CN109311975A - 用于治疗神经退行性紊乱的抗age抗体 - Google Patents
用于治疗神经退行性紊乱的抗age抗体 Download PDFInfo
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Abstract
一种治疗神经退行性紊乱或MD的方法,所述方法包括向受试者给予包含AGE抗体的组合物。
Description
背景技术
晚期糖基化终末产物(AGE,也称为经AGE修饰的蛋白或糖基化终末产物)来源于老化细胞中的蛋白质侧链与糖的非酶促反应(Ando,K.等,Membrane Proteins of HumanErythrocytes Are Modified by Advanced Glycation End Products during Aging inthe Circulation,Biochem Biophys Res Commun.,Vol.258,123,125(1999))。该过程起始于还原糖和氨基基团之间的可逆反应以形成席夫氏碱,进而形成共价键合的阿马多尔(Amadori)重排产物。一旦形成,阿马多尔产物经历进一步重排以生成AGE。由糖尿病(DM)引起的高血糖和氧化应激促进膜蛋白的这种翻译后修饰(Lindsey JB等,“Receptor ForAdvanced Glycation End-Products(RAGE)and soluble RAGE(sRAGE):CardiovascularImplications,”Diabetes Vascular Disease Research,Vol.6(1),7-14,(2009))。AGE与多种病理病症相关,包括糖尿病并发症、炎症、视网膜病变、肾病、动脉粥样硬化、中风、内皮细胞功能障碍和神经退行性紊乱(Bierhaus A,“AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus.I.The AGE concept,”Cardiovasc Res,Vol.37(3),586-600(1998))。
衰老细胞是部分功能或无功能的细胞并且处于不可逆的增殖停滞状态。衰老是细胞的独特状态,并且与生物标志物相关,如生物标志物p16lnk4a的活化和β-半乳糖苷酶的表达。衰老细胞还与参与细胞间信号传导的许多因子(包括促炎因子)的分泌相关。这些因子的分泌被称为衰老相关分泌表型或SASP。
经AGE修饰的蛋白也是衰老细胞的标志物。糖基化终末产物与衰老之间的这种关联是本领域公知的。参见例如Gruber,L.(WO 2009/143411,2009年11月26日)、Ando,K.等(Membrane Proteins of Human Erythrocytes Are Modified by Advanced GlycationEnd Products during Aging in the Circulation,Biochem Biophys Res Commun.,Vol.258,123,125(1999))、Ahmed,E.K.等(“Protein Modification and ReplicativeSenescence of Wl-38Human Embryonic Fibroblasts”Aging Cells,vol.9,252,260(2010))、Vlassara,H.等(Advanced Glycosylation Endproducts on Erythrocyte CellSurface Induce Receptor-Mediated Phagocytosis by Macrophages,J.Exp.Med.,Vol.166,539,545(1987))和Vlassara等(“High-affinity-receptor-mediated Uptakeand Degradation of Glucose-modified Proteins:A Potential Mechanism for theRemoval of Senescent Macromolecules”Proc.Natl.Acad.Sci.USAI,Vol.82,5588,5591(1985))。此外,Ahmed,E.K.等表明糖基化终末产物是“细胞和细胞外蛋白质自发损伤的主要原因之一”(Ahmed,E.K.等,参见上文,第353页)。因此,糖基化终末产物的积累与衰老和功能缺失相关。
最近研究确定了细胞衰老与年龄相关紊乱(如肌少症)之间的因果关系。明尼苏达州罗切斯特Mayo诊所的研究小组证明了如下效果:通过消除小鼠脂肪组织和肌肉组织中的衰老细胞可延迟小鼠的老化,且无明显副作用(Baker,DJ.等,“Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders”,Nature,Vol.479,pp.232-236,(2011))。证明了消除转基因小鼠中的衰老细胞大幅延迟了肌少症和白内障的发作,并且降低了骨骼肌和眼睛的衰老指标。该研究确定了用于移除衰老细胞的转基因小鼠的终生治疗及晚期治疗不产生负面副影响,并且选择性地延迟了依赖于细胞的年龄相关表型(同上,第234页第2栏第16行至第235页第1栏第2行)。该作者推测衰老细胞的移除可能代表一种用于治疗或延迟人年龄相关疾病以及改善健康人寿命的途径(同上,第235页第2栏第38-51行)。
神经退行性紊乱与中枢神经系统中异常细胞衰老相关。衰老星形胶质细胞的异常积累与阿尔兹海默病(AD)相关(Bhat,R.等,“Astrocyte Senescence as a Component ofAlzheimer’s Disease”,PLOS ONE,Vol.7(9),e45069,pp.1-10(2012年9月))。通过指征AD的淀粉样斑块(amyloid plaques)的存在加剧了小胶质细胞的衰老,小胶质细胞的衰老与正常老化有关(Flanary,B.E.等,“Evidence That Aging And Amyloid PromoteMicroglial Cell Senescence”,Rejuvenation Research,Vol.10(1),pp.61-74(2007年3月))。AD中星形胶质细胞和小胶质细胞与AGE一起存在进一步证明了衰老细胞的存在(Takeda,A.等,“Advanced glycation end products co-localize with astrocyes andmicroglial cells in Alzheimer’s disease brain”,Acta Neuropathologica,Vol.95,pp.555-558(1998))。基于最近报道的研究发现,Chinta等提出与帕金森氏病(PD)相关的环境压力因素可通过在非神经胶质细胞内引起衰老而部分地起作用,从而促进在该紊乱中发生的神经元完整性特征性下降(Chinta,S.J.等,“Environmental stress,ageing andglial cell senescence:a novel mechanistic link to Parkinson’s disease?”JIntern Med,Vol.273,pp.429-436(2013))。星形胶质细胞衰老同样与PD相关(M.Mori,“TheParkinsonian Brain:Cellular Senescence and Neurodegeneration,SAGE(2015年6月30日)(sage.buckinstitute.org/the-parkinsonian-brain-cellular-senescence-and-neuro degeneration/))。在过表达突变型超氧化物歧化酶-1(m-SOD1)的家族性肌萎缩性侧索硬化(ALS)的啮齿动物模型中,星形胶质细胞获取衰老表型的速度加快(Das,M.M.和Svendsen,C.N.,“Astrocytes show reduced support of motor neurons with agingthat is accelerated in a rodent model of ALS”,Neurobiology of Aging,Vol.36,pp.1130-1139(2015))。即使在多发性硬化(MS)中,小胶质细胞和巨噬细胞也会向强烈的促炎表型(近似于SASP)转变,并可通过释放促炎细胞因子和分子来加大神经元损伤(Luessi,F.等,“Neurodegeneration in multiple sclerosis:novel treatment strategies”,Expert Rev.Neurother.,Vol 9,pp.1061-1077(2012))。
胶质细胞(如星形胶质细胞和小胶质细胞)为正常脑功能提供支持。星形胶质细胞(也被统称为星形神经胶质(astroglia))是在脑和脊髓中发现的呈星形的胶质细胞。星形胶质细胞执行多种功能,例如向神经组织提供营养,维持细胞外液中的离子平衡,以及生化支持形成血脑屏障的细胞。小胶质细胞在脑和脊髓中作为巨噬细胞发挥作用。小胶质细胞从脑和脊髓中清除斑块、受损神经元以及传染物质。
部分神经退行性紊乱也与中枢神经系统外部的异常细胞衰老相关。存在于ALS患者的肌肉组织中的大多数卫星细胞(也被称为肌卫星细胞(myosatellite cells))展现出异常衰老样的形态,尽管它们可能能够在体外进行增殖(Pradat,P.-F.等,“Abnormalitiesof satellite cells function in amyotrophic lateral sclerosis”,AmyotrophicLateral Sclerosis,Vol.12,pp.264-271(2011))。卫星细胞是在成熟肌肉中发现的小的多能细胞,其能够产生另外的卫星细胞或分化成成肌细胞(myoblasts)及提供另外的肌核。在杜氏肌营养不良(MD)的动物模型中,观察到成肌细胞过早的衰老和降低的增殖能力(Wright,W.E.,“Myoblast Senescence in Muscular Dystrophy”,Exp Cell Res,Vol.157,pp.343-354(1985))。成肌细胞是分化为肌细胞(也称为肌肉细胞)的前体细胞。
神经退行性紊乱还与异常蛋白质积累相关(King,O.D.等,“The tip of theiceberg:RNA-binding proteins with prion-like domains in neurodegenerativedisease”,Brain Res.Vol.1462,pp.61-80(2012))。PD及路易体痴呆的特征在于形成路易小体,所述路易小体在神经细胞内部形成。路易小体的主要结构成分是处于原纤维形式的α-突触核蛋白。缠结和斑块的存在是AD的特征,其存在被用来确定性诊断该病症。由β淀粉样蛋白(也称为淀粉样β,Aβ或Abeta)组成的斑块在神经细胞之间积累。由tau蛋白组成的缠结在细胞内形成交结的纤维。朊病毒病(也称为传染性海绵状脑病(TSE))包括多种人和动物紊乱,例如克-雅氏病(Creutzfeldt-Jakob disease)、变异型克-雅氏病、牛海绵状脑病(“疯牛”病)、瘙痒病(scrapie,在绵羊和山羊中)、慢性消耗性疾病(在鹿和麋鹿(elk)中)、库鲁病以及致死性家族失眠症。朊病毒蛋白是错误折叠的蛋白质分子,其可通过传递错误折叠的蛋白质状态而进行传播,造成错误折叠蛋白质积累并引起组织损伤和细胞死亡(Dobson,D.M.,“The structural basis of protein folding and its links withhuman disease”Phil.Trans.R.Soc.Lond.B,Vol.356,pp.133-145(2001))。在这些疾病中,认为所述蛋白是错误折叠或形成异常聚集物的正常蛋白。在患有家族性ALS的一些患者的情况中,突变的超氧化物歧化酶-1(SOD1)形成包含体(inclusion)并积累(Kato,S.等,“Advanced glycation endproduct-modified superoxide dismutase-1(SOD1)-positiveinclusions are common to familial amyotrophic lateral sclerosis patients withSOD1gene mutations and transgenic mice expressing human SOD1with a G85Rmutation”Acta Neuropathol,Vol.100,pp.490-505(2000))。
在一些情况下,所述蛋白质被认为直接导致细胞死亡,而在另一些情况下,所述蛋白被认为引起炎症从而间接导致细胞死亡。炎症也被认为诱导细胞衰老,细胞衰老进而由于SASP进一步使炎症加剧,从而导致正反馈促进神经退行(Golde,T.E.等,“Proteinopathy-induced neuronal senescence:a hypothesis for brain failure inAlzheimer’s and other neurodegenerative diseases”Alzheimer’s Research&Therapy,Vol.1,No.5(2009年10月13日))。通过细胞间蛋白质转移,还可由衰老细胞使这些诱导炎症的蛋白质的扩散加剧(Biran,A.等,“Senescent cells communicate viaintercellular protein transfer”Genes&Development,Vol.29,pp.791-802(2015))。
神经退行性紊乱的免疫疗法(使用与神经退行性紊乱相关的神经退行性蛋白的抗体)表现出一些前景。即使在外周给予抗体(即不进入CNS)时,也观察到了积极效果。
发明内容
在第一方面,本发明为治疗神经退行性紊乱或MD的方法,所述方法包括向受试者给予包含AGE抗体的组合物。
在第二方面,本发明为杀死衰老胶质细胞的方法,所述方法包括向受试者给予包含AGE抗体的组合物。
在第三方面,本发明为杀死衰老成肌细胞和/或衰老肌卫星细胞的方法,所述方法包括向受试者给予包含AGE抗体的组合物。
在第四方面,本发明为治疗患有神经退行性紊乱或MD的受试者的方法,所述方法包括第一次给予AGE抗体;随后针对所述第一次给予在治疗所述神经退行性紊乱或MD方面的有效性,对所述受试者进行测试;随后第二次给予所述AGE抗体。
在第五方面,本发明为治疗神经退行性紊乱或MD的方法,所述方法包括杀死衰老胶质细胞、衰老成肌细胞和/或衰老肌卫星细胞,或者在衰老胶质细胞、衰老成肌细胞和/或衰老肌卫星细胞中诱导凋亡。
在第六方面,本发明为用于治疗神经退行性紊乱的组合物,所述组合物包含:(i)AGE抗体,以及(ii)血清、免疫系统细胞、或两者皆有。
定义
术语“神经退行性紊乱(neurodegenerative disorder)”是指在中枢神经系统(包括脑)中导致神经元功能缺失和/或死亡的紊乱。此类紊乱包括中枢神经系统神经退行性紊乱,例如AD;PD;路易体痴呆;MS;朊病毒病(也称为传染性海绵状脑病(TSE)),包括克-雅氏病、变异型克-雅氏病、牛海绵状脑病(“疯牛”病)、瘙痒病(在绵羊和山羊中)、慢性消耗性疾病(在鹿和麋鹿中)、库鲁病和致死性家族失眠症;以及ALS。
术语“晚期糖基化终末产物”、“AGE”、“经AGE修饰的蛋白或肽”、“糖基化终末产物”和“AGE抗原”是指作为以下的结果而形成的经修饰的蛋白或肽:糖与蛋白质侧链反应,进一步重排并形成不可逆的交联。该过程起始于还原糖和氨基基团之间的可逆反应以形成席夫氏碱,进而形成共价键合的阿马多尔重排产物。一旦形成,阿马多尔产物经历进一步的重排以生成AGE。经AGE修饰的蛋白和针对经AGE修饰的蛋白的抗体在Bucala的U.S.5,702,704(“Bucala”)和Al-Abed等的U.S.6,380,165(“Al-Abed”)中描述。未经历形成AGE所必需的重排的糖基化蛋白质或肽(例如在糖基化白蛋白上发现的N-脱氧果糖基赖氨酸)不是AGE。AGE可通过AGE修饰(也称为AGE表位或AGE部分)的存在来鉴定,所述AGE修饰如2-(2-呋喃甲酰基)-4(5)-(2-呋喃基)-1H-咪唑(“FFI”),5-羟甲基-1-烷基吡咯-2-甲醛(“吡咯素(Pyrraline)”),1-烷基-2-甲酰基-3,4-二糖基吡咯(“AFGP”)(一种非荧光模型AGE),羧甲基赖氨酸,以及戊糖素(pentosidine)。另一种AGE,ALI在Al-Abed中描述。
术语“神经退行性蛋白”是在患有神经退行性紊乱的患者中积累并与神经退行性紊乱相关的蛋白质。实例包括β-淀粉样蛋白斑块(与AD相关)、tau蛋白缠结(与AD相关)、突变的超氧化物歧化酶-1(与ALS相关)、朊病毒蛋白聚集物(与TSE相关)以及α突触核蛋白原纤维(alpha-synuclein protein fibrils)(与PD及路易体痴呆相关)。“神经退行性蛋白”处于在神经退行性紊乱过程中积累的蛋白的形式,通常为突变体或错误折叠的形式。
“结合至细胞上的经AGE修饰的蛋白的抗体”、“抗AGE抗体”或“AGE抗体”是指结合至经AGE修饰的蛋白或肽并包含抗体的恒定区的抗体或其它蛋白质,其中,被AGE修饰的蛋白或肽为通常发现结合在细胞表面上的蛋白或肽,所述细胞优选哺乳动物细胞,更优选人细胞、猫细胞、狗细胞、马细胞、骆驼科动物(例如骆驼或羊驼)细胞、牛细胞、绵羊细胞或山羊细胞。“结合至细胞上的经AGE修饰的蛋白的抗体”、“抗AGE抗体”或“AGE抗体”不包括以相同的特异性和选择性与经AGE修饰的蛋白或肽以及相同的未经AGE修饰的蛋白或肽两者结合(即,AGE修饰的存在不会增加结合)的抗体或其它蛋白质。经AGE修饰的白蛋白不是细胞上的经AGE修饰的蛋白,因为白蛋白并不是通常发现结合在细胞表面上的蛋白质。“结合至细胞上的经AGE修饰的蛋白的抗体”、“抗AGE抗体”或“AGE抗体”仅包括导致细胞移除、破坏或死亡的那些抗体。还包括例如缀合至毒素、药物或其它化学品或颗粒的抗体。优选地,所述抗体是单克隆抗体,但多克隆抗体也是可以的。
术语“衰老细胞”意味着处于不可逆的增殖停滞状态并且表达一种或多种衰老生物标志物(例如p16lnk4a的活化或β-半乳糖苷酶的表达)的细胞。还包括表达一种或多种衰老生物标志物、不在体内增殖但于特定条件下可在体外增殖的细胞,例如在ALS患者的肌肉中发现的一些卫星细胞。
术语“变体”是指与具体鉴定的序列不同的核苷酸序列、蛋白质序列或氨基酸序列,其中一个或多个核苷酸残基、蛋白残基或氨基酸残基删除、置换或添加。变体可为天然存在的等位变体或非天然存在的变体。所鉴定序列的变体可保留所鉴定序列的一些或全部功能特征。
术语“序列同一性百分比(%)”被定义为在对序列进行比对并且必要时引入空位以实现最大序列同一性百分比,并不将任何保守置换视为序列同一性的部分后,候选序列中与参比多肽序列中的氨基酸残基相同的氨基酸残基的百分比。用于测定氨基酸序列同一性百分比目的的比对可使用可公开获得的计算机软件(如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件)以各种方式来实现。优选地,使用序列比较计算机程序ALIGN-2来生成序列同一性%值。ALIGN-2序列比较计算机程序可从Genentech,Inc.(South SanFrancisco,CA)公开获得,或者可从源代码编译,所述源代码及其用户文件已提交美国版权局并且登记在美国版权登记号TXU510087下。ALIGN-2程序应被编译以在UNIX操作系统(包括数字UNIX V4.0D)上使用。所有序列比较参数均由ALIGN-2程序设置且不改变。
在采用ALIGN-2用于氨基酸序列比较的情形中,给定氨基酸序列A对于、与或相对于给定氨基酸序列B的序列同一性%(其可替代地措词为给定氨基酸序列A具有或包含对于、与或相对于给定氨基酸序列B的某一氨基酸序列同一性%)以如下计算:100×分数X/Y,其中,X为通过序列比对程序ALIGN-2在所述程序的A和B的比对中评分为相同匹配的氨基酸残基的数目,并且其中,Y为B中的氨基酸残基的总数。在氨基酸序列A的长度不等于氨基酸序列B的长度的情况下,A对于B的氨基酸序列同一性%将不等于B对于A的氨基酸序列同一性%。除非另有特别说明,否则在本文中使用的所有氨基酸序列同一性%值使用ALIGN-2计算机程序获得。
