CN107207588A - 针对tau的抗体和其用途 - Google Patents
针对tau的抗体和其用途 Download PDFInfo
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- CN107207588A CN107207588A CN201680008086.XA CN201680008086A CN107207588A CN 107207588 A CN107207588 A CN 107207588A CN 201680008086 A CN201680008086 A CN 201680008086A CN 107207588 A CN107207588 A CN 107207588A
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Abstract
针对人类tau聚集体的单克隆抗体、包含此类tau抗体的组合物,和使用此类tau抗体治疗神经退行性疾病(包括阿尔兹海默氏病、进行性核上性麻痹和匹克氏病)的方法。
Description
本发明处于医学领域中。具体而言,本发明涉及针对tau的抗体、包含此类tau抗体的组合物和使用此类tau抗体治疗神经退行性疾病(包括阿尔兹海默氏病(AD)、进行性核上性麻痹(PSP)和匹克氏病(PD))的方法。
Tau是促进微管组装和稳定性的轴突微管结合蛋白。AD和PSP是神经退行性疾病,其病理上特征在于异常tau聚集。更具体而言,据信在AD和PSP中过度磷酸化的tau促进不溶性tau原纤维聚集,导致微管去稳定和神经元毒性。细胞培养和鼠模型研究已显示,tau聚集体跨越神经元突触连接而扩展且隔离单体(天然或非聚集)tau,从而诱导tau聚集体形成。在神经退行性疾病诸如AD和PSP中的tau聚集和累积的神经解剖学进展表明,tau原纤维聚集沿神经元网络传播,最后导致微管去稳定且最后导致神经元功能局部受损。
tau聚集的密度和神经解剖学定位与AD和PSP神经病学症状和疾病进展强烈相关。例如,在AD中,tau形成神经元内神经纤维缠结(NFT),其倾向于依次从横嗅(transentorhinal)区至边缘区,至新皮质区发展,且其与痴呆症的严重程度和神经元损失的程度相关。在PSP中,tau聚集可见于皮质下区和皮质区内的神经元、星状胶质细胞和寡树突胶质细胞中,且已显示聚集的tau的密度与神经元损失的严重程度相关。
针对tau的抗体是已知的。例如,美国专利号8,926,974和国际公开号WO2011/026031、WO2012/049570和WO2013/050567公开针对tau的抗体和tau抗体用于治疗神经退行性疾病诸如AD的用途。然而,迄今为止仍没有批准用于治疗用途的靶向tau的抗体且目前尚无批准用于AD或PSP的疾病改变疗法。因此,仍需要替代性tau抗体。具体而言,仍需要特异性结合tau聚集体且减少tau聚集体形成、NFT形成和神经元损失的传播的替代性tau抗体。优选地,此类tau抗体也具有良好物理化学性质以有助于开发、制造和/或配制。
本发明提供结合人类tau的单克隆抗体且其包含轻链可变区(LCVR)和重链可变区(HCVR),其中LCVR包含互补决定区(CDR)LCDR1、LCDR2和LCDR3且HCVR包含CDR HCDR1、HCDR2和HCDR3。根据本发明的具体实施方案,LCDR1的氨基酸序列由SEQ ID NO.3给出,LCDR2的氨基酸序列由SEQ ID NO.4给出,LCDR3的氨基酸序列由SEQ ID NO.5给出,HCDR1的氨基酸序列由SEQ ID NO.6给出,HCDR2的氨基酸序列由SEQ ID NO.7给出且HCDR3的氨基酸序列由SEQ ID NO.8给出。在一个实施方案中,本发明提供结合人类tau的单克隆抗体,其包含LCVR和HCVR,其中LCVR的氨基酸序列由SEQ ID NO.9给出且HCVR的氨基酸序列由SEQ ID NO.10给出。在另一个实施方案中,本发明提供结合人类tau的单克隆抗体,其包含轻链(LC)和重链(HC),其中LC的氨基酸序列由SEQ ID NO.1给出且HC的氨基酸序列由SEQ ID NO.2给出。
本发明提供结合人类tau的单克隆抗体。在一个实施方案中,本发明提供结合人类tau的构象表位的单克隆抗体。在一个具体实施方案中,人类tau的构象表位包括人类tau的氨基酸残基7-9和312-322,其中人类tau的氨基酸序列由SEQ ID NO.13给出。
本发明进一步提供包含本发明的单克隆抗体和一种或多种药学上可接受的载体、稀释剂或赋形剂的药物组合物。此外,本发明提供治疗AD、PSP或PD的方法,其包括向有需要的患者施用本发明的药物组合物。
另外,本发明提供治疗神经退行性疾病的方法。更具体而言,本发明提供治疗AD、PSP或PD的方法,其包括向有需要的患者施用有效量的本发明单克隆抗体。
本发明还提供本发明单克隆抗体,其用于疗法中。更具体而言,本发明还提供本发明单克隆抗体,用于治疗AD、PSP或PD。
在一个实施方案中,本发明提供本发明单克隆抗体用于制造用于治疗AD、PSP或PD的药剂的用途。
本发明还涉及编码本发明单克隆抗体的核酸分子和表达载体。在一个实施方案中,本发明提供包含编码具有SEQ ID NO.1的氨基酸序列的多肽的多核苷酸序列的DNA分子。在一个实施方案中,本发明提供包含编码具有SEQ ID NO.2的氨基酸序列的多肽的多核苷酸序列的DNA分子。在另一个实施方案中,本发明提供包含编码具有SEQ ID NO.1的氨基酸序列的多肽的多核苷酸序列且包含编码具有SEQ ID NO.2的氨基酸序列的多肽的多核苷酸序列的DNA分子。在一个具体实施方案中,编码具有SEQ ID NO.1的氨基酸序列的多肽的多核苷酸序列由SEQ ID NO.11给出且编码具有SEQ ID NO.2的氨基酸序列的多肽的多核苷酸序列由SEQ ID NO.12给出。
此外,本发明提供根据方法制备的单克隆抗体,其中所述方法包括在使得表达单克隆抗体的条件下培养宿主细胞,所述宿主细胞包含编码具有SEQ ID NO.1的氨基酸序列的多肽的多核苷酸序列和编码具有SEQ ID NO.2的氨基酸序列的多肽的多核苷酸序列,和从所述宿主细胞回收包含LC和HC的单克隆抗体,其中LC的氨基酸序列由SEQ ID NO.1给出且HC的氨基酸序列由SEQ ID NO.2给出。
如本文所用,“抗体”是包含通过二硫键互联的2个HC和2个LC的免疫球蛋白分子。各LC和HC的氨基端部分包括约100-120个氨基酸的可变区,其主要负责经由其中所含有的CDR来识别抗原。CDR散布有更保守的称为框架区(“FR”)的区域。各LCVR和HCVR由3个CDR和4个FR构成,其从氨基端至羧基端以以下顺序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。LC的3个CDR称为“LCDR1、LCDR2和LCDR3”,且HC的3个CDR称为“HCDR1、HCDR2和HCDR3”。CDR含有与抗原形成特异性相互作用的大多数残基。抗体结合具体抗原的功能性能力主要受6个CDR影响。将氨基酸指定至本发明抗体的LCVR和HCVR区内的CDR结构域基于众所周知的Kabat编号规定(Kabat, 等人, Ann. NY Acad. Sci. 190:382-93 (1971); Kabat等人, Sequences of Proteins of Immunological Interest, 第五版, U.S. Department of Health andHuman Services, NIH Publication No. 91-3242 (1991))和North编号规定(North等人,A New Clustering of Antibody CDR Loop Conformations, Journal of MolecularBiology, 406:228-256 (2011))。
