所述VH由SEQ ID NO:18的氨基酸序列组成,且所述VL由SEQ ID NO: 23的氨基酸序列组成;或
(b)所述VH由SEQ ID NO:28的氨基酸序列组成,且所述VL由SEQ ID NO: 33的氨基酸序列组成。
2. 一种ERFE结合抗体或其ERFE结合片段,其中所述抗体包含:
(a)由SEQ ID NO:19至SEQ ID NO:21的氨基酸序列组成的重链互补决定区(CDR)和由SEQ ID NO:24至SEQ ID NO:26的氨基酸序列组成的轻链CDR;或
(b)由SEQ ID NO:29至SEQ ID NO:31的氨基酸序列组成的重链CDR和由SEQ ID NO:34至SEQ ID NO:36的氨基酸序列组成的轻链CDR。
3. 根据权利要求1或2所述的ERFE结合抗体或其ERFE结合片段,其中所述抗体包含重链和轻链,其中:
(a)所述重链由SEQ ID NO:17的氨基酸序列组成,且所述轻链由SEQ ID NO: 22的氨基酸序列组成;或
(b)所述重链由SEQ ID NO:27的氨基酸序列组成,且所述轻链由SEQ ID NO:32的氨基酸序列组成。
4.根据权利要求1或2所述的ERFE结合抗体或其ERFE结合片段,其中所述抗体是嵌合抗体、人源化抗体或抗体片段。
5.根据权利要求1或2所述的ERFE结合抗体或其ERFE结合片段,其中所述抗体被标记。
6.根据权利要求5所述的ERFE结合抗体或其ERFE结合片段,其中所述标记是生物素。
7.根据权利要求5所述的ERFE结合抗体或其ERFE结合片段,其中所述标记是辣根过氧化物酶。
8.一种用于夹心免疫测定的试剂盒,所述试剂盒包含捕获抗体和检测抗体,其中:
所述捕获抗体的VH由SEQ ID NO:28组成且所述捕获抗体的VL由SEQ ID NO:33组成,并且所述检测抗体的VH由SEQ ID NO:18组成且所述检测抗体的VL由SEQ ID NO:23 组成。
9. 一种用于夹心免疫测定的试剂盒,所述试剂盒包含捕获抗体和检测抗体,其中:
所述检测抗体重链互补决定区(CDR)由SEQ ID NO:19至SEQ ID NO:21的氨基酸序列组成,轻链CDR由SEQ ID NO:24至SEQ ID NO:26的氨基酸序列组成;且
所述捕获抗体重链CDR由SEQ ID NO:29至SEQ ID NO:31的氨基酸序列组成,轻链CDR由SEQ ID NO:34至SEQ ID NO:36的氨基酸序列组成。
10.根据权利要求8或9所述的试剂盒,其中所述捕获抗体与固体支持物缔合。
11.根据权利要求8-10中任一项所述的试剂盒,其中所述检测抗体与标记缔合。
12.根据权利要求11所述的试剂盒,其中所述标记是生物素。
13.根据权利要求11所述的试剂盒,其中所述标记是辣根过氧化物酶。
14.根据权利要求12所述的试剂盒,所述试剂盒还包含链霉亲和素-辣根过氧化物酶。
15.根据权利要求8-10中任一项所述的试剂盒,所述试剂盒还包含底物。
16.根据权利要求8-10中任一项所述的试剂盒,所述试剂盒还包含用于执行测定的说明书。
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PCT/US2018/022238 WO2018169999A1 (en) | 2017-03-13 | 2018-03-13 | Antibodies to human erythroferrone and uses thereof |
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EP3497127A1 (en) | 2016-08-05 | 2019-06-19 | Silarus Therapeutics, Inc. | Erfe specific antibodies compositions and methods of use |
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US20200231668A1 (en) | 2020-07-23 |
WO2018169999A1 (en) | 2018-09-20 |
US10604567B2 (en) | 2020-03-31 |
RU2019132201A (ru) | 2021-04-14 |
KR102628144B1 (ko) | 2024-01-23 |
CN110636857A (zh) | 2019-12-31 |
IL269318A (en) | 2019-11-28 |
US20180258168A1 (en) | 2018-09-13 |
NZ756975A (en) | 2022-12-23 |
US11142572B2 (en) | 2021-10-12 |
RU2019132201A3 (zh) | 2021-12-03 |
CN110636857A8 (zh) | 2020-02-11 |
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KR20190141141A (ko) | 2019-12-23 |
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