附图说明
图1是抗体结合实验中应答相对于时间的图表。
图2A为阿尔兹海默病样品的细胞的照片,显示出被染成红色的羧甲基赖氨酸和被染成绿色的磷酸化tau。
图2B为阿尔兹海默病样品的细胞的照片,显示出被染成红色的羧甲基赖氨酸和被染成绿色的淀粉样前体蛋白。
图2C为来自黑质的帕金森氏病样品的细胞的照片,显示出被染成红色的羧甲基赖氨酸和被染成绿色的α突触核蛋白。
图2D为来自腹侧被盖区的帕金森氏病样品的细胞的照片,显示出被染成红色的羧甲基赖氨酸和被染成绿色的α突触核蛋白。
具体实施方式
本发明使用结合至细胞上的经AGE修饰的蛋白的抗体来移除或杀死衰老胶质细胞(例如衰老星形胶质细胞和衰老小胶质细胞),以治疗神经退行性紊乱,例如,AD;PD;路易体痴呆;MS;朊病毒病(也称为传染性海绵状脑病(TSE)),包括克-雅氏病、变异型克-雅氏病、牛海绵状脑病(“疯牛”病)、瘙痒病(在绵羊和山羊中)、慢性消耗性疾病(在鹿和麋鹿中)、库鲁病及致死性家族失眠症;以及ALS。优选地,将所述抗体给予至中枢神经系统以最有效地移除这些衰老细胞;然而,由于星形胶质细胞帮助形成血脑屏障,外周给予(即,并不给予至中枢神经系统而是给予至外周循环系统)也是有效的。然后,存在于患者中枢神经系统中的干细胞将生长并扩增以替换被移除的细胞。或者,自体移植患者自身干细胞或移植供体干细胞(该干细胞可为离体扩增的)也可用来替换被移除的细胞。
本发明还使用结合至细胞上的经AGE修饰的蛋白的抗体来移除或杀死衰老胶质细胞和/或衰老肌卫星细胞,以治疗ALS。优选地,将所述抗体给予至外周循环(例如传统的静脉内给予)以最有效地移除这些衰老细胞。也可在发现衰老肌卫星细胞处肌内给予所述抗体。然后,存在于患者肌肉中的干细胞将生长并扩增以替换被移除的细胞。或者,自体移植患者自身干细胞或移植供体干细胞(该干细胞可为离体扩增的)也可用来替换被移除的细胞。
本发明还使用结合至细胞上的经AGE修饰的蛋白的抗体来移除或杀死衰老成肌细胞和/或衰老肌卫星细胞,以治疗MD和ALS。优选地,将所述抗体给予至外周循环(例如传统的静脉内给予)以最有效地移除这些衰老细胞。也可在发现衰老成肌细胞和肌卫星细胞处肌内给予所述抗体。然后,存在于患者肌肉中的干细胞将生长并扩增以替换被移除的细胞。或者,自体移植患者自身干细胞或移植供体干细胞(该干细胞可为离体扩增的)也可用来替换被移除的细胞。参见,例如Rouger等,“Systemic Delivery of Allogenic Muscle StemCells Induces Long-Term Muscle Repair and Clinical Efficacy in DuchenneMuscular Dystrophy Dogs”,The American Journal of Pathology,Vol.179,No.5,2501-2518(2011年11月)。
衰老起始于细胞损伤或应激(如生长因子的过度刺激)。损伤或应激负面地影响细胞中的线粒体DNA,从而使其产生自由基,所述自由基与细胞中的糖反应形成甲基乙二醛(MG)。MG反过来与蛋白质或脂质反应以生成晚期糖基化终末产物(AGE)。在蛋白质组分为赖氨酸的情况中,乙二醛发生反应形成羧甲基赖氨酸,羧甲基赖氨酸就是AGE。AGE还由血液中的糖与细胞外部蛋白的非酶促反应形成。
线粒体DNA的损伤或应激还引发DNA损伤应答,该DNA损伤应答诱导细胞产生细胞周期阻断蛋白(cell cycle blocking proteins)。这些阻断蛋白阻止细胞进行分裂。持续的损伤或应激导致:(1)mTOR产生,其进而活化蛋白质合成并使蛋白质分解失活;和(2)SASP(衰老相关的分泌表型),其中分泌生长刺激和抑制因子以在其它细胞中引起衰老(衰老细胞旁观者效应)。对细胞的进一步刺激导致程序性细胞死亡(凋亡)。
结合至细胞上的经AGE修饰的蛋白的抗体(“抗AGE抗体”或“AGE抗体”)是本领域中已知的。实例包括U.S.5,702,704(Bucala)和U.S.6,380,165(Al-Abed等)中所描述的那些。实例包括结合至一种或多种具有AGE修饰的经AGE修饰的蛋白的抗体以及此类抗体的混合物,所述AGE修饰例如FFI、吡咯素、AFGP、ALI、羧甲基赖氨酸、羧乙基赖氨酸和戊糖素。优选地,所述抗体结合经羧甲基赖氨酸修饰的蛋白质。优选地,所述抗体对将在其中使用该抗体的动物是非免疫原性的,例如对如下动物是非免疫原性的:人;伴侣动物,包括猫、狗和马;以及商业上重要的动物,例如骆驼(或羊驼)、牛(牛类)、绵羊和山羊。更优选地,所述抗体具有与动物的抗体相同的物种恒定区,以降低针对所述抗体的免疫应答,所述抗体例如为人源化抗体(用于人类)、猫源化抗体(用于猫)、犬源化抗体(用于狗)、马源化抗体(用于马)、骆驼源化抗体(用于骆驼或羊驼)、牛源化抗体(用于牛)、绵羊源化抗体(用于绵羊)或山羊源化抗体(用于山羊)。最优选地,所述抗体与将在其中使用该抗体的动物的抗体相同(除了可变区),例如人抗体、猫抗体、狗抗体、马抗体、骆驼抗体、牛抗体、绵羊抗体或山羊抗体。这些动物抗体的恒定区和其它部分的细节在下文描述。优选地,所述抗体是单克隆抗体。
特别优选的AGE抗体是结合至表现出羧甲基赖氨酸修饰的蛋白质或肽的抗体。羧甲基赖氨酸(也称为CML、N(ε)-(羧甲基)赖氨酸、N(6)-羧甲基赖氨酸、或2-氨基-6-(羧甲基氨基)己酸)由于氧化应激和化学糖基化而在蛋白质或肽和脂质上被发现,并且与老化有关。经CML修饰的蛋白质或肽被在各种细胞上表达的受体RAGE识别。CML已得到充分研究,并且CML相关产品是可商购的。例如,Cell Biolabs,Inc.销售CML-BSA抗原、CML多克隆抗体、CML免疫印迹试剂盒以及CML竞争性ELISA试剂盒(www.cellbiolabs.com/cml-assays)。特别优选的抗体包括可商购的小鼠抗糖基化终末产物抗体的可变区,所述可商购的小鼠抗糖基化终末产物抗体针对与匙孔血蓝蛋白缀合的羧甲基赖氨酸产生,可从R&D Systems,Inc.获得该羧甲基赖氨酸MAb(Clone 318003)(Minneapolis,MN;目录号MAB3247)),其被修饰成具有人恒定区(或者将在其中给予该抗体的动物的恒定区)。可商购的抗体(例如来自R&DSystems,Inc.的的羧甲基赖氨酸抗体,对应于目录号MAB3247)可能意图用于诊断目的,并且可能含有不适合用于动物或人的材料。优选地,在用于动物或人之前对可商购的抗体进行纯化和/或分离以除去毒素或其它潜在有害物质。
所述AGE抗体具有低的从抗体-抗原复合物解离的速率或kd(也称为kback或解离速率),优选至多9×10-3、8×10-3、7×10-3或6×10-3(sec-1)。AGE抗体对细胞的经AGE修饰的蛋白具有高亲和力,其可表现为至多9×10-6、8×10-6、7×10-6、6×10-6、5×10-6、4×10-6或3×10-6(M)的低的解离常数KD。优选地,所述AGE抗体的结合性质优于、相似于、或相同于图1中所示的从R&D Systems,Inc.获得的羧甲基赖氨酸MAb(Clone 318003)(Minneapolis,MN;目录号MAB3247)。
所述抗AGE抗体可通过抗体依赖性细胞介导的细胞毒性(ADCC)破坏经AGE修饰的细胞。ADCC是细胞介导的免疫防御机制,其中免疫系统的效应细胞主动裂解其膜表面抗原已被特异性抗体结合的靶细胞。ADCC可由自然杀伤(NK)细胞、巨噬细胞、中性粒细胞或嗜酸性粒细胞介导。效应细胞与结合抗体的Fc部分结合。
所述AGE抗体可缀合至引起经AGE修饰的细胞的破坏的试剂。此类试剂可以是毒素、细胞毒性试剂、磁性纳米颗粒以及磁性旋涡盘(magnetic spin-vortex discs)。
缀合至AGE抗体的毒素可被注射至患者中以选择性地靶向并移除经AGE修饰的细胞,所述毒素例如成孔毒素(PFT)(Aroian R.等,“Pore-Forming Toxins and CellularNon-Immune Defenses(CNIDs),”,Current Opinion in Microbiology,10:57-61(2007))。所述AGE抗体识别并结合至经AGE修饰的细胞。然后,毒素在细胞表面处引起孔形成并随后通过渗透裂解引起细胞移除。
缀合至AGE抗体的磁性纳米颗粒可被注射至患者中以靶向并移除经AGE修饰的细胞。可通过施加磁场来加热磁性纳米颗粒,以便选择性地移除经AGE修饰的细胞。
作为替代方案,磁性旋涡盘仅在施加磁场时磁化,以避免自聚集,自聚集可阻塞血管;当施加磁场时其开始旋转,导致靶细胞的膜破裂。缀合至AGE抗体的磁性旋涡盘特异性地靶向经AGE修饰的细胞类型,而不移除其它细胞。
抗体通常包含连接以形成“Y”形分子的两条多肽重链和两条多肽轻链。恒定区决定用于靶向抗原的机制。“Y”末端中的氨基酸序列(可变区)在不同抗体之间变化。该变化给予抗体结合抗原的特异性。包含轻链和重链的末端的可变区被进一步细分为高变区(HV-有时也称为互补决定区,或CDR)和框架(FR)区。当重组制备抗体时,也可能具有单一抗体,所述单一抗体具有结合至两种不同抗原的可变区(或互补决定区),其中“Y”的每个末端对各抗原而言是特异性的;这些抗体被称为双特异性抗体。
根据本发明的人源化抗AGE抗体可具有SEQ ID NO:22中所示的人恒定区氨基酸序列。人源化抗AGE抗体的重链互补决定区可具有SEQ ID NO:23(CDR1H)、SEQ ID NO:24(CDR2H)和SEQ ID NO:25(CDR3H)中所示的蛋白质序列中的一个或多个。人源化抗AGE抗体的轻链互补决定区可具有SEQ ID NO:26(CDR1L)、SEQ ID NO:27(CDR2L)和SEQ ID NO:28(CDR3L)中所示的蛋白质序列中的一个或多个。
人(智人)抗体免疫球蛋白G1的重链可具有或可包含SEQ ID NO:1的蛋白质序列。重链的可变结构域可具有或可包含SEQ ID NO:2的蛋白质序列。人(智人)抗体免疫球蛋白G1的κ轻链可具有或可包含SEQ ID NO:3的蛋白质序列。κ轻链的可变结构域可具有或可包含SEQ ID NO:4的蛋白质序列。可对可变区进行密码子优化、合成并克隆至含有人免疫球蛋白G1恒定区的表达载体中。此外,可变区可用于非人抗体的人源化。
抗体重链可由SEQ ID NO:12的DNA序列(鼠抗AGE免疫球蛋白G2b重链)编码。由SEQID NO:12编码的鼠抗AGE免疫球蛋白G2b重链的蛋白质序列在SEQ ID NO:16中示出。所述鼠抗体的可变区在SEQ ID NO:20中示出,其对应于SEQ ID NO:16的第25-142位。抗体重链可选择性地由SEQ ID NO:13的DNA序列(嵌合抗AGE人免疫球蛋白G1重链)编码。由SEQ ID NO:13编码的嵌合抗AGE人免疫球蛋白G1重链的蛋白质序列在SEQ ID NO:17中示出。嵌合抗AGE人免疫球蛋白包含第25-142位中SEQ ID NO:20的鼠可变区。抗体轻链可由SEQ ID NO:14的DNA序列(鼠抗AGEκ轻链)编码。由SEQ ID NO:14编码的鼠抗AGEκ轻链的蛋白质序列在SEQID NO:18中示出。所述鼠抗体的可变区在SEQ ID NO:21中示出,其对应于SEQ ID NO:18的第21-132位。抗体轻链可选择性地由SEQ ID NO:15的DNA序列(嵌合抗AGE人κ轻链)编码。由SEQ ID NO:15编码的嵌合抗AGE人κ轻链的蛋白质序列在SEQ ID NO:19中示出。嵌合抗AGE人免疫球蛋白包含第21-132位中SEQ ID NO:21的鼠可变区。
根据本发明的人源化抗AGE抗体可具有或可包含一个或多个人源化重链或人源化轻链。人源化重链可由SEQ ID NO:30、SEQ ID NO:32或SEQ ID NO:34的DNA序列编码。由SEQID NO:30、SEQ ID NO:32和SEQ ID NO:34编码的人源化重链的蛋白质序列分别在SEQ IDNO:29、SEQ ID NO:31和SEQ ID NO:33中示出。人源化轻链可由SEQ ID NO:36、SEQ ID NO:38或SEQ ID NO:40的DNA序列编码。由SEQ ID NO:36、SEQ ID NO:38和SEQ ID NO:40编码的人源化轻链的蛋白质序列分别在SEQ ID NO:35、SEQ ID NO:37和SEQ ID NO:39中示出。优选地,人源化抗AGE抗体使人序列的量最大化,同时保留原始抗体特异性。可构建含有重链和轻链的完整的人源化抗体,所述重链具有选自SEQ ID NO:29、SEQ ID NO:31和SEQ IDNO:33的蛋白质序列;以及所述轻链具有选自SEQ ID NO:35、SEQ ID NO:37和SEQ ID NO:39的蛋白质序列。
来自非人物种的抗体的蛋白质序列可被修饰为包含κ轻链(具有SEQ ID NO:4中所示的序列)或重链(具有SEQ ID NO:2中所示的序列)的可变结构域。非人物种可以是伴侣动物,例如家猫或家狗;或家畜,例如牛、马或骆驼。优选地,非人物种不是小鼠。马(家马,Equus caballus)抗体免疫球蛋白γ4的重链可具有或可包含SEQ ID NO:5(EMBL/GenBank登录号AY445518)的蛋白质序列。马(家马)抗体免疫球蛋白δ的重链可具有或可包含SEQ IDNO:6(EMBL/GenBank登录号AY631942)的蛋白质序列。狗(家犬,Canis familiaris)抗体免疫球蛋白A的重链可具有或可包含SEQ ID NO:7(GenBank登录号L36871)的蛋白质序列。狗(家犬)抗体免疫球蛋白E的重链可具有或可包含SEQ ID NO:8(GenBank登录号L36872)的蛋白质序列。猫(家猫,Felis catus)抗体免疫球蛋白G2的重链可具有或可包含SEQ ID NO:9(DDBJ/EMBL/GenBank登录号KF811175)的蛋白质序列。
骆驼科动物(例如骆驼(单峰驼(Camelus dromedarius)和双峰驼(Camelusbactrianus))、美洲驼(大羊驼(Lama glama)、羊驼(Lama pacos)和小羊驼(Lamavicugna))、羊驼(alpacas/Vicugna pacos)以及原驼(guanacos/Lama guanicoe)具有未在其它哺乳动物中发现的独特抗体。除了由重链和轻链四聚体组成的常规免疫球蛋白G抗体外,骆驼科动物还具有不含轻链并作为重链二聚体存在的重链免疫球蛋白G抗体。这些抗体被称为重链抗体、HCAb、单结构域抗体或sdAb,并且骆驼科动物重链抗体的可变结构域被称为VHH。骆驼科动物重链抗体缺乏重链CH1结构域并具有未在其它物种中发现的铰链区。阿拉伯骆驼(单峰驼)单结构域抗体的可变区可具有或可包含SEQ ID NO:10(GenBank登录号AJ245148)的蛋白质序列。阿拉伯骆驼(单峰驼)四聚体免疫球蛋白的重链的可变区可具有或可包含SEQ ID NO:11(GenBank登录号AJ245184)的蛋白质序列。
除了骆驼科动物外,重链抗体也在软骨鱼类(例如鲨鱼、鳐和魟)中被发现。这种类型的抗体被称为免疫球蛋白新抗原受体或IgNAR,并且IgNAR的可变结构域被称为VNAR。IgNAR作为各自由一个可变结构域和五个恒定结构域组成的两个相同的重链二聚体存在。像骆驼科动物一样,不存在轻链。
另外的非人物种的蛋白质序列可容易地在在线数据库中找到,例如国际免疫遗传学信息系统(www.imgt.org)、欧洲生物信息学研究所(www.ebi.ac.uk)、日本的DNA数据库(ddbj.nig.ac.jp/arsa)或美国国家生物技术信息中心(www.ncbi.nlm.nih.gov)。
另外的DNA序列和蛋白质序列可在美国临时专利申请No.62/485,246中发现,以引用的方式将其并入本文。
抗AGE抗体或其变体可包含与SEQ ID NO:2或SEQ ID NO:20的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的重链可变区,包括其翻译后修饰物。相对于参比序列,具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列同一性的可变区可含有置换(例如保守置换)、插入或删除,但包含所述序列的抗AGE抗体保留与AGE结合的能力。置换、插入或删除可发生在可变区之外的区域。
抗AGE抗体或其变体可包含与SEQ ID NO:4或SEQ ID NO:21的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的轻链可变区,包括其翻译后修饰体。相对于参比序列,具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列同一性的可变区可含有置换(例如保守置换)、插入或删除,但包含所述序列的抗AGE抗体保留与AGE结合的能力。置换、插入或删除可发生在可变区之外的区域。
或者,所述抗体可具有可商购的小鼠抗糖基化终末产物抗体(可从R&D Systems,Inc.获得的羧甲基赖氨酸MAb(Clone 318003)(Minneapolis,MN;目录号MAB3247))的互补决定区,所述小鼠抗糖基化终末产物抗体针对与匙孔血蓝蛋白缀合的羧甲基赖氨酸(CML-KLH)产生。
所述抗体可具有或可包含允许受试者的免疫系统破坏所靶向的细胞的恒定区。特别优选的是对羧甲基赖氨酸(其为人中最常见的AGE)具有特异性的单克隆抗体。优选地,此种抗体包含补体结合部分(Fc),其刺激系统自然杀伤(NK)细胞Fc受体增加,(1)使NK细胞与抗体结合,所述抗体进而与衰老细胞结合,以及(2)引发裂解反应。这使得衰老细胞经历凋亡并被分解成碎片,这些碎片被巨噬细胞吸收、分解并从体内清除。
也可使用与经AGE修饰的蛋白的多于一种类型AGE结合的抗体的混合物。
也可使用双特异性抗体,其为针对两种不同表位的AGE抗体。此类抗体将具有来自一种AGE抗体的可变区(或互补决定区)和来自不同抗体的可变区(或互补决定区)。
可使用抗体片段来代替完整抗体。例如,通过用酶消化,免疫球蛋白G可分解成更小的片段。木瓜蛋白酶消化切割重链间二硫桥的N末端侧,从而产生Fab片段。Fab片段包含轻链及重链的两个N末端结构域中的一个(也称为Fd片段)。胃蛋白酶消化切割重链间二硫桥的C末端侧,从而产生F(ab’)2片段。F(ab’)2片段包含两条轻链和由二硫桥连接的两个N末端结构域。胃蛋白酶消化也可形成Fv片段(可变片段)和Fc片段(可结晶片段)。Fv片段含有两个N末端可变结构域。Fc片段含有与细胞上的免疫球蛋白受体和补体级联的初始元件相互作用的结构域。胃蛋白酶还可在重链的第三恒定结构域(CH3)之前切割免疫球蛋白G以产生大片段F(abc)和小片段pFc'。也可使用单结构域抗体,所述单结构域抗体包含重链CDR并缀合至毒素或用于引起细胞死亡或破坏的其它部分,并且已知单结构域抗体能够穿过血脑屏障。或者,可通过重组产生抗体片段。
如果期望另外的抗体,可以使用公知的方法来生产。例如,可通过一次或多次注射免疫原以及佐剂(如果需要的话)来在哺乳动物宿主中产生多克隆抗体(pAb)。通常而言,通过皮下注射或腹膜内注射将免疫原(以及佐剂)注射到哺乳动物中。所述免疫原可为细胞的经AGE修饰的蛋白,例如AGE-抗凝血酶III、AGE-钙调蛋白、AGE-胰岛素、AGE-血浆铜蓝蛋白、AGE-胶原蛋白、AGE-组织蛋白酶B、AGE-白蛋白、AGE-晶状体蛋白、AGE-纤溶酶原激活物、AGE-内皮质膜蛋白、AGE-醛还原酶、AGE-转铁蛋白、AGE-纤维蛋白、AGE-铜/锌SOD、AGE-apoB、AGE-纤连蛋白、AGE-胰核糖、AGE-apo A-I和AGE-apo A-II、AGE-血红蛋白、AGE-Na+/K+-ATPase、AGE-纤溶酶原、AGE-髓磷脂、AGE-溶菌酶、AGE-免疫球蛋白、AGE-红细胞Glu转运蛋白、AGE-β-N-乙酰己糖胺酶(hexominase)、AGE-apo E、AGE-红细胞膜蛋白、AGE-醛糖还原酶、AGE-铁蛋白、AGE-红细胞血影蛋白、AGE-醇脱氢酶、AGE-触珠蛋白、AGE-微管蛋白、AGE-甲状腺激素、AGE-纤维蛋白原、AGE-β2-微球蛋白、AGE-山梨醇脱氢酶、AGE-α1-抗胰蛋白酶、AGE-碳酸脱水酶、AGE-RNAse、AGE-低密度脂蛋白、AGE-己糖激酶、AGE-apo C-I、AGE-RNAse、AGE-血红蛋白(例如AGE-人血红蛋白)、AGE-白蛋白(例如AGE-牛血清白蛋白(AGE-BSA)和AGE-人血清白蛋白)、AGE-低密度脂蛋白(AGE-LDL)以及AGE-胶原蛋白IV。完整的、裂解的或部分消化的经AGE修饰的细胞(例如,经AGE修饰的红血球)也可用作AGE抗原。佐剂的实例包括弗氏完全佐剂、单磷酰脂质A、合成海藻糖二霉菌酸酯(trehalose dicorynomycolate)、氢氧化铝(alum)、热休克蛋白HSP70或HSP96、含单磷酰脂质A的角鲨烯乳剂、α2-巨球蛋白和表面活性物质(包括油乳剂、普朗尼克多元醇(pleuronic polyols)、聚阴离子以及二硝基苯酚)。为了改善免疫应答,可将免疫原缀合至在宿主中具有免疫原性的多肽,例如匙孔血蓝蛋白(KLH)、血清白蛋白、牛甲状腺球蛋白、霍乱毒素、不稳定性肠毒素、二氧化硅颗粒或大豆胰蛋白酶抑制剂。或者,pAb可在鸡中制备,产生IgY分子。