LC被归类为κ或λ,其各自特征在于如本领域已知的具体恒定区。本发明单克隆抗体包括κ LC。HC被归类为γ、μ、α、δ或ε并将抗体的同种型分别定义为IgG、IgM、IgA、IgD、或IgE。本发明单克隆抗体包括IgG HC。IgG抗体可进一步分为亚类,例如IgG1、IgG2、IgG3、IgG4。在一个具体实施方案中,本发明单克隆抗体是IgG4。各HC的羧基端部分定义主要负责效应子功能的恒定区。在一个具体实施方案中,本发明单克隆抗体在各HC的恒定区中具有降低效应子功能的一种或多种修饰。在一个更具体实施方案中,本发明单克隆抗体是IgG4并在两个HC的恒定区中具有降低效应子功能的修饰,包括在残基230和231两者处的氨基酸丙氨酸(残基编号基于SEQ ID NO.2的例举的HC)。在一个甚至更具体实施方案中,本发明单克隆抗体是IgG4并在两个HC的恒定区中具有降低效应子功能的修饰,包括在残基230和231两者处的氨基酸丙氨酸,并在两个HC的恒定区中具有促进稳定性的其他修饰,包括在残基224处的氨基酸脯氨酸和缺失在残基443处的氨基酸赖氨酸(残基编号基于SEQ ID NO.2的例举的HC)。
本发明抗体是单克隆抗体(“mAb”)。本发明mAb是含有2个HC和2个LC的完整mAb。如本文所提及,mAb是衍生自单一拷贝或克隆(包括例如任何真核、原核或噬菌体克隆)的抗体,而不是其产生的方法。单克隆抗体可例如通过杂交瘤技术、重组技术、噬菌体展示技术、合成技术(例如CDR移植)或此类技术或本领域已知的其他技术的组合产生。
产生和纯化抗体的方法是本领域众所周知的且可见于例如Harlow和Lane(1988),Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press, ColdSpring harbor,N.Y.,第5-8章和第15章,ISBN 0-87969-314-2。例如,可用来自特征为患有AD的患者的脑组织的人类tau成对螺旋丝(“PHF”)来免疫小鼠(Jicha等人,J. Neurosci.Res., 15:48(2), 128-132(1997年4月))且可回收、纯化所得抗体,并使用本领域众所周知的常规方法来测定氨基酸序列。本发明单克隆抗体经工程改造以含有一个或多个围绕衍生自非人类抗体的CDR的人类框架区。人类框架种系序列可从ImMunoGeneTics(INGT)(经由其网站http://imgt.cines.fr)或从The Immunoglobulin FactsBook (Marie-PauleLefranc和Gerard Lefranc, Academic Press, 2001, ISBN 012441351)获得。根据本发明的具体实施方案,用于本发明单克隆抗体中的具体种系HC框架区和LC框架区分别包括5-51和A27。
在本发明的具体实施方案中,抗体或编码其的核酸以分离形式提供。如本文所用,术语“分离的”是指不含或实质上不含在细胞环境中发现的其他大分子物质的蛋白、肽或核酸。
本发明单克隆抗体可使用已知方法来制备并纯化。例如,编码HC(例如由SEQ IDNO.2给出的氨基酸序列)和LC(例如由SEQ ID NO.1给出的氨基酸序列)的cDNA序列可经克隆并工程改造至GS(谷氨酰胺合成酶)表达载体中。然后,工程改造的免疫球蛋白表达载体可稳定转染至CHO细胞中。如本领域技术人员应理解,抗体的哺乳动物表达将导致通常在Fc区中在高度保守的N-糖基化位点处的糖基化。稳定克隆可针对特异性结合至tau聚集体的抗体的表达来验证。可在生物反应器中将阳性克隆扩展至用于抗体产生的无血清培养基中。抗体已分泌至其中的培养基可通过常规技术来纯化。例如,培养基可方便地施加至已使用相容缓冲液诸如磷酸盐缓冲盐水来平衡的蛋白A或G琼脂糖FF柱。洗涤柱以移除非特异性结合组分。将结合的抗体例如通过pH梯度来洗脱,且抗体级分诸如通过SDS-PAGE来检测且然后合并。抗体可使用常用技术浓缩和/或无菌过滤。可溶性聚集体和多聚体可通过常用技术有效移除,所述技术包括大小排阻、疏水相互作用、离子交换或羟磷灰石色谱。产物可立刻冷冻(例如在-70℃下)或可冻干。
本发明单克隆抗体可用于患者的治疗中。更具体而言,预期本发明抗体治疗一类称为tau蛋白病变的神经退行性病症,其包括AD、PSP和PD。尽管预期本发明单克隆抗体可用于治疗AD、PSP和PD,但此类抗体也可用于治疗其他tau蛋白病变包括慢性创伤性脑病。如本文可互换使用,“治疗”(“treatment”和/或“treating”和/或“treat”)意指其中可减缓、中断、阻止、控制、停止或逆转本文所述病症的进展的所有过程,但不一定指示所有病症症状的完全消除。治疗包括施用本发明抗体用于治疗人类的疾病或病况,所述疾病或病况会受益于tau聚集体形成、NFT形成和神经元损失中的至少一种的传播的减少,且所述治疗包括:(a)抑制疾病的进一步进展,即阻止其发展;和(b)减轻疾病,即引起疾病或病症消退或缓解其症状或并发症。
如本文可互换使用,术语“患者”、“受试者”和“个体”是指人类。在某些实施方案中,患者的特征进一步在于会受益于tau聚集体形成、NFT形成和神经元损失中的至少一种的传播的减少的疾病、病症或病况(例如,神经退行性病症)。在另一个实施方案中,患者进一步特征在于处于发展神经退行性病症、疾病或病况的风险中,所述神经退行性病症、疾病或病况会受益于tau聚集体形成、NFT形成和神经元损失中的至少一种的传播的减少。
如本文所用,术语“结合(bind或binds)”tau是指抗体与人类tau聚集体的表位的相互作用。更优选地,表位是人类tau的构象表位。在一个具体实施方案中,术语“结合(bind或binds)”tau是指与构象表位的相互作用,该构象表位包括人类tau聚集体的氨基酸残基7-9和312-322(残基编号基于SEQ ID NO.13的例举的人类tau)。应理解,存在已知例如由剪接变体导致的人类tau蛋白的变型。然而,此类已知变型具有包括SEQ ID NO.13的氨基酸残基7-9和312-322的构象表位。然而,已知变体可导致SEQ ID NO.13的氨基酸残基7-9和312-322的残基编号改变。尽管在一些变体中可改变残基编号,但构成表位的氨基酸保持相同。如本文所用的术语“表位”是指抗原的由本发明单克隆抗体所识别的不连续三维位点。
本发明单克隆抗体可并入药物组合物中,该药物组合物可通过本领域众所周知的方法制备且包含本发明单克隆抗体和一种或多种药学上可接受的载体和/或稀释剂(例如,Remington, The Science and Practice of Pharmacy,第22版,Loyd V.编辑,Pharmaceutical Press,2012,其提供如从业者通常已知的配制技术的概要)。用于药物组合物的合适载体包括当与本发明单克隆抗体组合时,保持分子的活性且不与患者的免疫系统反应的任何材料。
包含本发明单克隆抗体的药物组合物可通过肠胃外途径(例如皮下、静脉内、腹膜内、肌内或经皮)施用于处于如本文所述的疾病或病症的风险中或展现如本文所述的疾病或病症的患者。本发明的药物组合物含有“有效”或“治疗有效”量(在本文中可互换使用)的本发明单克隆抗体。有效量是指实现期望治疗结果的必需量(在剂量下且对于时间段且对于施用方式)。单克隆抗体的有效量可根据诸如以下的因素变化:个体的疾病状态、年龄、性别和体重和单克隆抗体引起个体中的期望反应的能力。有效量也是治疗有益效应胜过本发明单克隆抗体的任何毒性或有害效应的量。
工程改造的Tau抗体
当构建本发明单克隆tau抗体时遇到与化学和物理稳定性相关联的重大问题。所遇到的问题包括低结合亲和力、免疫原性、聚集、HC二聚化、以及可变区脱酰胺、氧化、异构化和错折叠。
例如,鼠IgG1抗体MC-1(“MC-1”)(Albert Einstein College of Medicine,Jicha等人,1997),识别tau蛋白在氨基酸残基7-9和312-322(残基编号基于具有SEQ ID NO.13的氨基酸序列的例举的人类tau蛋白)的构象表位,该抗体最初通过将3个MC-1鼠HC CDR工程改造至多个人类HC框架种系基因中和将3个MC-1鼠LC CDR工程改造至多个人类LC框架种系基因中而人源化。MC-1的人源化构建体利用重链和轻链框架的96种不同组合,其表示12个HC框架种系家族(特定人类HC框架:1-24、1-46、1-69、2-05、3-15、3-23、3-53、3-72、4-04、4-39、5-51和6-01)中的每一个和8个LC种系家族(特定人类LC框架:A-26、A-27、B-2、B-3、L-2、L-12、O11和O-2)中的每一个。将各别框架种系基因克隆于重链和轻链人类IgG4表达载体中且转染于HEK293细胞中用于表达且通过ELISA分析结合。尽管多个框架对在ELISA中展示一定水平的与人类tau的结合,但是所得抗体构建体显示极多问题,包括结合亲和力差、聚集、HC二聚化,和化学稳定性问题,诸如可变区中的脱酰胺、氧化和异构化。