单克隆抗体(mAb)也可通过如下制造:免疫宿主或宿主的淋巴细胞,收集分泌(或潜在分泌)mAb的淋巴细胞,将这些淋巴细胞融合至无限繁殖的细胞(例如骨髓瘤细胞),并筛选分泌期望的mAb的那些细胞。也可使用其它技术,例如EBV杂交瘤技术。通过将编码抗体可变结构域的基因剪接到人(或其它动物)免疫球蛋白的恒定结构域的基因来生成嵌合抗体的技术产生“嵌合抗体”,所述嵌合抗体在氨基酸水平上基本上为人(人源化)的或基本上“源化”为另一动物(如猫、狗、马、骆驼或羊驼、牛、绵羊或山羊)的。如果需要,mAb可通过常规方法从培养基或腹水中纯化,例如蛋白质A-琼脂糖凝胶、羟基磷灰石层析、凝胶电泳、透析、硫酸铵沉淀或亲和层析。此外,人单克隆抗体可通过免疫含有第三拷贝IgG人转基因座(trans-loci)和沉默的内源小鼠Ig基因座的转基因小鼠或者使用人转基因小鼠来生成。人源化单克隆抗体及其片段的生产还可通过噬菌体展示技术来生成。
“药学上可接受的载体”包括与药物给予相容的任何和所有溶剂、分散介质、包衣剂、抗细菌和抗真菌剂、等渗剂和吸收延迟剂等。此类载体或稀释剂的优选实例包括水、盐水、林格氏溶液和葡萄糖溶液。补充的活性化合物也可被并入这些组合物中。用于肠胃外给予的溶液和悬浮液可包括无菌稀释剂,例如注射用水、盐水溶液、聚乙二醇、甘油、丙二醇或其它合成溶剂;抗细菌剂,例如苄醇或对羟基苯甲酸甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;缓冲剂,例如乙酸盐、柠檬酸盐或磷酸盐;以及用于调节张力的试剂,例如氯化钠或葡萄糖。pH可用酸或碱(如盐酸或氢氧化钠)调节。肠胃外制剂可被包封在由玻璃或塑料制成的安瓿、一次性注射器或多剂量小瓶中。
适合于注射的药物组合物包含无菌水溶液或分散体,用于临时制备无菌可注射溶液或分散体。各种赋形剂可包含在适于注射的抗体的药物组合物中。对于注射给予,合适的载体包括生理盐水、抑菌水、(BASF;Parsippany,NJ)或磷酸盐缓冲盐水(PBS)。在所有情况下,组合物必须是无菌的并且应该是液体的,以便使用注射器来给予。此类组合物在制造和储存期间应该是稳定的并且必须将其保藏以免受微生物(如细菌和真菌)污染。各种抗细菌和抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、苯酚、抗坏血酸和硫柳汞)可含有微生物污染。组合物中可包含等渗剂例如糖、多元醇(例如甘露糖醇、山梨醇)和氯化钠。可延迟吸收的组合物中包含诸如单硬脂酸铝和明胶的试剂。无菌可注射溶液可通过如下制备:以所需的量将抗体和任选的其它治疗组分掺入所需的具有一种成分或成分组合的合适的溶剂中,然后进行灭菌。制备无菌可注射溶液的无菌固体的制备方法包括通过真空干燥和冷冻干燥来产生固体。
为了通过吸入给予,抗体被作为从喷雾器或含有合适推进剂(例如二氧化碳等气体)的加压容器喷射的气溶胶递送。抗体也可作为干粉通过吸入递送,例如使用iSPERSETM吸入药物递送平台(PULMATRIX,Lexington,Mass.)。当通过吸入给予时,在各种动物(包括人)中,使用的AGE抗体(该抗体是鸡抗体(IgY))可能是非免疫原性的。
各类型抗体合适的剂量水平通常为约0.01至500mg/千克患者体重。优选地,剂量水平将为约0.1mg/kg至约250mg/kg;更优选地为约0.5mg/kg至约100mg/kg。合适的剂量水平可为约0.01mg/kg至250mg/kg、约0.05mg/kg至100mg/kg或约0.1mg/kg至50mg/kg。在该范围内,剂量可为0.05mg/kg至0.5mg/kg、0.5mg/kg至5mg/kg或5mg/kg至50mg/kg。虽然各类型的抗体能够以每天1次至4次(例如每天一次或两次)的方案给予,但抗体通常在体内具有长的半衰期。因此,各类型的抗体能够以每天一次、每周一次、每两周或三周一次、每月一次或每60天至90天一次给予。
可通过测量神经功能或认知功能的变化,或者通过与神经退行性紊乱相关的神经退行性蛋白的存在的增加或减少来对接受AGE抗体给药的受试者进行测试,以确定对于治疗神经退行性紊乱所述AGE抗体是否有效。在大多数神经退行性紊乱的情况中,对神经退行性紊乱的存在、严重程度和/或进程进行测量的测试是公知的。可重复抗体的给予和随后的测试,直至获得所期望的治疗结果,例如,通过评估患者的神经退行性紊乱或者评估患者的衰老细胞是否已被杀死。
可创建单位剂型以便于给予和剂量均一性。单位剂型是指作为单一剂量适合于待治疗受试者的物理上离散的单位,其含有与所需的药物载体相关的治疗有效量的一种或多种类型的抗体。优选地,单位剂型在密封容器中并且是无菌的。
通过本文所述的方法可治疗可发展神经退行性紊乱的任何哺乳动物。人是治疗的优选哺乳动物。可治疗的其它哺乳动物包括小鼠、大鼠、山羊、绵羊、奶牛、马和伴侣动物(例如狗或猫)。需要治疗的受试者可通过神经退行性紊乱的诊断来鉴定。
在中枢神经系统神经退行性紊乱的情况中,优选的是将含有AGE抗体的组合物直接给予至中枢神经系统。此种给予的实例包括鞘内给予;给予至脑的脑室系统(脑室内给予),例如,通过导管或永久性分流器,或可在脑室造瘘术过程中放置的其它给予装置(参见,例如Takami,A.等,“Treatment of primary central nervous system lymphoma withinduction of complement-dependent cytotoxicity by intraventricularadministration of autologous-serum-supplemented rituximab”,Cancer Sci.Vol.97,pp.80-83(2006年1月));以及通过增强对流输送(CED)给予(参见,例如,Chen,K.S.等,“MONOCLONAL ANTIBODY THERAPY FOR MALIGNANT GLIOMA”,Glioma第10章:Immunotherapeutic Approaches,pp.132-141(R.Yamanaka编;Landes Bioscience andSpringer Science+Business Media,2012))。所有此类中枢神经系统给予还可任选地包括给予血清补充剂(如自体血清)以增强AGE抗体的细胞杀伤性能;可在给予AGE抗体之前、同时或之后给予血清补充剂。任选地,本文所述的含有AGE抗体的组合物的任一种可进一步含有血清补充剂(例如自体血清补充剂)。代替血清补充剂或除血清补充剂之外,还可使用经纯化的免疫系统细胞(自体免疫系统细胞或来自供体的免疫系统细胞);此类细胞的实例包括自然杀伤细胞。除了患者或供体的自然杀伤细胞之外或替代患者或供体的自然杀伤细胞,也可使用经工程化直接结合至抗体或经工程化直接结合至AGE抗原(例如羧甲基赖氨酸)的人工自然杀伤细胞(如)(参见www.nantkwest.com)。
所述抗AGE抗体可用于细胞分离过程,例如磁性细胞分离。在磁性细胞分离中,抗AGE抗体通过被称为包被的过程与磁珠连接。然后,经包被的磁珠可特异性地结合至经AGE修饰的细胞。与包被在磁珠上的抗AGE抗体结合的经AGE修饰的细胞然后将对施加的磁场作出反应,从而使得经AGE修饰的细胞与未经AGE修饰的细胞分离。磁性细胞分离可用于从组织样品和流体样品中分离经AGE修饰的细胞。所述磁珠可为微珠(0.5-500μm)或纳米颗粒(5-500nm)。包被在磁珠上的抗AGE抗体还可用于分离过程,如免疫分析和免疫沉淀。同样地,包被在磁珠上的抗AGE抗体可用于特异性地靶向并从组织样品和流体样品中分离经AGE修饰的蛋白质或肽。抗AGE抗体可用于其它细胞分离过程,例如流式细胞术和细胞分选。
所述抗AGE抗体可用于细胞纯化过程,如免疫淘选(immunopanning)和免疫吸附。纯化过程在从组织培养物、细胞培养物或血液中分离期望的或不想要的细胞方面是有用的。细胞纯化可用于移植,如骨髓移植;或输注(transfusion),如输血(bloodtransfusion)。细胞纯化在化疗期间的自体干细胞移植中特别有用,移除转移性恶性细胞并富集有益的干细胞。使用抗AGE抗体的免疫淘选或免疫吸附可从组织培养物、细胞培养物或血液样品中分离经AGE修饰的细胞。
对应于SEQ ID NO:1的单字母氨基酸序列显示如下:
上述氨基酸序列的第16-133位对应于SEQ ID NO:2。上述氨基酸序列的第46-50位对应于SEQ ID NO:41。上述氨基酸序列的第65-81位对应于SEQ ID NO:42。上述氨基酸序列的第114-122位对应于SEQ ID NO:43。
对应于SEQ ID NO:3的单字母氨基酸序列显示如下:
上述氨基酸序列的第16-128位对应于SEQ ID NO:4。任选地,SEQ ID NO:4的第128位的精氨酸(Arg或R)残基可被省略。上述氨基酸序列的第39-54位对应于SEQ ID NO:44。上述氨基酸序列的第70-76位对应于SEQ ID NO:45。上述氨基酸序列的第109-117位对应于SEQ ID NO:46。
对应于SEQ ID NO:12的DNA序列显示如下:
对应于SEQ ID NO:13的DNA序列显示如下:
对应于SEQ ID NO:14的DNA序列显示如下:
对应于SEQ ID NO:15的DNA序列显示如下:
对应于SEQ ID NO:16的单字母氨基酸序列显示如下:
上述氨基酸序列的第123位的丙氨酸残基可任选地被替换为丝氨酸残基。上述氨基酸序列的第124位的酪氨酸残基可任选地被替换为苯丙氨酸残基。上述氨基酸序列的第25-142位对应于SEQ ID NO:20。SEQ ID NO:20可任选地包含在第123位和第124位的置换。SEQ ID NO:20可任选地含有在末端缬氨酸残基之后的一个另外的赖氨酸残基。
对应于SEQ ID NO:17的单字母氨基酸序列显示如下:
对应于SEQ ID NO:18的单字母氨基酸序列显示如下:
上述氨基酸序列的第21-132位对应于SEQ ID NO:21。
对应于SEQ ID NO:19的单字母氨基酸序列显示如下:
对应于SEQ ID NO:22的单字母氨基酸序列显示如下:
对应于SEQ ID NO:23的单字母氨基酸序列是SYTMGVS。
对应于SEQ ID NO:24的单字母氨基酸序列是TISSGGGSTYYPDSVKG。
对应于SEQ ID NO:25的单字母氨基酸序列是QGGWLPPFAX,其中X可以是任何天然存在的氨基酸。
对应于SEQ ID NO:26的单字母氨基酸序列是RASKSVSTSSRGYSYMH。
对应于SEQ ID NO:27的单字母氨基酸序列是LVSNLES。
对应于SEQ ID NO:28的单字母氨基酸序列是QHIRELTRS。
对应于SEQ ID NO:29的单字母氨基酸序列是:
对应于SEQ ID NO:30的DNA序列是:
对应于SEQ ID NO:31的单字母氨基酸序列是:
对应于SEQ ID NO:32的DNA序列是:
对应于SEQ ID NO:33的单字母氨基酸序列是:
对应于SEQ ID NO:34的DNA序列是:
对应于SEQ ID NO:35的单字母氨基酸序列是:
对应于SEQ ID NO:36的DNA序列是:
对应于SEQ ID NO:37的单字母氨基酸序列是:
对应于SEQ ID NO:38的DNA序列是:
对应于SEQ ID NO:39的单字母氨基酸序列是:
对应于SEQ ID NO:40的DNA序列是:
实施例
实施例1:测试抗体的亲和力和动力学
使用Na,Na-双(羧甲基)-L-赖氨酸三氟乙酸盐(Sigma-Aldrich,St.Louis,MO)作为用于经AGE修饰的蛋白的模型底物来分析测试抗体的亲和力和动力学。使用S系列传感器芯片CM5(GE Healthcare,Pittsburgh,PA),在BIACORETM T200(GE Healthcare,Pittsburgh,PA)上进行无标记的相互作用分析,,其中Fc1设置为空白,并将Fc2用测试抗体(分子量150,000Da)固定。运行缓冲液为在25℃的温度下的HBS-EP缓冲剂(10mM HEPES、150mM NaCl、3mM EDTA和0.05%P-20,pH 7.4)。软件是BIACORETM T200评估软件2.0版。在分析中使用双重对照(Fc2-1和仅注射缓冲剂),并将数据拟合至Langmuir 1:1结合模型。
表1:亲和力和动力学分析的实验设置
应答相对于时间的图表在图1中示出。从分析确定以下值:ka(1/Ms)=1.857×103;kd(1/s)=6.781×10-3;KD(M)=3.651×10-6;Rmax(RU)=19.52;并且Chi2=0.114。由于拟合的Chi2值小于Rmax的10%,因此拟合是可靠的。
实施例2:鼠抗AGE IgG2b抗体和嵌合抗AGE IgG1抗体的构建和生产
对鼠抗AGE抗体和嵌合人抗AGE抗体进行制备。鼠抗AGE抗体IgG2b重链的DNA序列在SEQ ID NO:12中示出。嵌合人抗AGE抗体IgG1重链的DNA序列在SEQ ID NO:13中示出。鼠抗AGE抗体κ轻链的DNA序列在SEQ ID NO:14中示出。嵌合人抗AGE抗体κ轻链的DNA序列在SEQ ID NO:15中示出。合成基因序列并将其克隆到高表达哺乳动物载体中。对序列进行密码子优化。在进行转染之前,对完成的构建体进行序列确认。
在转染前一天将HEK293细胞接种在摇瓶中,并使用无血清的化学成分确定的培养基使其生长。将DNA表达构建体瞬时转染至0.03升悬浮HEK293细胞中。20小时后,对细胞进行取样以获得存活力和活细胞计数,并对滴度进行测量(Octet QKe,ForteBio)。在整个瞬时转染生产运行中取得其它读数。在第5天收获培养物,并就细胞密度、存活力和滴度对各自的其它样品进行测量。
通过离心和过滤从瞬时转染生产运行中收获并澄清鼠抗AGE抗体和嵌合抗AGE抗体的条件培养基。将上清液在蛋白A柱上运行并用低pH缓冲剂洗脱。在进行等分之前使用0.2μm膜过滤器进行过滤。纯化和过滤后,根据OD280和消光系数计算蛋白质浓度。产量和等分部分的总结在表2中示出:
表2:产量和等分部分
蛋白质 | 浓度(mg/mL) | 体积(mL) | 小瓶的数量 | 总产量(mg) |
鼠抗-AGE | 0.08 | 1.00 | 3 | 0.24 |
嵌合抗-AGE | 0.23 | 1.00 | 3 | 0.69 |
进行CE-SDS分析(LabChip GXII,PerkinElmer)并绘制电泳图。
实施例3:鼠(亲本)抗AGE抗体和嵌合抗AGE抗体的结合
通过直接结合ELISA对实施例2中描述的鼠(亲本)抗AGE抗体和嵌合抗AGE抗体的结合进行研究。使用抗羧甲基赖氨酸(CML)抗体(R&D Systems,MAB3247)作为对照。将CML缀合至KLH(CML-KLH),并将CML和CML-KLH两者过夜包被至ELISA板上。使用HRP-山羊抗小鼠Fc来检测对照和鼠(亲本)抗AGE抗体。使用HRP-山羊抗人Fc来检测嵌合抗AGE抗体。
在pH 6.5的1×磷酸盐缓冲剂中将抗原稀释至1μg/mL。用100μL/孔的经稀释的抗原包被96孔微量滴定ELISA板,并使其在4℃下静置过夜。用1×PBS、2.5%BSA封闭板,并在第二天早上在室温下放置1-2小时。以50μg/mL的起始浓度用1×PBS、1%BSA连续稀释来制备抗体样品。以1:5,000稀释二抗。将100μL抗体稀释液施加至每个孔。在微板振荡器上将板在室温下孵育0.5-1小时。将板用1×PBS洗涤3次。将100μL/孔的经稀释的HRP缀合的山羊抗人Fc二抗施加至孔中。将板在微板振荡器上孵育1小时。然后将板用1×PBS洗涤3次。向每孔中加入100μL HRP底物TMB以使板显影。在3-5分钟过后,通过加入100μL的1N HCl终止反应。以仅用CML包被进行另一直接结合ELISA。使用酶标仪读取OD450处的吸光度。
CML ELISA和CML-KLH ELISA的OD450吸光度原始数据在以下板图中示出。使用了孔板中的96个孔中的48个。板图中的空白孔表示未使用的孔。
CML ELISA和CML-KLH ELISA的板图:
仅CML ELISA的OD450吸光度原始数据在以下板图中示出。使用了孔板中的96个孔中的24个。板图中的空白孔表示未使用的孔。
仅CML ELISA的板图:
也针对抗体浓度对OD450吸光度数据进行了绘制。
对照和嵌合抗AGE抗体显示结合至CML和CML-KLH两者。鼠(亲本)抗AGE抗体显示与CML或CML-KLH的结合非常弱至不结合。重复ELISA的数据证实了对照和嵌合抗AGE与CML的结合。所有缓冲剂对照均显示阴性信号。
实施例4:人源化抗体
通过生成多个杂交序列来设计人源化抗体,所述杂交序列将亲本(小鼠)抗体序列的选定部分与人框架序列融合。受体框架基于整个框架中的总体序列同一性、匹配界面位置、类似分类的CDR规范位置以及必须除去的N-糖基化位点的存在来进行鉴定。基于两种不同的重链和轻链人受体框架设计了三条人源化轻链和三条人源化重链。重链的氨基酸序列在SEQ ID NO:29、SEQ ID NO:31和SEQ ID NO:33中示出,分别由SEQ ID NO:30、SEQ ID NO:32和SEQ ID NO:34中所示的DNA序列编码。轻链的氨基酸序列在SEQ ID NO:35、SEQ ID NO:37和SEQ ID NO:39中示出,分别由SEQ ID NO:36、SEQ ID NO:38和SEQ ID NO:40中所示的DNA序列编码。通过肉眼和计算机建模对人源化序列进行系统地分析,以分离最有可能保留抗原结合的序列。目标是使最终人源化抗体中人序列的量最大化,同时保留原始抗体的特异性。可对轻和重人源化链进行组合,以产生九种不同的完全人源化抗体。
对三条重链和三条轻链进行分析以确定它们的人性(humanness)。根据Gao,S.H.等,“Monoclonal antibody humanness score and its applications”,BMCBiotechnology,13:55(2013年7月5日)中所描述的方法来计算抗体人性得分。人性得分表示抗体可变区序列看起来的人样。对于重链,79或更高的得分表示看起来人样;对于轻链,86或更高的得分表示看起来人样。三条重链、三条轻链、亲本(小鼠)重链和亲本(小鼠)轻链的人性在下表3中示出:
表3:抗体人性
通过首先合成可变区序列来构建全长抗体基因。对序列进行优化以用于在哺乳动物细胞中表达。然后,将这些可变区序列克隆到已含有人Fc结构域的表达载体中;对于重链,使用IgG1。
使用不存在血清的化学成分确定的培养基,通过将重链和轻链的质粒转染到悬浮HEK293细胞中,来进行人源化抗体的小批量生产。使用MabSelect SuRe蛋白A培养基(GEHealthcare)纯化条件培养基中的完整抗体。
由具有SEQ ID NO:29、SEQ ID NO:31和SEQ ID NO:33中所示的氨基酸序列的三条重链和具有SEQ ID NO:35、SEQ ID NO:37和SEQ ID NO:39中所示的氨基酸序列的三条轻链各自组合产生了九种人源化抗体。还制备了比较嵌合亲本抗体。抗体和它们各自的滴度在下表4中示出:
表4:抗体及它们各自的滴度
抗体 | 滴度(mg/L) |
嵌合亲本 | 23.00 |
SEQ ID NO:29+SEQ ID NO:35 | 24.67 |
SEQ ID NO:29+SEQ ID NO:37 | 41.67 |
SEQ ID NO:29+SEQ ID NO:39 | 29.67 |
SEQ ID NO:31+SEQ ID NO:35 | 26.00 |
SEQ ID NO:31+SEQ ID NO:37 | 27.33 |