因此,将修饰工程改造以开发具有改善结合亲和力、消除或减少的HC二聚化、减少的免疫原性和改善的化学和物理稳定性的tau抗体。在HCDR2和HCDR3以及LCDR1、LCDR2和LCDR3中工程改造氨基酸修饰(相对于MC-1,Jicha等人,1997)。修饰的鼠抗体基本上如上所述通过将3个HC CDR工程改造至多个人类HC框架种系基因中并将3个LC CDR工程改造至多个人类LC框架种系基因中而人源化。此外,实施广泛蛋白稳定性研究,并针对表达和热稳定性性质以及结合亲和力性质来筛选工程改造的单克隆抗体。含有7个CDR突变(氨基酸位置基于反映于表1中例举的本发明抗体的线性氨基酸残基编号:HCDR2中的N61E和E62K;HCDR3中的P103V和Y105D;LCDR1中的G34Q;LCDR2中的S57D;和LCDR3中的H98L)的单克隆抗体被鉴定为改善本发明单克隆抗体的结合亲和力、化学和物理稳定性和免疫原性(相对于MC-1,Jicha等人,1997)。在MC-1或人源化的MC-1抗体构建体的表征中都未鉴定到上述修饰。
例举的本发明的工程改造的tau单克隆抗体呈现于表1中。例举的工程改造的tau单克隆抗体包括人类HC框架5-51和人类LC框架A27。例举的工程改造的tau单克隆抗体的各个区域的关系如下(氨基酸的编号应用线性编号;将氨基酸指定至可变结构域基于可在www.imgt.org获得的International Immunogenetics Information System®;将氨基酸指定至CDR结构域基于众所周知的North编号规定,除了基于众所周知的Kabat编号规定的HCDR2):
表1:例举的本发明的工程改造的tau单克隆抗体的氨基酸区域。
以下实施例和测定展示,本发明单克隆抗体可用于治疗与tau聚集体的传播相关的神经退行性病症,诸如AD、PSP或PD。然而,应理解,以下实施例以说明性而非限制性方式陈述,且本领域普通技术人员可作出各种修改。
实施例
工程改造的Tau抗体的表达
本发明的工程改造的tau单克隆抗体可基本上如下文来表达和纯化。含有SEQ IDNO.11的DNA序列(编码SEQ ID NO.1的LC氨基酸序列)和SEQ ID NO.12的DNA序列(编码SEQID NO.2的HC氨基酸序列)的谷氨酰胺合成酶(GS)表达载体用于通过电穿孔来转染中国仓鼠卵巢细胞系(CHO)。表达载体编码SV早期(猿猴病毒40E)启动子和GS的基因。GS的表达容许生物化学合成CHO细胞所需的氨基酸谷氨酰胺。转染后,细胞经历使用50μM L-甲硫氨酸亚砜亚胺(L-methionine sulfoximine, MSX)的集团选择(bulk selection)。通过MSX的GS的抑制用于增加选择的严格性。可针对CHO野生型细胞选择将表达载体cDNA整合至宿主细胞基因组的转录活跃区中的细胞(其表达内源性水平的GS)。将转染合并物以低密度铺板以允许稳定表达细胞的接近克隆的过度生长。针对抗体表达筛选主孔且然后在无血清悬浮液培养物中按比例放大以用于生产。抗体分泌至其中的澄清培养基施加至已用相容缓冲液诸如磷酸盐缓冲盐水(pH 7.4)平衡的蛋白A亲和柱。使用1M NaCl洗涤柱以移除非特异性结合组分。例如用pH(约)3.5的柠檬酸钠来洗脱结合的tau单克隆抗体并用1M Tris缓冲液来中和级分。诸如通过SDS-PAGE或分析大小排阻来检测Tau单克隆抗体级分且然后合并。可溶性聚集体和多聚体可通过常用技术有效移除,所述技术包括大小排阻、疏水相互作用、离子交换或羟磷灰石色谱。本发明tau单克隆抗体使用常用技术来浓缩和/或无菌过滤。在这些色谱步骤后,tau单克隆抗体的纯度大于95%。本发明tau单克隆抗体可立刻在-70℃下冷冻或在4℃下储存几个月。
结合动力学和亲和力
用BIACORE® 2000仪器(在25℃下用HBS-EP+运行缓冲液(GE Healthcare, 10 mMHepes pH7.4 + 150 mM NaCl + 3 mM EDTA + 0.05%表面活性剂P20)引发)测量的表面等离子共振(SPR)测定用于测量实施例1的例举的tau单克隆抗体与人类单体(例如天然或非聚集)tau和人类tau聚集体两者(两者都具有如示于SEQ ID NO: 13中的氨基酸序列)的结合。人源化的MC-1抗体构建体(具有框架组合:5-51重链,A27轻链)与人类单体tau和人类tau聚集体的结合以相同方式测量。
除非如注明,所有试剂和材料均来自BIACORE® AB (Upsala, Sweden)。使用在所有4个流动室(FC)上含有固定化蛋白A的CM5芯片(使用标准NHS-EDC胺偶联产生)来采用捕获方法。通过稀释于运行缓冲液中来制备0.5μg/mL的抗体样品。通过稀释于运行缓冲液中来将单体tau和原纤维tau制备为2000、1000、500、250、125、62.5、31.25、15.63、7.82、3.91、1.95和0(空白)nM的浓度。各分析循环由以下组成:(1)将抗体样品捕获于单独流动室(FC2、FC3和FC4)上;(2)以50μL/min的速率经各别FC注射250μL(300秒)单体tau或tau原纤维聚集体;(3)返回至缓冲液流持续20min以监测解离相;(4)用注射25μL(30秒)pH 1.5的甘氨酸使芯片表面再生;(5)用注射50μL(60秒)HBS-EP+来平衡芯片表面。
使用标准双重参照处理结合至tau聚集体的数据并使用Biacore 2000评估软件(4.1版)拟合至1:1结合模型,以测定结合速率(kon, M-1s-1单位)、解离速率(koff, s-1单位)和Rmax (RU单位)。平衡解离常数(KD)根据关系KD = koff/kon来计算且以摩尔单位计。由于快速结合和解离速率,结合至单体tau的数据无法通过如上文所述的SPR精确测定。因此,结合至单体tau的KD通过使用稳态结合拟合模型从绘制抗原浓度对反应单位的曲线来获得。所得结合数据提供于表2中。
表2:与人类单体tau和聚集tau两者的SPR结合数据。
*KD结果视为相对的,因为所述结果未针对亲合力的影响进行均一化。
提供于表2中的结果展示,实施例1的tau单克隆抗体不具有可测量的与单体tau的结合,使得可通过Biacore分析精确测定亲和力值(由于快速结合和解离速率)。相反,提供于表2中的结果展示,与人源化的MC-1抗体构建体相比,实施例1的tau单克隆抗体具有与tau聚集体的改善亲和力。
酶联免疫吸附测定(ELISA)用于测定实施例1的例举的tau单克隆抗体与来自AD脑匀浆的聚集tau原纤维的相对结合亲和力。AD脑匀浆从AD患者的脑的约80g皮质制备。简言之,以约10ml/1g(组织)将缓冲液(TBS/1mM PMSF/1X Complete®蛋白酶抑制剂混合物(Roche,p/n.11 697 498 001)和磷酸酶抑制剂(ThermoFischer,p/n.78428))添加至AD脑组织中。使用手持式Kinematica Polytron以速度6-7将组织匀浆化。然后,使用Parr Bomb(Parr Instrument,p/n.4653)在1500psi氮气下将组织进一步匀浆化30min。将匀浆在4℃下以28,000g(J14 Beckman转子)旋转30min。收集上清液,合并且在Sepharose 400Superflow的4cm高保护柱上运行以移除较大碎片,然后以每小时50-60ml的流速在25mlMC1-Affigel 10柱上运行,以纯化结合MC1的tau原纤维。为了使纯化的回收率最大化,通过MC-1柱在4℃下经18-20小时再循环上清液。将保护柱移除并使用至少40个柱体积用TBS洗涤MC1柱。然后,将结合的tau聚集体用2个柱体积的3M KSCN洗脱,收集于约1ml级分中。各洗脱级分中的蛋白浓度通过微量滴定板Bradford测定来检查。将含有阳性蛋白水平的级分合并,使用Centricon(Millipore Ultracel-30K)在4℃下浓缩至约2ml并使用Slide-A-Lyzer盒(10K MWCO 3-12ml, Pierce)针对1升TBS透析过夜。从AD脑匀浆纯化的tau原纤维内的tau浓度通过夹心ELISA使用DA-9捕获抗体和CP27检测抗体来测量。
将PBS中的纯化的tau原纤维(50μl)以对应于0.7μg/ml总tau的浓度包被于96孔板(Coastar,p/n.3690)的孔上。将板在4℃下孵育过夜,然后用150μl PBST(含有0.05%Tween-20的PBS)洗涤3次,在室温下于100μl BB3(ImmunoChemistry Technology,p/n.643)中封闭至少1小时(通常2小时)。封闭之后,将封闭缓冲液从孔移除。将实施例1的例举的tau单克隆抗体和人源化的MC-1抗体构建体(具有框架组合:5-51重链,A27轻链)于0.25%酪蛋白缓冲液中稀释为1000nM储备液,然后以二倍稀释度连续稀释23次。将50μl储备液和连续稀释的抗体(实施例1的例举的tau单克隆抗体或人源化的MC-1抗体构建体)添加至单独孔中并在室温下孵育2小时,然后将板用200μl PBST/孔洗涤4次。添加50μl抗人类IgG-HRP抗体(以1:4000稀释至0.25%酪蛋白缓冲液中)并在室温下孵育1小时,然后将板用200μlPBST/孔洗涤4次。添加50μl TMB/H2O2并在室温下孵育约10分钟。通过添加50μl终止溶液(2N H2SO4)来终止反应并在450nm下测量比色信号。将数据输入Prism 6(GraphPad)程序中并使用非线性回归曲线拟合和S型剂量反应来产生EC50值。结果呈现于表3中。
表3.与纯化的AD Tau原纤维的结合的EC50比较
测定的抗体 | EC50 (pM) |
实施例1的例举的tau mAb | 6.8 |
人源化MC-1 Ab构建体 | 409.1 |
如表3中所反映,例举的本发明tau单克隆抗体展示60倍优于人源化MC-1抗体构建体的与纯化tau原纤维的改善亲和力(如通过EC50所测量)。
实施例1的tau单克隆抗体对tau聚集体相对于对tau单体的选择性通过直接ELISA来测定。在实质上如上文所提供的ELISA程序后,以对应于“高”浓度(1μg/mL)或“低”浓度(15ng/mL)的浓度将重组tau(rTau)包被于96孔板上。当包被于微孔板上时,高浓度的rTau聚集,模拟与聚集的tau的结合。当包被于微孔板上时,低浓度的rTau模拟与tau单体的结合。分别包被有高或低浓度的rTau的板暴露于实施例1的例举的tau单克隆抗体,且例举的tau单克隆抗体与各别浓度的rTau的结合实质上如上文的ELISA测定中所述来测量。结果提供于表4中。
表4. 与“高”相对于“低”浓度的rTau的结合的EC50比较
rTau单体浓度 | EC50 (pM) |
“高” (1µg/mL) | 6.0 |
“低” (15ng/mL) | 722.7 |
如表4中所反映,实施例1的例举的tau单克隆抗体展示120倍优于单体tau的与聚集tau的改善亲和力(如通过EC50所测量)。
离体靶标参与(Target Engagement)研究
实施例1的例举的tau单克隆抗体与源自人类脑的聚集的tau的结合通过福尔马林固定的石蜡包埋(FFPE)的从以下获得的脑切片的免疫组织化学染色来测定:“正常”个体(显示最低tau聚集);AD患者(展现严重tau聚集和NFT形成,以及淀粉样蛋白斑块病理);PD患者(展现严重tau聚集)。还对源自不具有人类tau的“对照”野生型小鼠的脑切片实施染色以测定背景非特异性染色水平。
将FFPE切片脱石蜡且再水化。此后,对切片实施抗原修复(使用Lab Vision PT模块系统,Thermo Scientific),其包括在100℃下在柠檬酸盐缓冲液(Thermo Scientific,p/n.TA-250-PM1X)中加热切片20分钟,然后将切片于dH2O中冷却。然后,将切片暴露于以下7个孵育步骤(在室温下):(1)于0.03% H2O2中10min.;(2)于正常山羊血清(Vector Labs.,p/n.S-1000)稀释于PBST中的1:20稀释液中30min.;(3)于实施例1的例举的tau单克隆抗体或人源化的MC-1抗体构建体(具有框架组合:5-51重链,A27轻链)中60min.(例举的tau单克隆抗体和人源化的MC-1抗体构建体两者都均一化至1mg/ml,然后于PBST中稀释至1:4000的稀释液,之后与切片一起孵育);(4)于以1.1μg/ml的浓度于PBST中的兔抗人类IgG4(针对例举的抗体的Fc区产生)中30min.;(5)于生物素化的山羊抗兔IgG(Vector Labs., p/n. BA-1000)稀释于PBST中的1:200稀释液中30min.;(6)于抗生物素蛋白-生物素复合物溶液(Vector Labs., p/n. PK-7100)中30min.;(7)于3,3’-二氨基联苯胺(Vector Labs., p/n.SK-4105)中5min.。在上述7个步骤的每一个之间均使用PBST洗涤切片。在上述7个孵育步骤之后,用苏木精复染切片,脱水并盖上盖玻片。对于小鼠“对照”组织切片,对上述方案进行以下修改:在孵育步骤(3)中,使用例举的tau单克隆抗体和人源化的MC-1抗体构建体两者的1:8000稀释液(相对于1:4000稀释液);并用生物素化的山羊抗人类IgG(VectorLabs.,p/n. BA-3000)于PBST中的1:200稀释液中的单一30min.来替代孵育步骤(4)和(5)。
在实质上如上文所述的程序之后,实施对实施例1的例举的tau单克隆抗体与源自人类脑的tau的结合的分析。结果提供于表5中。
表5. 与FFPE AD脑切片中的聚集的tau的结合的半定量分析。
提供于表5中的结果反映,如与人源化的MC-1抗体构建体相比,在来自AD和PD患者两者的海马体脑切片中,实施例1的例举的tau单克隆抗体展示显著较高的对聚集的tau的染色水平。提供于表5中的结果也展示,实施例1的例举的tau单克隆抗体并未展示高于人源化的MC-1抗体构建体的非特异性结合(在正常对照人类切片中,例举的tau单克隆抗体展示与最少量的聚集的tau的结合)。此外,由于AD和PD特征在于编码tau的基因的独特剪接变体,所以这些结果支持如下结论:实施例1的例举的tau单克隆抗体特异性结合包含人类tau的氨基酸残基7-9和312-322(残基编号基于SEQ ID NO.13的例举的人类tau)的构象表位,该构象表位是AD和PD两者的tau聚集体共有的。
Tau聚集体传播的体外中和
已知来自约5个月龄P301S小鼠的匀浆脑制备物在天然非聚集tau存在的情况下诱导天然tau的聚集且展示tau聚集的传播样效应。将来自4.5至5个月龄P301S小鼠的脑组织的Sarkosyl不溶性匀浆制备物超声处理并用OPTI-MEM(GIBCO,Life Tech.,p/n. 31985-062)稀释以使得所测量的tau(每制备物)达到0.77μg/ml的终浓度。各制备物与实施例1的例举的tau单克隆抗体(浓度:21.00、7.00、2.33、0.78、0.26、0.09、0.03和0.01μg/ml)或人源化的MC-1抗体构建体(浓度:50.00、16.67、5.56、1.85、0.62、0.21、0.07、0.02和0.01μg/ml)之一在室温下孵育30分钟。
将HEK293细胞(人类胚肾细胞系)通过电穿孔转染以诱导性表达人类tau的突变体形式(1N4L,其在残基301处用丝氨酸取代脯氨酸(P301S)(残基编号基于SEQ ID NO.13的例举的人类tau))。(Falcon B.等人,J. Biol. Chem. 290:1049-1065,2015)。稳定转染的HEK293细胞以1×104个细胞/孔的浓度铺板于96孔板的孔中的完全培养基(D-MEM培养基(Invitrogen,p/n. 11965-092),10%胎牛血清(Invitrogen,p/n. 16000),1×青霉素链霉素(Invitrogen,p/n. 15140-122),5μg/ml杀稻瘟菌素(Blasticin,Invitrogen,p/n.R210-01),200μg/ml博莱霉素(Invitrogen,p/n. R250-01))中。将板在37℃下孵育3天。孵育后,每孔以1:1000稀释度添加1mg/ml四环素(至1μg四环素/ml培养基的终浓度)以诱导表达突变体tau。然后将板在37℃下孵育24小时。孵育后,将培养基移除并添加50μl匀浆制备物与各别浓度之一的实施例1的例举的tau单克隆抗体或人源化的MC-1抗体构建体(如上文所述制备)之一。将板孵育3小时,然后移除匀浆制备物并将100μl含有1μg/ml四环素的完全培养基和相同各别浓度的例举的tau单克隆抗体或人源化的MC-1抗体构建体添加至每一各别孔。将板在37℃下孵育24小时,然后移除培养基并将100μl完全培养基和相同各别浓度的例举的tau单克隆抗体或人源化的MC-1抗体构建体添加至各别孔。将板在37℃下孵育48小时。孵育后,用200μl DPBS洗涤细胞并流干。