SEQ ID NO:31+SEQ ID NO:39 | 35.33 |
SEQ ID NO:33+SEQ lD NO:35 | 44.00 |
SEQ ID NO:33+SEQ ID NO:37 | 30.33 |
SEQ ID NO:33+SEQ ID NO:39 | 37.33 |
可对人源化抗体的结合进行评估,例如,通过剂量依赖性结合ELISA或基于细胞的结合分析。
实施例5:免疫组织学研究
组织样品获得自患有阿尔兹海默病和帕金森氏病的患者。两个阿尔兹海默病样品取自海马体。一个帕金森氏病样品取自黑质,而另一帕金森氏病样品取自腹侧被盖区。使用如上所述的抗AGE抗体针对羧甲基赖氨酸(CML)对所有细胞进行染色。针对磷酸化tau(磷酸tau)或单独地针对淀粉样前体蛋白,对阿尔兹海默病细胞进行染色。针对α突触核蛋白,对帕金森氏病细胞进行染色。使用DAPI复染色剂对细胞的核染色进行鉴定。(由亚利桑那州立大学的Diego Mastroeni博士进行实验并准备图像。)
图2A为阿尔兹海默病样品的细胞的照片,显示出被染成红色的羧甲基赖氨酸和被染成绿色的磷酸化tau。
图2B为阿尔兹海默病样品的细胞的照片,显示出被染成红色的羧甲基赖氨酸和被染成绿色的淀粉样前体蛋白。
图2C为来自黑质的帕金森氏病样品的细胞的照片,显示出被染成红色的羧甲基赖氨酸和被染成绿色的α突触核蛋白。
图2D为来自腹侧被盖区的帕金森氏病样品的细胞的照片,显示出被染成红色的羧甲基赖氨酸和被染成绿色的α突触核蛋白。
CML(公知的AGE)没有与阿尔兹海默病和帕金森氏病中的确定病变共定位。相反,CML出现在胶质细胞上。怀疑阿尔兹海默病样品中CML免疫反应性与小胶质细胞有关,而帕金森氏病样品中CML免疫反应性与星形胶质细胞有关。结果表明在阿尔兹海默病和帕金森氏病中存在衰老胶质细胞。预期使用抗AGE抗体移除衰老胶质细胞将会引起由神经干细胞/祖细胞再生胶质细胞。(参见,例如,Leonard,BW等,“Subventricular zone neuralprogenitors from rapid brain autopsies of elderly subjects with and withoutneurodegenerative disease”,The Journal of Comparative Neurology,Vol.515,pp.269-294(2009))。
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序列表
<110> Lewis S. Gruber
<120> 用于治疗神经退行性紊乱的抗AGE抗体
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<210> 1
<211> 463
<212> PRT
<213> 人工序列
<220>
<223> 经修饰的智人免疫球蛋白G1重链
<400> 1
Met Asn Leu Leu Leu Ile Leu Thr Phe Val Ala Ala Ala Val Ala Gln
1 5 10 15
Val Gln Leu Leu Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser
20 25 30
Val Lys Leu Ala Cys Lys Ala Ser Gly Tyr Leu Phe Thr Thr Tyr Trp
35 40 45
Met His Trp Leu Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
50 55 60
Glu Ile Ser Pro Thr Asn Gly Arg Ala Tyr Tyr Asn Ala Arg Phe Lys
65 70 75 80
Ser Glu Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr Met
85 90 95
Gln Leu Ser Ser Leu Thr Ser Glu Ala Ser Ala Val Tyr Tyr Cys Ala
100 105 110
Arg Ala Tyr Gly Asn Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu
115 120 125
Val Thr Val Ser Val Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
130 135 140
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
145 150 155 160
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
165 170 175
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
180 185 190
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
195 200 205
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
210 215 220
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
225 230 235 240
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
245 250 255
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
290 295 300
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
305 310 315 320
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
325 330 335
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
340 345 350
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
355 360 365
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
370 375 380
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
385 390 395 400
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
405 410 415
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
420 425 430
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
435 440 445
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 2
<211> 118
<212> PRT
<213> 家鼠(Mus musculus)
<400> 2
Gln Val Gln Leu Leu Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ala Cys Lys Ala Ser Gly Tyr Leu Phe Thr Thr Tyr
20 25 30
Trp Met His Trp Leu Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Ser Pro Thr Asn Gly Arg Ala Tyr Tyr Asn Ala Arg Phe
50 55 60
Lys Ser Glu Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Ala Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Tyr Gly Asn Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Val
115
<210> 3
<211> 234
<212> PRT
<213> 人工序列
<220>
<223> 经修饰的智人免疫球蛋白G1 κ轻链
<400> 3
Met Asn Leu Leu Leu Ile Leu Thr Phe Val Ala Ala Ala Val Ala Asp
1 5 10 15
Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp
20 25 30
Gln Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser Leu Val Asn Ser Asn
35 40 45
Gly Asn Thr Phe Leu Gln Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro
50 55 60
Lys Leu Leu Ile Tyr Lys Val Ser Leu Arg Phe Ser Gly Val Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser
85 90 95
Arg Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser Gln Ser Thr
100 105 110
His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 4
<211> 113
<212> PRT
<213> 家鼠(Mus musculus)
<400> 4
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser Leu Val Asn Ser
20 25 30
Asn Gly Asn Thr Phe Leu Gln Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Leu Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg
<210> 5
<211> 327
<212> PRT
<213> 家马(Equus caballus)
<400> 5
Ala Ser Thr Thr Ala Pro Lys Val Phe Pro Leu Ala Ser His Ser Ala
1 5 10 15
Ala Thr Ser Gly Ser Thr Val Ala Leu Gly Cys Leu Val Ser Ser Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ser Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Met Val Thr Val Pro Ala Ser Ser Leu Lys Ser Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys
85 90 95
Lys Ile Val Ile Lys Glu Cys Asn Gly Gly Cys Pro Ala Glu Cys Leu
100 105 110
Gln Val Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val
115 120 125
Leu Met Ile Ser Arg Thr Pro Thr Val Thr Cys Val Val Val Asp Val
130 135 140
Gly His Asp Phe Pro Asp Val Gln Phe Asn Trp Tyr Val Asp Gly Val
145 150 155 160
Glu Thr His Thr Ala Thr Thr Glu Pro Lys Gln Glu Gln Phe Asn Ser
165 170 175
Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gln His Lys Asp Trp Leu
180 185 190
Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Ala Leu Pro Ala
195 200 205
Pro Val Glu Arg Thr Ile Ser Lys Pro Thr Gly Gln Pro Arg Glu Pro
210 215 220
Gln Val Tyr Val Leu Ala Pro His Arg Asp Glu Leu Ser Lys Asn Lys
225 230 235 240
Val Ser Val Thr Cys Leu Val Lys Asp Phe Tyr Pro Thr Asp Ile Asp
245 250 255
Ile Glu Trp Lys Ser Asn Gly Gln Pro Glu Pro Glu Thr Lys Tyr Ser
260 265 270
Thr Thr Pro Ala Gln Leu Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Glu Thr Asn Arg Trp Gln Gln Gly Thr Thr Phe Thr
290 295 300
Cys Ala Val Met His Glu Ala Leu His Asn His Tyr Thr Glu Lys Ser
305 310 315 320
Val Ser Lys Ser Pro Gly Lys
325
<210> 6
<211> 415
<212> PRT
<213> 家马(Equus caballus)
<400> 6
Ser Leu Glu Asp Thr Ala Val Ile Pro Leu Phe Ser Glu Cys Lys Ala
1 5 10 15
Pro Lys Glu Asp Asp Val Val Ser Leu Ala Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Pro Val Gln Val Thr Trp Glu Pro Glu Met Gln Asn Gln
35 40 45
Lys Pro Trp Thr Phe Pro Ala Met Lys Lys Gly Gln Glu Tyr Ile His
50 55 60
Val Phe Ser Leu Thr Thr Trp Trp Lys Pro Gly Ser His Ser Cys Thr
65 70 75 80
Val His His Lys Ala Ser Ser Phe Arg Lys Lys Met Thr Phe Gln Glu
85 90 95
Pro Ala Ser Trp Ala Pro Gln Arg Thr Ser Ala Leu Pro Val Thr Ser
100 105 110
Lys Glu Pro Thr Pro Ala Pro Thr Thr Leu Arg Lys Ser Glu Pro Ser
115 120 125
Thr Arg His Thr Gln Pro Glu Thr Gln Lys Pro Arg Ile Pro Val Asp
130 135 140
Thr Pro Leu Lys Glu Cys Gln Ser His Thr His Pro Pro Ser Ile Tyr
145 150 155 160
Leu Leu His Pro Pro Leu Gln Gly Leu Trp Leu Lys Gly Glu Ala Thr
165 170 175
Phe Thr Cys Leu Val Val Gly Asp Asp Leu Lys Asp Ala His Leu Ser
180 185 190
Trp Glu Leu Ser Glu Arg Ser Asn Gly Met Phe Val Glu Ser Gly Pro
195 200 205
Leu Glu Lys His Thr Asn Gly Ser Gln Ser Arg Ser Ser Arg Leu Ala
210 215 220
Leu Pro Arg Ser Ser Trp Ala Met Gly Thr Ser Val Thr Cys Lys Leu
225 230 235 240
Ser Tyr Pro Asn Leu Leu Ser Ser Met Glu Val Val Gly Leu Lys Glu
245 250 255
His Ala Ala Ser Ala Pro Arg Ser Leu Thr Val His Ala Leu Thr Thr
260 265 270
Pro Gly Leu Asn Ala Ser Pro Gly Ala Thr Ser Trp Leu Gln Cys Lys
275 280 285
Val Ser Gly Phe Ser Pro Pro Glu Ile Val Leu Thr Trp Leu Glu Gly
290 295 300
Gln Arg Glu Val Asp Pro Ser Trp Phe Ala Thr Ala Arg Pro Thr Ala
305 310 315 320
Gln Pro Gly Asn Thr Thr Phe Gln Thr Trp Ser Ile Leu Leu Val Pro
325 330 335
Thr Ile Pro Gly Pro Pro Thr Ala Thr Tyr Thr Cys Val Val Gly His
340 345 350
Glu Ala Ser Arg Gln Leu Leu Asn Thr Ser Trp Ser Leu Asp Thr Gly
355 360 365
Gly Leu Ala Met Thr Pro Glu Ser Lys Asp Glu Asn Ser Asp Asp Tyr
370 375 380
Ala Asp Leu Asp Asp Ala Gly Ser Leu Trp Leu Thr Phe Met Ala Leu
385 390 395 400
Phe Leu Ile Thr Leu Leu Tyr Ser Gly Phe Val Thr Phe Ile Lys
405 410 415
<210> 7
<211> 334
<212> PRT
<213> 家犬(Canis familiaris )
<400> 7
Ser Lys Thr Ser Pro Ser Val Phe Pro Leu Ser Leu Cys His Gln Glu
1 5 10 15
Ser Glu Gly Tyr Val Val Ile Gly Cys Leu Val Gln Gly Phe Phe Pro
20 25 30
Pro Glu Pro Val Asn Val Thr Trp Asn Ala Gly Lys Asp Ser Thr Ser
35 40 45
Val Lys Asn Phe Pro Pro Met Lys Ala Ala Thr Gly Ser Leu Tyr Thr
50 55 60
Met Ser Ser Gln Leu Thr Leu Pro Ala Ala Gln Cys Pro Asp Asp Ser
65 70 75 80
Ser Val Lys Cys Gln Val Gln His Ala Ser Ser Pro Ser Lys Ala Val
85 90 95
Ser Val Pro Cys Lys Asp Asn Ser His Pro Cys His Pro Cys Pro Ser
100 105 110
Cys Asn Glu Pro Arg Leu Ser Leu Gln Lys Pro Ala Leu Glu Asp Leu
115 120 125