将细胞重悬于每孔50μl H缓冲液(TBS,pH 7.4,含有2mM EGTA、5mM EDTA、蛋白酶和磷酸酶抑制剂(Thermo Scientific,p/n. 784420))中并超声浴处理10分钟。通过BCATM蛋白测定(Thermo Scientific,p/n. PI-23227)测量总蛋白浓度。通过夹心ELISA测定tau聚集体水平。在4℃下将96孔板用50μl 2μg/ml AT8抗体包被过夜。将板用PBST洗涤3次,然后在室温下用100μl BB3封闭1小时。使用AD脑总提取物通过在0.25%酪蛋白缓冲液中使用两倍稀释度从40μg/ml的起始浓度连续稀释至0.3125μg/ml的终浓度来制备标准曲线。将细胞裂解物稀释至0.25%酪蛋白缓冲液中至约0.1mg/ml的总蛋白浓度。然后,将50ul各标准样品稀释液或稀释的细胞样品添加至经封闭的板的单独孔中并在4℃下孵育过夜,然后将板用PBST洗涤4次。生物素化的CP27抗体以1:2000稀释于0.25%酪蛋白缓冲液中且然后将50μl添加至含有样品的孔中。将板在室温下孵育2小时,然后将板用PBST洗涤4次。将链霉抗生物素蛋白-HRP(Invitrogen, p/n. SNN2004)以1:5000稀释于0.25%酪蛋白缓冲液中且然后将50μl添加至各孔中,并将板在室温下孵育1小时。孵育后,将板用PBST洗涤4次并添加50μlH2O2和TMB的1:1混合物(Thermo Scientific,p/n. 34021)。将板在室温下孵育10min.且通过添加50μl H2SO4来终止反应。在450nm或650nm下测量比色信号。将AT8阳性tau水平针对各样品中的总蛋白水平均一化。将各样品的均一化值针对对照样品(未用抗体处理)中的AT8阳性tau水平进一步均一化。各样品中对tau聚集体传播的抑制%通过从100减去进一步均一化的值来确定,并将各样品的抑制值%输入Prism 6软件程序(GraphPad)中,其应用非线性回归曲线拟合和S型剂量反应来产生EC50值。结果提供于表6中。
表6. 代表tau聚集体传播抑制的EC50值。
实施例1的例举的工程改造的Tau Ab | 人源化MC-1 Ab构建体 | |
EC50 (表示AT8-阳性Tau聚集体传播的抑制(ng/mL)) | 16 | 476 |
。
提供于表6中的结果反映,实施例1的例举的tau单克隆抗体在抑制诱导的tau聚集体传播方面展示约30倍改善。
Tau聚集体传播的体内中和
已知来自约5个月龄P301S小鼠的匀浆脑干制备物在注射至正常10周龄雌性P301S小鼠的海马体中后诱导天然非聚集tau的聚集,展示tau聚集的传播样效应。来自4.5至5个月龄P301S小鼠的脑干组织的匀浆制备物以实质上与上文所述相同的方式来制备。
向正常10周龄雌性P301S小鼠于海马体的左半球中注射5μl匀浆脑制备物和:7.5μg实施例1的例举的tau单克隆抗体(N=12);或7.5μg对照人类IgG4抗体(N=11)。注射后4周,将小鼠处死并收集左半球和右半球,石蜡包埋,并将6μm连续切片封固于载玻片上。将含有前囟(A-P=-2.30)的载玻片脱石蜡,使包埋的组织再水化且通过于柠檬酸盐缓冲液中将载玻片加热至100℃持续20min.来实施抗原修复。将载玻片于dH2O中冷却并在室温下根据以下步骤孵育:(a)于(0.03%)H2O2中10min.;(b)于正常山羊血清的1:20稀释液中30min.;(c)于PG-5抗体的1:8000稀释液(于PBST中稀释)中60min.(PG-5抗体从Peter Davies博士,Albert Einstein College of Medicine of Yeshiva University的实验室获得;当磷酸化时,PG-5抗体特异性结合tau的残基409处的丝氨酸,残基编号基于SEQ ID NO.13的例举的人类tau);(d)于生物素化的山羊抗小鼠IgG抗体的1:200稀释液(于PBST中稀释)中30min.;(e)于抗生物素蛋白-生物素复合物溶液中30min.;和(f)于3,3’-二氨基联苯胺中5min.。使用PBST用于在各别步骤之间洗涤。于3,3’-二氨基联苯胺中孵育5min.后,将切片用苏木精复染,然后再水化并盖上盖玻片。通过Scanscope AT Slide扫描仪(Aperio)在20×放大率下测量染色信号。将PG-5免疫反应性定量并使用Imagescope软件(v.11.1.2.780,Aperio)的正像素算法表示为百分比。结果提供于表7中。
表7. 左海马体和右海马体中分别的平均%PG-5免疫反应性。
提供于表7中的结果展示,如与对照IgG4抗体相比,实施例1的例举的tau单克隆抗体降低左海马体和右海马体两者中的tau聚集水平。如所显示,与对照IgG4抗体相比,例举的tau单克隆抗体分别在左海马体中产生多60.5%的tau聚集减少并在右海马体中产生多66.5%的tau聚集减少。这些结果展示,例举的tau单克隆抗体具有针对tau聚集的传播的中和活性。
Tg4510鼠模型中的体内效力分析
转基因Tg4510小鼠表达人类tau的突变体形式(4R0N,其在残基301处用亮氨酸取代脯氨酸(P301L),Ramsden M.等人,J. Neuroscience., 25: 10637-10647 (2005)和Santacruz K.等人,Science(2005);残基编号基于SEQ ID NO.13的例举的人类tau)。Tg4510小鼠在海马体和新皮质区中展现P301L突变体人类tau的高表达水平,其展示年龄依赖性tau聚集进展。
本发明tau抗体可在Tg4510小鼠中诱导免疫原性反应。因此,为了测试本发明tau单克隆抗体用于啮齿类动物模型中长期施用的治疗潜力,构建替代鼠tau抗体,其靶向相同构象表位且相对于实施例1的例举的tau单克隆抗体反映类似水平的改善亲和力。替代tau抗体对纯化的AD tau原纤维的亲和力(EC50)为13.1pM,如上文所述(针对实施例1的例举的tau单克隆抗体)通过ELISA来测量。
将8周龄雌性Tg4510小鼠分组为3个单独组。第一组(N=15)用对照小鼠IgG1抗体(15mg/kg)每周注射两次,持续9周。第二组(N=15)用从注射有MC-1杂交瘤的小鼠腹水产生的重组MC-1抗体(15mg/kg)每周注射两次,持续9周。第三组(N=15)用替代鼠tau抗体(15mg/kg)每周注射两次,持续9周。最终施用后,将小鼠处死并收集其脑。收集皮质部分和海马体切片,石蜡包埋,并将6μm连续切片封固于载玻片上用于免疫组织化学用途。
将收集的脑的剩余皮质区在皮质体积的10倍体积的H缓冲液中通过脉冲式超声处理来匀浆化,在4℃下以21,000g旋转20min.且从各皮质收集上清液的等份试样,且通过BCATM蛋白测定(Thermo Scientific,p/n. PI-23227)根据制造商的方案来测定总蛋白水平。将剩余的上清液在4℃下以100,000g旋转1小时,丢弃上清液,并将获得的不溶性沉淀重悬于H缓冲液中(体积为丢弃的上清液体积的½)。将重悬的沉淀超声处理,且实质上如上文所述,使用AT8捕获抗体和CP27检测抗体通过ELISA来测定各沉淀中的AT8阳性tau聚集体水平。将AT8阳性tau聚集体水平针对总蛋白水平均一化。
类似地,将来自收集的脑的剩余海马体于海马体体积的10倍体积的H缓冲液中通过脉冲式超声处理来匀浆化,在4℃下以21,000g旋转20min.且从各海马体收集上清液并测定总蛋白水平。实质上如上文所述使用AT8捕获抗体和CP27检测抗体通过ELISA来测定上清液中的AT8阳性tau聚集体水平。将AT8阳性tau聚集体水平针对总蛋白水平均一化。结果提供于表8中。