Leu Leu Gly Ser Asn Ala Ser Leu Thr Cys Thr Leu Ser Gly Leu Lys
130 135 140
Asp Pro Lys Gly Ala Thr Phe Thr Trp Asn Pro Ser Lys Gly Lys Glu
145 150 155 160
Pro Ile Gln Lys Asn Pro Glu Arg Asp Ser Cys Gly Cys Tyr Ser Val
165 170 175
Ser Ser Val Leu Pro Gly Cys Ala Asp Pro Trp Asn His Gly Asp Thr
180 185 190
Phe Ser Cys Thr Ala Thr His Pro Glu Ser Lys Ser Pro Ile Thr Val
195 200 205
Ser Ile Thr Lys Thr Thr Glu His Ile Pro Pro Gln Val His Leu Leu
210 215 220
Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu Leu Val Thr Leu Thr
225 230 235 240
Cys Leu Val Arg Gly Phe Lys Pro Lys Asp Val Leu Val Arg Trp Leu
245 250 255
Gln Gly Thr Gln Glu Leu Pro Gln Glu Lys Tyr Leu Thr Trp Glu Pro
260 265 270
Leu Lys Glu Pro Asp Gln Thr Asn Met Phe Ala Val Thr Ser Met Leu
275 280 285
Arg Val Thr Ala Glu Asp Trp Lys Gln Gly Glu Lys Phe Ser Cys Met
290 295 300
Val Gly His Glu Ala Leu Pro Met Ser Phe Thr Gln Lys Thr Ile Asp
305 310 315 320
Arg Leu Ala Gly Lys Pro Thr His Val Asn Val Ser Val Val
325 330
<210> 8
<211> 426
<212> PRT
<213> 家犬(Canis familiaris)
<400> 8
Thr Ser Gln Asp Leu Ser Val Phe Pro Leu Ala Ser Cys Cys Lys Asp
1 5 10 15
Asn Ile Ala Ser Thr Ser Val Thr Leu Gly Cys Leu Val Thr Gly Tyr
20 25 30
Leu Pro Met Ser Thr Thr Val Thr Trp Asp Thr Gly Ser Leu Asn Lys
35 40 45
Asn Val Thr Thr Phe Pro Thr Thr Phe His Glu Thr Tyr Gly Leu His
50 55 60
Ser Ile Val Ser Gln Val Thr Ala Ser Gly Lys Trp Ala Lys Gln Arg
65 70 75 80
Phe Thr Cys Ser Val Ala His Ala Glu Ser Thr Ala Ile Asn Lys Thr
85 90 95
Phe Ser Ala Cys Ala Leu Asn Phe Ile Pro Pro Thr Val Lys Leu Phe
100 105 110
His Ser Ser Cys Asn Pro Val Gly Asp Thr His Thr Thr Ile Gln Leu
115 120 125
Leu Cys Leu Ile Ser Gly Tyr Val Pro Gly Asp Met Glu Val Ile Trp
130 135 140
Leu Val Asp Gly Gln Lys Ala Thr Asn Ile Phe Pro Tyr Thr Ala Pro
145 150 155 160
Gly Thr Lys Glu Gly Asn Val Thr Ser Thr His Ser Glu Leu Asn Ile
165 170 175
Thr Gln Gly Glu Trp Val Ser Gln Lys Thr Tyr Thr Cys Gln Val Thr
180 185 190
Tyr Gln Gly Phe Thr Phe Lys Asp Glu Ala Arg Lys Cys Ser Glu Ser
195 200 205
Asp Pro Arg Gly Val Thr Ser Tyr Leu Ser Pro Pro Ser Pro Leu Asp
210 215 220
Leu Tyr Val His Lys Ala Pro Lys Ile Thr Cys Leu Val Val Asp Leu
225 230 235 240
Ala Thr Met Glu Gly Met Asn Leu Thr Trp Tyr Arg Glu Ser Lys Glu
245 250 255
Pro Val Asn Pro Gly Pro Leu Asn Lys Lys Asp His Phe Asn Gly Thr
260 265 270
Ile Thr Val Thr Ser Thr Leu Pro Val Asn Thr Asn Asp Trp Ile Glu
275 280 285
Gly Glu Thr Tyr Tyr Cys Arg Val Thr His Pro His Leu Pro Lys Asp
290 295 300
Ile Val Arg Ser Ile Ala Lys Ala Pro Gly Lys Arg Ala Pro Pro Asp
305 310 315 320
Val Tyr Leu Phe Leu Pro Pro Glu Glu Glu Gln Gly Thr Lys Asp Arg
325 330 335
Val Thr Leu Thr Cys Leu Ile Gln Asn Phe Phe Pro Ala Asp Ile Ser
340 345 350
Val Gln Trp Leu Arg Asn Asp Ser Pro Ile Gln Thr Asp Gln Tyr Thr
355 360 365
Thr Thr Gly Pro His Lys Val Ser Gly Ser Arg Pro Ala Phe Phe Ile
370 375 380
Phe Ser Arg Leu Glu Val Ser Arg Val Asp Trp Glu Gln Lys Asn Lys
385 390 395 400
Phe Thr Cys Gln Val Val His Glu Ala Leu Ser Gly Ser Arg Ile Leu
405 410 415
Gln Lys Trp Val Ser Lys Thr Pro Gly Lys
420 425
<210> 9
<211> 335
<212> PRT
<213> 家猫(Felis catus)
<400> 9
Ala Ser Thr Thr Ala Ser Ser Val Phe Pro Leu Ala Pro Ser Cys Gly
1 5 10 15
Thr Thr Ser Gly Ala Thr Val Ala Leu Ala Cys Leu Val Leu Gly Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ser Val Leu Gln Ala Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Met Val Thr Val Pro Ser Ser Arg Trp Leu Ser Asp Thr
65 70 75 80
Phe Thr Cys Asn Val Ala His Arg Pro Ser Ser Thr Lys Val Asp Lys
85 90 95
Thr Val Pro Lys Thr Ala Ser Thr Ile Glu Ser Lys Thr Gly Glu Gly
100 105 110
Pro Lys Cys Pro Val Pro Glu Ile Pro Gly Ala Pro Ser Val Phe Ile
115 120 125
Phe Pro Pro Lys Pro Lys Asp Thr Leu Ser Ile Ser Arg Thr Pro Glu
130 135 140
Val Thr Cys Leu Val Val Asp Leu Gly Pro Asp Asp Ser Asn Val Gln
145 150 155 160
Ile Thr Trp Phe Val Asp Asn Thr Glu Met His Thr Ala Lys Thr Arg
165 170 175
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
180 185 190
Pro Ile Leu His Gln Asp Trp Leu Lys Gly Lys Glu Phe Lys Cys Lys
195 200 205
Val Asn Ser Lys Ser Leu Pro Ser Ala Met Glu Arg Thr Ile Ser Lys
210 215 220
Ala Lys Gly Gln Pro His Glu Pro Gln Val Tyr Val Leu Pro Pro Thr
225 230 235 240
Gln Glu Glu Leu Ser Glu Asn Lys Val Ser Val Thr Cys Leu Ile Lys
245 250 255
Gly Phe His Pro Pro Asp Ile Ala Val Glu Trp Glu Ile Thr Gly Gln
260 265 270
Pro Glu Pro Glu Asn Asn Tyr Gln Thr Thr Pro Pro Gln Leu Asp Ser
275 280 285
Asp Gly Thr Tyr Phe Leu Tyr Ser Arg Leu Ser Val Asp Arg Ser His
290 295 300
Trp Gln Arg Gly Asn Thr Tyr Thr Cys Ser Val Ser His Glu Ala Leu
305 310 315 320
His Ser His His Thr Gln Lys Ser Leu Thr Gln Ser Pro Gly Lys
325 330 335
<210> 10
<211> 96
<212> PRT
<213> 单峰驼(Camelus dromedarius)
<400> 10
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Arg Glu Arg Glu Gly Val
35 40 45
Ala Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
<210> 11
<211> 96
<212> PRT
<213> 单峰驼(Camelus dromedarius)
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Met Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
<210> 12
<211> 1434
<212> DNA
<213> 人工序列
<220>
<223> 鼠抗AGE IgG2b重链
<400> 12
atggacccca agggcagcct gagctggaga atcctgctgt tcctgagcct ggccttcgag 60
ctgagctacg gccaggtgca gctgctgcag ccaggtgccg agctcgtgaa acctggcgcc 120
tctgtgaagc tggcctgcaa ggcttccggc tacctgttca ccacctactg gatgcactgg 180
ctgaagcaga ggccaggcca gggcctggaa tggatcggcg agatctcccc caccaacggc 240
agagcctact acaacgcccg gttcaagtcc gaggccaccc tgaccgtgga caagtcctcc 300
aacaccgcct acatgcagct gtcctccctg acctctgagg cctccgccgt gtactactgc 360
gccagagctt acggcaacta cgagttcgcc tactggggcc agggcaccct cgtgacagtg 420
tctgtggcta agaccacccc tccctccgtg taccctctgg ctcctggctg tggcgacacc 480
accggatcct ctgtgaccct gggctgcctc gtgaagggct acttccctga gtccgtgacc 540
gtgacctgga actccggctc cctgtcctcc tccgtgcaca cctttccagc cctgctgcag 600
tccggcctgt acaccatgtc ctccagcgtg acagtgccct cctccacctg gccttcccag 660
accgtgacat gctctgtggc ccaccctgcc tcttccacca ccgtggacaa gaagctggaa 720
ccctccggcc ccatctccac catcaaccct tgccctccct gcaaagaatg ccacaagtgc 780
cctgccccca acctggaagg cggcccttcc gtgttcatct tcccacccaa catcaaggac 840
gtgctgatga tctccctgac ccccaaagtg acctgcgtgg tggtggacgt gtccgaggac 900
gaccctgacg tgcagatcag ttggttcgtg aacaacgtgg aagtgcacac cgcccagacc 960
cagacacaca gagaggacta caacagcacc atcagagtgg tgtctaccct gcccatccag 1020
caccaggact ggatgtccgg caaagaattc aagtgcaaag tgaacaacaa ggacctgccc 1080
agccccatcg agcggaccat ctccaagatc aagggcctcg tgcgggctcc ccaggtgtac 1140
attctgcctc caccagccga gcagctgtcc cggaaggatg tgtctctgac atgtctggtc 1200
gtgggcttca accccggcga catctccgtg gaatggacct ccaacggcca caccgaggaa 1260
aactacaagg acaccgcccc tgtgctggac tccgacggct cctacttcat ctactccaag 1320
ctgaacatga agacctccaa gtgggaaaag accgactcct tctcctgcaa cgtgcggcac 1380
gagggcctga agaactacta cctgaagaaa accatctccc ggtcccccgg ctag 1434
<210> 13
<211> 1416
<212> DNA
<213> 人工序列
<220>
<223> 嵌合抗AGE人IgG1抗体重链
<400> 13
atggacccca agggcagcct gagctggaga atcctgctgt tcctgagcct ggccttcgag 60
ctgagctacg gccaggtgca gctgctgcag ccaggtgccg agctcgtgaa acctggcgcc 120
tctgtgaagc tggcctgcaa ggcttccggc tacctgttca ccacctactg gatgcactgg 180
ctgaagcaga ggccaggcca gggcctggaa tggatcggcg agatctcccc caccaacggc 240
agagcctact acaacgcccg gttcaagtcc gaggccaccc tgaccgtgga caagtcctcc 300
aacaccgcct acatgcagct gtcctccctg acctctgagg cctccgccgt gtactactgc 360
gccagagctt acggcaacta cgagttcgcc tactggggcc agggcaccct cgtgacagtg 420
tctgtggcta gcaccaaggg ccccagcgtg ttccctctgg cccccagcag caagagcacc 480
agcggcggaa ccgccgccct gggctgcctg gtgaaggact acttccccga gcccgtgacc 540
gtgtcctgga acagcggcgc tctgaccagc ggagtgcaca ccttccctgc cgtgctgcag 600
agcagcggcc tgtactccct gagcagcgtg gtgaccgtgc ccagcagcag cctgggcacc 660
cagacctaca tctgcaacgt gaaccacaag ccctccaaca ccaaggtgga caagaaggtg 720
gagcctaaga gctgcgacaa gacccacacc tgccctccct gccccgcccc cgagctgctg 780
ggcggaccca gcgtgttcct gttccctccc aagcccaagg acaccctgat gatcagccgc 840
acccccgagg tgacctgcgt ggtggtggac gtgagccacg aggaccccga ggtgaagttc 900
aactggtacg tggacggcgt ggaggtgcac aacgccaaga ccaagcctcg ggaggagcag 960
tacaactcca cctaccgcgt ggtgagcgtg ctgaccgtgc tgcaccagga ctggctgaac 1020
ggcaaggagt acaagtgcaa ggtgagcaac aaggccctgc ccgctcccat cgagaagacc 1080
atcagcaagg ccaagggcca gccccgggag cctcaggtgt acaccctgcc ccccagccgc 1140
gacgagctga ccaagaacca ggtgagcctg acctgcctgg tgaagggctt ctacccctcc 1200
gacatcgccg tggagtggga gagcaacggc cagcctgaga acaactacaa gaccacccct 1260
cccgtgctgg acagcgacgg cagcttcttc ctgtacagca agctgaccgt ggacaagtcc 1320
cggtggcagc agggcaacgt gttcagctgc agcgtgatgc acgaggccct gcacaaccac 1380
tacacccaga agagcctgag cctgagcccc ggatag 1416
<210> 14
<211> 720
<212> DNA
<213> 人工序列
<220>
<223> 鼠抗-AGE κ轻链
<400> 14
atggagaccg acaccctgct gctctgggtg ctgctgctct gggtgcccgg ctccaccgga 60
gacgtcgtga tgacccagac ccctctgtcc ctgcctgtgt ctctgggcga ccaggcctcc 120
atctcctgcc ggtctagaca gtccctcgtg aactccaacg gcaacacctt cctgcagtgg 180
tatctgcaga agcccggcca gtcccccaag ctgctgatct acaaggtgtc cctgcggttc 240
tccggcgtgc ccgacagatt ttccggctct ggctctggca ccgacttcac cctgaagatc 300
tcccgggtgg aagccgagga cctgggcctg tacttctgca gccagtccac ccacgtgccc 360
cctacatttg gcggaggcac caagctggaa atcaaacggg cagatgctgc 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 tgagtgttga 720
<210> 15
<211> 720
<212> DNA
<213> 人工序列
<220>
<223> 嵌合抗-AGE人κ轻链
<400> 15
atggagaccg acaccctgct gctctgggtg ctgctgctct gggtgcccgg ctccaccgga 60
gacgtcgtga tgacccagac ccctctgtcc ctgcctgtgt ctctgggcga ccaggcctcc 120
atctcctgcc ggtctagaca gtccctcgtg aactccaacg gcaacacctt cctgcagtgg 180
tatctgcaga agcccggcca gtcccccaag ctgctgatct acaaggtgtc cctgcggttc 240
tccggcgtgc ccgacagatt ttccggctct ggctctggca ccgacttcac cctgaagatc 300
tcccgggtgg aagccgagga cctgggcctg tacttctgca gccagtccac ccacgtgccc 360
cctacatttg gcggaggcac caagctggaa atcaagcgga ccgtggccgc ccccagcgtg 420
ttcatcttcc ctcccagcga cgagcagctg aagtctggca ccgccagcgt ggtgtgcctg 480
ctgaacaact tctacccccg cgaggccaag gtgcagtgga aggtggacaa cgccctgcag 540
agcggcaaca gccaggagag cgtgaccgag caggactcca aggacagcac ctacagcctg 600
agcagcaccc tgaccctgag caaggccgac tacgagaagc acaaggtgta cgcctgcgag 660
gtgacccacc agggactgtc tagccccgtg accaagagct tcaaccgggg cgagtgctaa 720
<210> 16
<211> 477
<212> PRT
<213> 人工序列
<220>
<223> 鼠抗-AGE IgG2b重链
<400> 16
Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser
1 5 10 15
Leu Ala Phe Glu Leu Ser Tyr Gly Gln Val Gln Leu Leu Gln Pro Gly
20 25 30
Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ala Cys Lys Ala
35 40 45
Ser Gly Tyr Leu Phe Thr Thr Tyr Trp Met His Trp Leu Lys Gln Arg
50 55 60
Pro Gly Gln Gly Leu Glu Trp Ile Gly Glu Ile Ser Pro Thr Asn Gly
65 70 75 80
Arg Ala Tyr Tyr Asn Ala Arg Phe Lys Ser Glu Ala Thr Leu Thr Val
85 90 95
Asp Lys Ser Ser Asn Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser
100 105 110
Glu Ala Ser Ala Val Tyr Tyr Cys Ala Arg Ala Tyr Gly Asn Tyr Glu
115 120 125
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Val Ala Lys
130 135 140
Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly 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 Ser Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Ser Val
180 185 190
His Thr Phe Pro Ala Leu Leu Gln Ser Gly Leu Tyr Thr Met Ser Ser
195 200 205
Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys
210 215 220
Ser Val Ala His Pro Ala Ser Ser Thr Thr Val Asp Lys Lys Leu Glu
225 230 235 240
Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Cys Pro Pro Cys Lys Glu
245 250 255
Cys His Lys Cys Pro Ala Pro Asn Leu Glu Gly Gly Pro Ser Val Phe
260 265 270
Ile Phe Pro Pro Asn Ile Lys Asp Val Leu Met Ile Ser Leu Thr Pro
275 280 285
Lys Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val
290 295 300
Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr
305 310 315 320
Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Ile Arg Val Val Ser Thr
325 330 335
Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys
340 345 350
Lys Val Asn Asn Lys Asp Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser
355 360 365
Lys Ile Lys Gly Leu Val Arg Ala Pro Gln Val Tyr Ile Leu Pro Pro
370 375 380
Pro Ala Glu Gln Leu Ser Arg Lys Asp Val Ser Leu Thr Cys Leu Val
385 390 395 400
Val Gly Phe Asn Pro Gly Asp Ile Ser Val Glu Trp Thr Ser Asn Gly
405 410 415
His Thr Glu Glu Asn Tyr Lys Asp Thr Ala Pro Val Leu Asp Ser Asp
420 425 430
Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Met Lys Thr Ser Lys Trp
435 440 445
Glu Lys Thr Asp Ser Phe Ser Cys Asn Val Arg His Glu Gly Leu Lys
450 455 460
Asn Tyr Tyr Leu Lys Lys Thr Ile Ser Arg Ser Pro Gly
465 470 475
<210> 17
<211> 471
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗-AGE人IgG1重链
<400> 17
Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser
1 5 10 15
Leu Ala Phe Glu Leu Ser Tyr Gly Gln Val Gln Leu Leu Gln Pro Gly
20 25 30
Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ala Cys Lys Ala
35 40 45
Ser Gly Tyr Leu Phe Thr Thr Tyr Trp Met His Trp Leu Lys Gln Arg
50 55 60
Pro Gly Gln Gly Leu Glu Trp Ile Gly Glu Ile Ser Pro Thr Asn Gly
65 70 75 80
Arg Ala Tyr Tyr Asn Ala Arg Phe Lys Ser Glu Ala Thr Leu Thr Val
85 90 95
Asp Lys Ser Ser Asn Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser
100 105 110
Glu Ala Ser Ala Val Tyr Tyr Cys Ala Arg Ala Tyr Gly Asn Tyr Glu
115 120 125
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Val Ala Ser
130 135 140
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
145 150 155 160
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
165 170 175
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
180 185 190
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
195 200 205
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
210 215 220
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
225 230 235 240
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
245 250 255
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
260 265 270
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
275 280 285
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
290 295 300
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
305 310 315 320
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
325 330 335
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
340 345 350
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
355 360 365
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
370 375 380
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
385 390 395 400
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
405 410 415
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
420 425 430
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
435 440 445
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
450 455 460
Ser Leu Ser Leu Ser Pro Gly
465 470
<210> 18
<211> 239
<212> PRT
<213> 人工序列
<220>
<223> 鼠抗-AGEκ轻链
<400> 18
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro
20 25 30
Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser
35 40 45
Leu Val Asn Ser Asn Gly Asn Thr Phe Leu Gln Trp Tyr Leu Gln Lys
50 55 60
Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Leu Arg Phe
65 70 75 80
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
85 90 95
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe
100 105 110
Cys Ser Gln Ser Thr His Val Pro Pro 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> 19
<211> 239
<212> PRT
<213> 人工序列
<220>
<223> 嵌合抗-AGE人κ轻链
<400> 19
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro
20 25 30
Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser
35 40 45
Leu Val Asn Ser Asn Gly Asn Thr Phe Leu Gln Trp Tyr Leu Gln Lys
50 55 60
Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Leu Arg Phe
65 70 75 80
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
85 90 95
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe
100 105 110
Cys Ser Gln Ser Thr His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys
115 120 125
Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
130 135 140
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu
145 150 155 160
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
165 170 175
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
180 185 190
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
195 200 205
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln
210 215 220
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 20
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 鼠抗-AGE IgG2b重链(可变区)
<400> 20
Gln Val Gln Leu Leu Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ala Cys Lys Ala Ser Gly Tyr Leu Phe Thr Thr Tyr
20 25 30
Trp Met His Trp Leu Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Ser Pro Thr Asn Gly Arg Ala Tyr Tyr Asn Ala Arg Phe
50 55 60
Lys Ser Glu Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Ala Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Tyr Gly Asn Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Val
115
<210> 21
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 鼠抗-AGE κ轻链(可变区)
<400> 21
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser Leu Val Asn Ser
20 25 30
Asn Gly Asn Thr Phe Leu Gln Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Leu Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 22
<211> 326
<212> PRT
<213> 人工序列
<220>
<223> 人恒定区
<400> 22
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115 120 125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130 135 140
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
145 150 155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
165 170 175
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
180 185 190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
195 200 205
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ser Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly Lys
325