表8.经由ELISA测量的皮质和海马体脑匀浆中的AT8-阳性tau聚集体的水平
提供于表8中的结果展示,相对于对照mIgG1处理的小鼠,替代鼠tau抗体分别使皮质和海马体两者中的tau聚集体水平下降24%和35%。结果进一步显示,用重组鼠MC-1抗体处理的小鼠未显示优于对照mIgG1处理的小鼠的改善的tau聚集体水平下降。
还实质上如上文所述通过免疫组织化学使用PG-5来测量从收集的脑制备的石蜡包埋切片的皮质和海马体中的tau聚集水平。通过转换成log10值将数据均一化且结果概述于表9中。
表9.皮质和海马体中的%PG-5免疫反应性的平均log10值。
提供于表9中的结果展示,相对于对照mIgG1抗体,替代鼠tau抗体降低皮质(18%)和海马体(43%)两者中的tau聚集体水平,而相对于对照mIgG1抗体,重组鼠MC-1抗体在皮质或海马体中并未展示值得注意的tau聚集体水平的降低。
工程改造的Tau单克隆抗体的物理化学性质
实施例1的例举的tau单克隆抗体展示良好溶解度、化学稳定性和物理稳定性。
溶解度:
期望足够高溶解度以能够便利地给药。例如,通过1.0mL注射将1mg/kg剂量施用于100kg患者将需要100mg/ml的溶解度。另外,还期望在高浓度下将抗体维持在不具有高分子量(HMW)聚集的单体状态。通过用10K分子量截止过滤器(Amicon U.C.过滤器,Millipore,目录号UFC903024)将15mg例举的抗体浓缩至小于100μl的体积来分析实施例1的例举的tau单克隆抗体的溶解度。使用Nanodrop 2000(Thermo Scientific)通过在A280下的UV吸光度来测量样品的终浓度。
在实质上如上文所述的程序后,实施例1的例举的tau单克隆抗体显示以下溶解度:大于140mg/ml(在pH 6的10mM柠檬酸盐缓冲液中);大于177mg/ml(在pH 6的10mM柠檬酸盐与150mM NaCl中);和大于170mg/ml(在pH 7.4的PBS缓冲液中)。另外,在高浓度下仅存在低水平的HMW(从约3%至约5.4%)且未观察到相分离。
化学和物理稳定性:
化学稳定性促进具有足够保质期的药物制剂的开发。通过将例举的tau抗体于10mM柠檬酸盐中配制至1mg/ml的浓度并缓冲至pH 4、5、6或7来评价实施例1的例举的tau单克隆抗体的化学稳定性。将配制的样品在加速降解研究中在4℃、25℃或40℃下孵育4周。抗体的电荷概况的改变(其反映化学改变)根据标准程序使用毛细管等电聚焦(cIEF)来评价。
在实质上如上文所述的程序之后,实施例1的例举的tau单克隆抗体展示呈现于表10中的化学稳定性结果。
表10. 相对于在4℃下孵育的样品,通过cIEF测量的经4周的主峰%和通过SEC测量
的HMW聚集体%的变化的概述。
提供于表10中的结果展示,在40℃下储存4周后,实施例1的例举的tau抗体当在pH5下配制时具有仅1.1个百分点的主峰减少%,且当在pH 6(抗体配制中的常用pH)下配制时具有仅0.3个百分点的减少。另外,质谱分析展示在40℃下储存4周后仅观察到最低降解(约1.5% LCDR1脱酰胺,且在所有CDR序列中降解少于5%),指示实施例1的例举的tau单克隆抗体具有足够化学稳定性以促进具有足够保质期的溶液制剂的开发。
对于比较的目的,通过将抗体在40℃下在pH8下孵育2周来实施人源化的MC-1抗体构建体(具有框架组合:5-51重链,A27轻链)的化学和物理稳定性。人源化的MC-1抗体构建体显示显著化学降解,包括LCDR1中的12%脱酰胺、HCDR3中的5%脱酰胺和10%异构化以及HC框架中的3%氧化。
在实施例1的例举的tau单克隆抗体的4周加速降解研究之后,通过将例举的单克隆抗体于10mM柠檬酸盐中配制至1mg/ml的浓度且缓冲为pH 4或6来评价结合亲和力。将配制的样品在加速降解研究中在4℃或40℃下孵育4周。孵育后,根据实质上如上文所述的ELISA程序通过直接ELISA来测定实施例1的例举的tau单克隆抗体与包被于96孔板上的rTau(15ng/ml)的结合亲和力。以一式两份实施的上文所述的结合亲和力研究的结果提供于表11中。
表11. 加速降解研究后的EC50比较。
表11展示,与在4℃下孵育的对照样品相比,对于4周加速降解之后的样品,实施例1的例举的tau单克隆抗体与低浓度的rTau的结合亲和力保持类似。
序列
SEQ ID NO: 1-实施例1的例举的tau单克隆抗体的LC
SEQ ID NO: 2-实施例1的例举的tau单克隆抗体的HC
SEQ ID NO: 3-实施例1的例举的tau单克隆抗体的LCDR1
SEQ ID NO: 4-实施例1的例举的tau单克隆抗体的LCDR2
SEQ ID NO: 5-实施例1的例举的tau单克隆抗体的LCDR3
SEQ ID NO: 6-实施例1的例举的tau单克隆抗体的HCDR1
SEQ ID NO: 7-实施例1的例举的tau单克隆抗体的HCDR2
SEQ ID NO: 8-实施例1的例举的tau单克隆抗体的HCDR3
SEQ ID NO: 9-实施例1的例举的tau单克隆抗体的LCVR
SEQ ID NO: 10-实施例1的例举的tau单克隆抗体的HCVR
SEQ ID NO: 11-编码例举的LC(SEQ ID NO: 1)的核苷酸序列
SEQ ID NO: 12-编码例举的HC(SEQ ID NO: 2)的核苷酸序列
SEQ ID NO: 13-人类全长Tau的氨基酸序列
序列表
<110> ELI LILLY AND COMPANY
<120> 针对TAU的抗体和其用途
<130> X20624
<150> US 62/121,116
<151> 2015-02-26
<160> 13
<170> PatentIn version 3.5
<210> 1
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 实施例1的例举的tau单克隆抗体的LC
<400> 1
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gln Asn Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Asp Asn Arg Phe Ser Gly Ile Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr Leu Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 2
<211> 442
<212> PRT
<213> 人工序列
<220>
<223> 实施例1的例举的tau单克隆抗体的HC
<400> 2
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Ser Asn Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Leu Pro Gly Ser Asp Ser Ile Lys Tyr Glu Lys Asn Phe
50 55 60
Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Arg Gly Asn Tyr Val Asp Asp Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440
<210> 3
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 实施例1的例举的tau单克隆抗体的LCDR1
<400> 3
Arg Ser Ser Gln Ser Leu Val His Ser Asn Gln Asn Thr Tyr Leu His
1 5 10 15
<210> 4
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 实施例1的例举的tau单克隆抗体的LCDR2
<400> 4
Tyr Lys Val Asp Asn Arg Phe Ser
1 5
<210> 5