<210> 23
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDR1H(重链)
<400> 23
Ser Tyr Thr Met Gly Val Ser
1 5
<210> 24
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDR2H(重链)
<400> 24
Thr Ile Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 25
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDR3H(重链)
<220>
<221> misc_feature
<222> (10)..(10)
<223> Xaa可为任意天然存在的氨基酸
<400> 25
Gln Gly Gly Trp Leu Pro Pro Phe Ala Xaa
1 5 10
<210> 26
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDR1L(轻链)
<400> 26
Arg Ala Ser Lys Ser Val Ser Thr Ser Ser Arg Gly Tyr Ser Tyr Met
1 5 10 15
His
<210> 27
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDR2L(轻链)
<400> 27
Leu Val Ser Asn Leu Glu Ser
1 5
<210> 28
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDR3L(轻链)
<400> 28
Gln His Ile Arg Glu Leu Thr Arg Ser
1 5
<210> 29
<211> 468
<212> PRT
<213> 人工序列
<220>
<223> 人源化重链
<400> 29
Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser
1 5 10 15
Leu Ala Phe Glu Leu Ser Tyr Gly Gln Val Gln Leu Val Gln Ser Gly
20 25 30
Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala
35 40 45
Ser Gly Tyr Leu Phe Thr Thr Tyr Trp Met His Trp Val Arg Gln Ala
50 55 60
Pro Gly Gln Gly Leu Glu Trp Met Gly Glu Ile Ser Pro Thr Asn Gly
65 70 75 80
Arg Ala Tyr Tyr Asn Gln Lys Phe Gln Gly Arg Val Thr Met Thr Val
85 90 95
Asp Lys Ser Thr Asn Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser
100 105 110
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala Tyr Gly Asn Tyr Phe
115 120 125
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
145 150 155 160
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
210 215 220
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu
225 230 235 240
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Glu
245 250 255
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Lys Asn Gln
370 375 380
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
385 390 395 400
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
405 410 415
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
420 425 430
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
435 440 445
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
450 455 460
Leu Ser Pro Gly
465
<210> 30
<211> 1408
<212> DNA
<213> 人工序列
<220>
<223> 人源化重链
<400> 30
atggacccca agggcagcct gagctggaga atcctgctgt tcctgagcct ggccttcgag 60
ctgagctacg gccaggtgca gctggtgcag tctggcgccg aagtgaagaa acctggcgcc 120
tccgtgaggt gtcctgcaag gcttccggct acctgttcac cacctactgg atgcactggg 180
tgcgacaggc ccctggacag ggcctggaat ggatgggcga gatctcccct accaacggca 240
gagcctacta caacagaaat tccagggcag agtgaccatg accgtggaca agtccaccaa 300
caccgtgtac atggaactgt cctccctgcg gagcgaggac accgccgtgt actactgcgc 360
tagagcctac ggcaactacg attcgcctac tggggccagg gcaccctcgt gacagtgtcc 420
tctgctagca ccaagggccc cagcgtgttc cctctggccc ccagcagcaa gagcaccagc 480
ggcggaaccg ccgccctggg ctgcctggga aggactactt ccccgagccc gtgaccgtgt 540
cctggaacag cggcgctctg accagcggag tgcacacctt ccctgccgtg ctgcagagca 600
gcggcctgta ctccctgagc agcgtggtga ccgtgccagc agcagcctgg gcacccagac 660
ctacatctgc aacgtgaacc acaagccctc caacaccaag gtggacaaga aggtggagcc 720
taagagctgc gacaagaccc acacctgccc tccctgcccc gccccgagct gctgggcgga 780
cccagcgtgt tcctgttccc tcccaagccc aaggacaccc tgatgatcag ccgcaccccc 840
gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc ccgaggtgag ttcaactggt 900
acgtggacgg cgtggaggtg cacaacgcca agaccaagcc tcgggaggag cagtacaact 960
ccacctaccg cgtggtgagc gtgctgaccg tgctgcacca ggactggctg aacggcagga 1020
gtacaagtgc aaggtgagca acaaggccct gcccgctccc atcgagaaga ccatcagcaa 1080
ggccaagggc cagccccggg agcctcaggt gtacaccctg ccccccagcc gcgacgagct 1140
gacaagaacc aggtgagcct gacctgcctg gtgaagggct tctacccctc cgacatcgcc 1200
gtggagtggg agagcaacgg ccagcctgag aacaactaca agaccacccc tcccgtgctg 1260
gacagcgacg cagcttcttc ctgtacagca agctgaccgt ggacaagtcc cggtggcagc 1320
agggcaacgt gttcagctgc agcgtgatgc acgaggccct gcacaaccac tacacccaga 1380
agagcctgag cctgagcccg gatagtaa 1408
<210> 31
<211> 468
<212> PRT
<213> 人工序列
<220>
<223> 人源化重链
<400> 31
Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser
1 5 10 15
Leu Ala Phe Glu Leu Ser Tyr Gly Gln Val Gln Leu Val Gln Ser Gly
20 25 30
Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala
35 40 45
Ser Gly Tyr Leu Phe Thr Thr Tyr Trp Met His Trp Val Arg Gln Ala
50 55 60
Pro Gly Gln Gly Leu Glu Trp Met Gly Glu Ile Ser Pro Thr Asn Gly
65 70 75 80
Arg Ala Tyr Tyr Asn Ala Lys Phe Gln Gly Arg Val Thr Met Thr Val
85 90 95
Asp Lys Ser Thr Asn Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser
100 105 110
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala Tyr Gly Asn Tyr Phe
115 120 125
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
145 150 155 160
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
210 215 220
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu
225 230 235 240
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Glu
245 250 255
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Lys Asn Gln
370 375 380
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
385 390 395 400
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
405 410 415
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
420 425 430
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
435 440 445
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
450 455 460
Leu Ser Pro Gly
465
<210> 32
<211> 1408
<212> DNA
<213> 人工序列
<220>
<223> 人源化重链
<400> 32
atggacccca agggcagcct gagctggaga atcctgctgt tcctgagcct ggccttcgag 60
ctgagctacg gccaggtgca gctggtgcag tctggcgccg aagtgaagaa acctggcgcc 120
tccgtgaggt gtcctgcaag gcttccggct acctgttcac cacctactgg atgcactggg 180
tgcgacaggc ccctggacag ggcctggaat ggatgggcga gatctcccct accaacggca 240
gagcctacta caaccaaaat tccagggcag agtgaccatg accgtggaca agtccaccaa 300
caccgcttac atggaactgt cctccctgcg gagcgaggac accgccgtgt actactgcgc 360
tagagcctac ggcaactacg attcgcctac tggggccagg gcaccctcgt gacagtgtcc 420
tctgctagca ccaagggccc cagcgtgttc cctctggccc ccagcagcaa gagcaccagc 480
ggcggaaccg ccgccctggg ctgcctggga aggactactt ccccgagccc gtgaccgtgt 540
cctggaacag cggcgctctg accagcggag tgcacacctt ccctgccgtg ctgcagagca 600
gcggcctgta ctccctgagc agcgtggtga ccgtgccagc agcagcctgg gcacccagac 660
ctacatctgc aacgtgaacc acaagccctc caacaccaag gtggacaaga aggtggagcc 720
taagagctgc gacaagaccc acacctgccc tccctgcccc gccccgagct gctgggcgga 780
cccagcgtgt tcctgttccc tcccaagccc aaggacaccc tgatgatcag ccgcaccccc 840
gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc ccgaggtgag ttcaactggt 900
acgtggacgg cgtggaggtg cacaacgcca agaccaagcc tcgggaggag cagtacaact 960
ccacctaccg cgtggtgagc gtgctgaccg tgctgcacca ggactggctg aacggcagga 1020
gtacaagtgc aaggtgagca acaaggccct gcccgctccc atcgagaaga ccatcagcaa 1080
ggccaagggc cagccccggg agcctcaggt gtacaccctg ccccccagcc gcgacgagct 1140
gacaagaacc aggtgagcct gacctgcctg gtgaagggct tctacccctc cgacatcgcc 1200
gtggagtggg agagcaacgg ccagcctgag aacaactaca agaccacccc tcccgtgctg 1260
gacagcgacg cagcttcttc ctgtacagca agctgaccgt ggacaagtcc cggtggcagc 1320
agggcaacgt gttcagctgc agcgtgatgc acgaggccct gcacaaccac tacacccaga 1380
agagcctgag cctgagcccg gatagtaa 1408
<210> 33
<211> 468
<212> PRT
<213> 人工序列
<220>
<223> 人源化重链
<400> 33
Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser
1 5 10 15
Leu Ala Phe Glu Leu Ser Tyr Gly Gln Val Gln Leu Val Gln Ser Gly
20 25 30
Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala
35 40 45
Ser Gly Tyr Leu Phe Thr Thr Tyr Trp Met His Trp Val Arg Gln Ala
50 55 60
Pro Gly Gln Gly Leu Glu Trp Met Gly Glu Ile Ser Pro Thr Asn Gly
65 70 75 80
Arg Ala Tyr Tyr Asn Ala Lys Phe Gln Gly Arg Val Thr Met Thr Val
85 90 95
Asp Lys Ser Ile Asn Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser
100 105 110
Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala Tyr Gly Asn Tyr Phe
115 120 125
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
145 150 155 160
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
210 215 220
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu
225 230 235 240
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Glu
245 250 255
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Lys Asn Gln
370 375 380
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
385 390 395 400
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
405 410 415
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
420 425 430
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
435 440 445
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
450 455 460
Leu Ser Pro Gly
465
<210> 34
<211> 1408
<212> DNA
<213> 人工序列
<220>
<223> 人源化重链
<400> 34
atggacccca agggcagcct gagctggaga atcctgctgt tcctgagcct ggccttcgag 60
ctgagctacg gccaggtgca gctggtgcag tctggcgccg aagtgaagaa acctggcgcc 120
tccgtgaggt gtcctgcaag gcttccggct acctgttcac cacctactgg atgcactggg 180
tgcgacaggc ccctggacag ggcctggaat ggatgggcga gatctcccct accaacggca 240