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 实施例1的例举的tau单克隆抗体的LCDR3
<400> 5
Ser Gln Ser Thr Leu Val Pro Leu Thr
1 5
<210> 6
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 实施例1的例举的tau单克隆抗体的HCDR1
<400> 6
Lys Gly Ser Gly Tyr Thr Phe Ser Asn Tyr Trp Ile Glu
1 5 10
<210> 7
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 实施例1的例举的tau单克隆抗体的HCDR2
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Glu Ile Leu Pro Gly Ser Asp Ser Ile Lys Tyr Glu Lys Asn Phe Lys
1 5 10 15
Gly
<210> 8
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 实施例1的例举的tau单克隆抗体的HCDR3
<400> 8
Ala Arg Arg Gly Asn Tyr Val Asp Asp
1 5
<210> 9
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 实施例1的例举的tau单克隆抗体的LCVR
<400> 9
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gln Asn Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Asp Asn Arg Phe Ser Gly Ile Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr Leu Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 10
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 实施例1的例举的tau单克隆抗体的HCVR
<400> 10
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Ser Asn Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Leu Pro Gly Ser Asp Ser Ile Lys Tyr Glu Lys Asn Phe
50 55 60
Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Arg Gly Asn Tyr Val Asp Asp Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 11
<211> 657
<212> DNA
<213> 人工序列
<220>
<223> 编码例举的LC (SEQ ID NO:1)的核苷酸序列
<400> 11
gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gatctagtca gagccttgta cacagtaatc agaacaccta tttacattgg 120
taccagcaga aacctggcca ggctcccagg ctcctcatct ataaagttga caaccgattt 180
tctggcatcc cagacaggtt cagtggcagt gggtctggga cagacttcac tctcaccatc 240
agcagactgg agcctgaaga ttttgcagtg tattactgtt ctcaaagtac actggttccg 300
ctcacgttcg gcggagggac caaggtggag atcaaacgga ccgtggctgc accatctgtc 360
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgc 657
<210> 12
<211> 1326
<212> DNA
<213> 人工序列
<220>
<223> 编码例举的HC (SEQ ID NO: 2)的核苷酸序列
<400> 12
gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggggagtc tctgaagatc 60
tcctgtaagg gttctggcta cacattcagt aactactgga tagagtgggt gcgccagatg 120
cccgggaaag gcctggagtg gatgggggag attttacctg gaagtgatag tattaagtac 180
gaaaagaatt tcaagggcca ggtcaccatc tcagccgaca agtccatcag caccgcctac 240
ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgc gagaaggggg 300
aactacgtgg acgactgggg ccagggcacc ctggtcaccg tctcctcagc ttctaccaag 360
ggcccatcgg tcttcccgct agcgccctgc tccaggagca cctccgagag cacagccgcc 420
ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480
gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540
ctcagcagcg tggtgaccgt gccctccagc agcttgggca cgaagaccta cacctgcaac 600
gtagatcaca agcccagcaa caccaaggtg gacaagagag ttgagtccaa atatggtccc 660
ccatgcccac cctgcccagc acctgaggcc gccgggggac catcagtctt cctgttcccc 720
ccaaaaccca aggacactct catgatctcc cggacccctg aggtcacgtg cgtggtggtg 780
gacgtgagcc aggaagaccc cgaggtccag ttcaactggt acgtggatgg cgtggaggtg 840
cataatgcca agacaaagcc gcgggaggag cagttcaaca gcacgtaccg tgtggtcagc 900
gtcctcaccg tcctgcacca ggactggctg aacggcaagg agtacaagtg caaggtctcc 960
aacaaaggcc tcccgtcctc catcgagaaa accatctcca aagccaaagg gcagccccga 1020
gagccacagg tgtacaccct gcccccatcc caggaggaga tgaccaagaa ccaggtcagc 1080
ctgacctgcc tggtcaaagg cttctacccc agcgacatcg ccgtggagtg ggaaagcaat 1140
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1200
ttcctctaca gcaggctaac cgtggacaag agcaggtggc aggaggggaa tgtcttctca 1260
tgctccgtga tgcatgaggc tctgcacaac cactacacac agaagagcct ctccctgtct 1320
ctgggt 1326
<210> 13
<211> 441