gagcctacta caaccaaaat tccagggcag agtgaccatg accgtggaca agtccatcaa 300
caccgcttac atggaactgt ccagactgcg gagcgatgac accgccgtgt actactgcgc 360
tagagcctac ggcaactacg attcgcctac tggggccagg gcaccctcgt gacagtgtcc 420
tctgctagca ccaagggccc cagcgtgttc cctctggccc ccagcagcaa gagcaccagc 480
ggcggaaccg ccgccctggg ctgcctggga aggactactt ccccgagccc gtgaccgtgt 540
cctggaacag cggcgctctg accagcggag tgcacacctt ccctgccgtg ctgcagagca 600
gcggcctgta ctccctgagc agcgtggtga ccgtgccagc agcagcctgg gcacccagac 660
ctacatctgc aacgtgaacc acaagccctc caacaccaag gtggacaaga aggtggagcc 720
taagagctgc gacaagaccc acacctgccc tccctgcccc gccccgagct gctgggcgga 780
cccagcgtgt tcctgttccc tcccaagccc aaggacaccc tgatgatcag ccgcaccccc 840
gaggtgacct gcgtggtggt ggacgtgagc cacgaggacc ccgaggtgag ttcaactggt 900
acgtggacgg cgtggaggtg cacaacgcca agaccaagcc tcgggaggag cagtacaact 960
ccacctaccg cgtggtgagc gtgctgaccg tgctgcacca ggactggctg aacggcagga 1020
gtacaagtgc aaggtgagca acaaggccct gcccgctccc atcgagaaga ccatcagcaa 1080
ggccaagggc cagccccggg agcctcaggt gtacaccctg ccccccagcc gcgacgagct 1140
gacaagaacc aggtgagcct gacctgcctg gtgaagggct tctacccctc cgacatcgcc 1200
gtggagtggg agagcaacgg ccagcctgag aacaactaca agaccacccc tcccgtgctg 1260
gacagcgacg cagcttcttc ctgtacagca agctgaccgt ggacaagtcc cggtggcagc 1320
agggcaacgt gttcagctgc agcgtgatgc acgaggccct gcacaaccac tacacccaga 1380
agagcctgag cctgagcccg gatagtaa 1408
<210> 35
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> 人源化轻链
<400> 35
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro
20 25 30
Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
35 40 45
Leu Val Asn Ser Asn Gly Asn Thr Phe Leu Gln Trp Tyr Gln Gln Arg
50 55 60
Pro Gly Gln Ser Pro Arg Leu Leu Ile Tyr Lys Val Ser Leu Arg Phe
65 70 75 80
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
85 90 95
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
100 105 110
Cys Ser Gln Ser Thr His Val Pro Pro Thr Phe Gly Gly Gly Thr Val
115 120 125
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
130 135 140
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
165 170 175
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
195 200 205
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
210 215 220
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 36
<211> 715
<212> DNA
<213> 人工序列
<220>
<223> 人源化轻链
<400> 36
atggagaccg acaccctgct gctctgggtg ctgctgctct gggtgcccgg ctccaccgga 60
gacgtcgtga tgacccagtc ccctctgtcc ctgcctgtga ccctgggaca gcctgcctcc 120
atctcctcag atcctcccag tccctcgtga actccaacgg caacaccttc ctgcagtggt 180
atcagcagcg gcctggccag agccccagac tgctgatcta caaggtgtcc ctgcggttct 240
ccggcgtgcc cgacgatttt ccggctctgg ctctggcacc gacttcaccc tgaagatctc 300
ccgggtggaa gccgaggacg tgggcgtgta ctactgctcc cagagcaccc acgtgccccc 360
tacatttggc ggaggcacca agtggaaatc aagcggaccg tggccgcccc cagcgtgttc 420
atcttccctc ccagcgacga gcagctgaag tctggcaccg ccagcgtggt gtgcctgctg 480
aacaacttct acccccgcga ggccaagggc agtggaaggt ggacaacgcc ctgcagagcg 540
gcaacagcca ggagagcgtg accgagcagg actccaagga cagcacctac agcctgagca 600
gcaccctgac cctgagcaag gccgactacg agaagacaag gtgtacgcct gcgaggtgac 660
ccaccaggga ctgtctagcc ccgtgaccaa gagcttcaac cggggcgagt gctaa 715
<210> 37
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> 人源化轻链
<400> 37
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro
20 25 30
Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser
35 40 45
Leu Val Asn Ser Asn Gly Asn Thr Phe Leu Gln Trp Tyr Gln Gln Arg
50 55 60
Pro Gly Gln Ser Pro Arg Leu Leu Ile Tyr Lys Val Ser Leu Arg Phe
65 70 75 80
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
85 90 95
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
100 105 110
Cys Ser Gln Ser Thr His Val Pro Pro Thr Phe Gly Gly Gly Thr Val
115 120 125
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
130 135 140
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
165 170 175
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
195 200 205
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
210 215 220
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 38
<211> 715
<212> DNA
<213> 人工序列
<220>
<223> 人源化轻链
<400> 38
atggagaccg acaccctgct gctctgggtg ctgctgctct gggtgcccgg ctccaccgga 60
gacgtcgtga tgacccagtc ccctctgtcc ctgcctgtga ccctgggaca gcctgcctcc 120
atctcctcag atccaggcag tccctcgtga actccaacgg caacaccttc ctgcagtggt 180
atcagcagcg gcctggccag agccccagac tgctgatcta caaggtgtcc ctgcggttct 240
ccggcgtgcc cgacgatttt ccggctctgg ctctggcacc gacttcaccc tgaagatctc 300
ccgggtggaa gccgaggacg tgggcgtgta ctactgctcc cagagcaccc acgtgccccc 360
tacatttggc ggaggcacca agtggaaatc aagcggaccg tggccgcccc cagcgtgttc 420
atcttccctc ccagcgacga gcagctgaag tctggcaccg ccagcgtggt gtgcctgctg 480
aacaacttct acccccgcga ggccaagggc agtggaaggt ggacaacgcc ctgcagagcg 540
gcaacagcca ggagagcgtg accgagcagg actccaagga cagcacctac agcctgagca 600
gcaccctgac cctgagcaag gccgactacg agaagacaag gtgtacgcct gcgaggtgac 660
ccaccaggga ctgtctagcc ccgtgaccaa gagcttcaac cggggcgagt gctaa 715
<210> 39
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> 人源化轻链
<400> 39
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Val Val Met Thr Gln Ser Pro Leu Ser Ser Pro
20 25 30
Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
35 40 45
Leu Val Asn Ser Asn Gly Asn Thr Phe Leu Gln Trp Tyr His Gln Arg
50 55 60
Pro Gly Gln Pro Pro Arg Leu Leu Ile Tyr Lys Val Ser Leu Arg Phe
65 70 75 80
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ala Gly Lys Asp Phe
85 90 95
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
100 105 110
Cys Ser Gln Ser Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Leu
115 120 125
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
130 135 140
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
165 170 175
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
195 200 205
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
210 215 220
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 40
<211> 715
<212> DNA
<213> 人工序列
<220>
<223> 人源化轻链
<400> 40
atggagaccg acaccctgct gctctgggtg ctgctgctct gggtgcccgg ctccaccgga 60
gacgtcgtga tgacccagtc ccctctgtcc agtcctgtga ccctgggaca gcctgcctcc 120
atctcctcag atcctcccag tccctcgtga actccaacgg caacaccttc ctgcagtggt 180
atcaccagcg gcctggccag cctcccagac tgctgatcta caaggtgtcc ctgcggttct 240
ccggcgtgcc cgacgatttt ccggctctgg cgctggcaag gacttcaccc tgaagatctc 300
ccgggtggaa gccgaggacg tgggcgtgta ctactgctcc cagagcaccc acgtgccccc 360
tacatttggc cagggcacca actggaaatc aagcggaccg tggccgcccc cagcgtgttc 420
atcttccctc ccagcgacga gcagctgaag tctggcaccg ccagcgtggt gtgcctgctg 480
aacaacttct acccccgcga ggccaagggc agtggaaggt ggacaacgcc ctgcagagcg 540
gcaacagcca ggagagcgtg accgagcagg actccaagga cagcacctac agcctgagca 600
gcaccctgac cctgagcaag gccgactacg agaagacaag gtgtacgcct gcgaggtgac 660
ccaccaggga ctgtctagcc ccgtgaccaa gagcttcaac cggggcgagt gctaa 715
Claims (35)
1.一种治疗神经退行性紊乱或MD的方法,所述方法包括向受试者给予包含AGE抗体的组合物。
2.一种杀死衰老胶质细胞的方法,所述方法包括向受试者给予包含AGE抗体的组合物。
3.一种杀死衰老成肌细胞和/或衰老肌卫星细胞的方法,所述方法包括向受试者给予包含AGE抗体的组合物。
4.一种治疗患有神经退行性紊乱或MD的受试者的方法,所述方法包括:
第一次给予AGE抗体;随后
针对所述第一次给予在治疗所述神经退行性紊乱或MD方面的有效性,对所述受试者进行测试;随后
第二次给予所述AGE抗体。
5.一种治疗神经退行性紊乱或MD的方法,所述方法包括杀死衰老胶质细胞、衰老成肌细胞和/或衰老肌卫星细胞,或者在衰老胶质细胞、衰老成肌细胞和/或衰老肌卫星细胞中诱导凋亡。
6.一种用于治疗神经退行性紊乱的组合物,所述组合物包含:
(i)AGE抗体;
(ii)血清、免疫系统细胞或两者皆有。
7.如前述权利要求中任一项所述的方法,其中,所述组合物进一步包含药学上可接受的载体。
8.如前述权利要求中任一项所述的方法,其中,所述受试者选自于由人、小鼠、大鼠、山羊、绵羊、奶牛、马、狗以及猫所组成的组。
9.如前述权利要求中任一项所述的方法,其中,所述受试者为人。
10.如前述权利要求中任一项所述的方法或组合物,其中,所述AGE抗体对选自于由如下所组成的组中的物种是非免疫原性的:人、猫、狗、马、骆驼、羊驼、牛、绵羊和山羊。
11.如前述权利要求中任一项所述的方法或组合物,其中,所述AGE抗体与AGE抗原结合,所述AGE抗原包含呈现AGE修饰的至少一种蛋白质或肽,所述AGE修饰选自于由FFI、吡咯素、AFGP、ALI、羧甲基赖氨酸、羧乙基赖氨酸和戊糖素所组成的组。
12.如前述权利要求中任一项所述的方法或组合物,其中,所述AGE抗体结合经羧甲基赖氨酸修饰的蛋白质。
13.如前述权利要求中任一项所述的方法或组合物,其中,
所述组合物是无菌的,并且
所述组合物处于单位剂型。
14.如前述权利要求中任一项所述的方法,其中,所述组合物进一步包含血清。
15.如前述权利要求中任一项所述的方法,其中,所述血清为自体血清。
16.如前述权利要求中任一项所述的方法,其中,所述组合物进一步包含免疫系统细胞。
17.如前述权利要求中任一项所述的方法,其中,所述免疫系统细胞来自所述受试者。
18.如前述权利要求中任一项所述的方法,其中,所述免疫系统细胞包括自然杀伤细胞。
19.如前述权利要求中任一项所述的方法,其中,所述自然杀伤细胞来自所述受试者。
20.如前述权利要求中任一项所述的方法,其中,所述自然杀伤细胞包括人工自然杀伤细胞。
21.如前述权利要求中任一项所述的方法,其中,所述组合物进一步包含:
(i)药学上可接受的载体;
(ii)血清;以及
(iii)自然杀伤细胞。
22.如前述权利要求中任一项所述的方法,其中,所述受试者患有神经退行性紊乱,所述神经退行性紊乱选自于由AD、PD、路易体痴呆、MS、朊病毒病和ALS所组成的组。
23.如前述权利要求中任一项所述的方法,其中,所述受试者患有选自于由AD、PD和ALS所组成的组中的神经退行性紊乱。
24.如前述权利要求中任一项所述的方法,其中,所述给予包括向所述受试者的中枢神经系统给予。
25.如前述权利要求中任一项所述的方法,其中,向所述中枢神经系统给予包括鞘内给予、脑室内给予以及通过增强对流输送给予。
26.如前述权利要求中任一项所述的方法,其中,所述受试者患有ALS或MD,并且所述给予包括向所述受试者的肌肉给予。
27.如前述权利要求中任一项所述的方法,其中,所述给予杀死所述受试者中的衰老胶质细胞。
28.如前述权利要求中任一项所述的方法,其中,所述衰老胶质细胞为衰老星形胶质细胞和/或衰老小胶质细胞。
29.如前述权利要求中任一项所述的方法,其中,所述给予杀死所述受试者中的衰老成肌细胞和/或衰老肌卫星细胞。
30.如前述权利要求中任一项所述的方法,其中,所述受试者患有MD或ALS。
31.如前述权利要求中任一项所述的组合物,其中,所述组合物包含所述血清。
32.如前述权利要求中任一项所述的组合物,其中,所述组合物包含所述免疫系统细胞。
33.如前述权利要求中任一项所述的组合物,其中,所述免疫系统细胞为自然杀伤细胞。
34.如前述权利要求中任一项所述的组合物,其中,所述自然杀伤细胞为人工自然杀伤细胞。
35.如前述权利要求中任一项所述的方法或组合物,其中,所述AGE抗体为缀合至引起细胞破坏的试剂的单结构域抗体。
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AU2017250301A1 (en) | 2018-11-15 |
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