<212> PRT
<213> 人工序列
<220>
<223> 人类全长Tau的氨基酸序列
<400> 13
Met Ala Glu Pro Arg Gln Glu Phe Glu Val Met Glu Asp His Ala Gly
1 5 10 15
Thr Tyr Gly Leu Gly Asp Arg Lys Asp Gln Gly Gly Tyr Thr Met His
20 25 30
Gln Asp Gln Glu Gly Asp Thr Asp Ala Gly Leu Lys Glu Ser Pro Leu
35 40 45
Gln Thr Pro Thr Glu Asp Gly Ser Glu Glu Pro Gly Ser Glu Thr Ser
50 55 60
Asp Ala Lys Ser Thr Pro Thr Ala Glu Asp Val Thr Ala Pro Leu Val
65 70 75 80
Asp Glu Gly Ala Pro Gly Lys Gln Ala Ala Ala Gln Pro His Thr Glu
85 90 95
Ile Pro Glu Gly Thr Thr Ala Glu Glu Ala Gly Ile Gly Asp Thr Pro
100 105 110
Ser Leu Glu Asp Glu Ala Ala Gly His Val Thr Gln Ala Arg Met Val
115 120 125
Ser Lys Ser Lys Asp Gly Thr Gly Ser Asp Asp Lys Lys Ala Lys Gly
130 135 140
Ala Asp Gly Lys Thr Lys Ile Ala Thr Pro Arg Gly Ala Ala Pro Pro
145 150 155 160
Gly Gln Lys Gly Gln Ala Asn Ala Thr Arg Ile Pro Ala Lys Thr Pro
165 170 175
Pro Ala Pro Lys Thr Pro Pro Ser Ser Gly Glu Pro Pro Lys Ser Gly
180 185 190
Asp Arg Ser Gly Tyr Ser Ser Pro Gly Ser Pro Gly Thr Pro Gly Ser
195 200 205
Arg Ser Arg Thr Pro Ser Leu Pro Thr Pro Pro Thr Arg Glu Pro Lys
210 215 220
Lys Val Ala Val Val Arg Thr Pro Pro Lys Ser Pro Ser Ser Ala Lys
225 230 235 240
Ser Arg Leu Gln Thr Ala Pro Val Pro Met Pro Asp Leu Lys Asn Val
245 250 255
Lys Ser Lys Ile Gly Ser Thr Glu Asn Leu Lys His Gln Pro Gly Gly
260 265 270
Gly Lys Val Gln Ile Ile Asn Lys Lys Leu Asp Leu Ser Asn Val Gln
275 280 285
Ser Lys Cys Gly Ser Lys Asp Asn Ile Lys His Val Pro Gly Gly Gly
290 295 300
Ser Val Gln Ile Val Tyr Lys Pro Val Asp Leu Ser Lys Val Thr Ser
305 310 315 320
Lys Cys Gly Ser Leu Gly Asn Ile His His Lys Pro Gly Gly Gly Gln
325 330 335
Val Glu Val Lys Ser Glu Lys Leu Asp Phe Lys Asp Arg Val Gln Ser
340 345 350
Lys Ile Gly Ser Leu Asp Asn Ile Thr His Val Pro Gly Gly Gly Asn
355 360 365
Lys Lys Ile Glu Thr His Lys Leu Thr Phe Arg Glu Asn Ala Lys Ala
370 375 380
Lys Thr Asp His Gly Ala Glu Ile Val Tyr Lys Ser Pro Val Val Ser
385 390 395 400
Gly Asp Thr Ser Pro Arg His Leu Ser Asn Val Ser Ser Thr Gly Ser
405 410 415
Ile Asp Met Val Asp Ser Pro Gln Leu Ala Thr Leu Ala Asp Glu Val
420 425 430
Ser Ala Ser Leu Ala Lys Gln Gly Leu
435 440
Claims (16)
1.结合人类tau的单克隆抗体,其包含轻链可变区(LCVR)和重链可变区(HCVR),其中所述LCVR包含互补决定区(CDR) LCDR1、LCDR2和LCDR3且所述HCVR包含CDR HCDR1、HCDR2和HCDR3,其中LCDR1的氨基酸序列由SEQ ID NO: 3给出,LCDR2的氨基酸序列由SEQ ID NO: 4给出,LCDR3的氨基酸序列由SEQ ID NO: 5给出,HCDR1的氨基酸序列由SEQ ID NO: 6给出,HCDR2的氨基酸序列由SEQ ID NO: 7给出且HCDR3的氨基酸序列由SEQ ID NO: 8给出。
2.权利要求1的单克隆抗体,其包含轻链可变区(LCVR)和重链可变区(HCVR),其中所述LCVR的氨基酸序列由SEQ ID NO: 9给出且所述HCVR的氨基酸序列由SEQ ID NO: 10给出。
3.权利要求1-2中任一项的单克隆抗体,其包含轻链(LC)和重链(HC),其中所述LC的氨基酸序列由SEQ ID NO: 1给出且所述HC的氨基酸序列由SEQ ID NO: 2给出。
4.DNA分子,其包含编码具有SEQ ID NO: 1的氨基酸序列的多肽的多核苷酸序列。
5.DNA分子,其包含编码具有SEQ ID NO: 2的氨基酸序列的多肽的多核苷酸序列。
6.DNA分子,其包含编码具有SEQ ID NO: 1的氨基酸序列的多肽的多核苷酸序列,和包含编码具有SEQ ID NO: 2的氨基酸序列的多肽的多核苷酸序列。
7.哺乳动物细胞,所述哺乳动物细胞包含权利要求4的DNA分子和权利要求5的DNA分子,其中所述细胞能够表达单克隆抗体,所述单克隆抗体包含具有SEQ ID NO: 1的氨基酸序列的轻链和具有SEQ ID NO: 2的氨基酸序列的重链。
8.哺乳动物细胞,所述哺乳动物细胞包含权利要求6的DNA分子,其中所述细胞能够表达单克隆抗体,所述单克隆抗体包含具有SEQ ID NO: 1的氨基酸序列的轻链和具有SEQ IDNO: 2的氨基酸序列的重链。
9.用于产生单克隆抗体的方法,所述单克隆抗体包含具有SEQ ID NO: 1的氨基酸序列的轻链和具有SEQ ID NO: 2的氨基酸序列的重链,所述方法包括在使得表达所述单克隆抗体的条件下培养权利要求7和8中任一项的哺乳动物细胞,和回收表达的单克隆抗体。
10.单克隆抗体,其由权利要求9的方法产生。
11.药物组合物,其包含权利要求1至3中任一项的单克隆抗体和一种或多种药学上可接受的载体、稀释剂或赋形剂。
12.治疗阿尔兹海默氏病、进行性核上性麻痹或匹克氏病的方法,其包括向有需要的患者施用有效量的权利要求1至3中任一项的单克隆抗体。
13.治疗阿尔兹海默氏病、进行性核上性麻痹或匹克氏病的方法,其包括向有需要的患者施用权利要求11的药物组合物。
14.权利要求1至3中任一项的单克隆抗体,其用于疗法中。
15.权利要求1至3中任一项的单克隆抗体,其用于治疗选自阿尔兹海默氏病、进行性核上性麻痹和匹克氏病的疾病。
16.权利要求1至3中任一项的单克隆抗体,其用于制造用于治疗阿尔兹海默氏病、进行性核上性麻痹或匹克氏病的药剂。
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