CN116782929A - 抗-trem1中和抗体用于治疗运动神经元变性病症的用途 - Google Patents
抗-trem1中和抗体用于治疗运动神经元变性病症的用途 Download PDFInfo
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Abstract
本发明提供了结合并且中和TREM1的抗体或其抗原结合片段,其用于在治疗运动神经元变性病症,特别是肌萎缩性侧索硬化中使用。
Description
本发明涉及抗-TREM1抗体,其用于在治疗运动神经元变性病症中使用,和更特别地用于治疗肌萎缩性侧索硬化(ALS)。
发明背景
肌萎缩性侧索硬化(ALS)是由遗传和不可遗传因素引起的多因素神经变性疾病,其导致脊髓、脑干和初级运动皮层中的运动神经元变性(Al-Chalabi和Hardiman,2013)。90%的ALS病例是散发的(sALS),而5%–20%报告了该疾病的家族史(fALS)(Al-Chalabi等人,2017)。
绝大部分的家族性ALS病例归因于在超氧化物歧化酶1基因(SOD1)中的遗传突变和在编码C9ORF72的基因中的重复核苷酸扩展(家族性ALS的大约40-50%和散发性ALS的~10%)(Philips等人,2015)。最经常使用的ALS转基因小鼠模型,SOD1小鼠,重演了人ALS病理学的许多症状。SOD1小鼠模型已在基础和转化研究中进行了广泛研究,目的是了解ALS的机制和治疗这种状况的可能方法。
ALS的散发性和家族性形式共有大多数神经病理学特征。相似的生物学途径在两者中都受到影响(Butovsky等人,2012;Lincencum等人,2010)。同时,临床表现在年龄、疾病发作的位点、疾病进展速率和存活方面是异质的(Beers,D.R.等人,2019)。ALS是非细胞自主性疾病。导致运动神经元死亡的过程是多因素的并且反映了在遗传因素和环境因素之间的复杂的相互作用。来自临床研究的证据暗示,失调的免疫应答对这种异质性做出了贡献。
神经炎症(异常的小胶质细胞和外周免疫激活)是驱动ALS的遗传和散发形式的病理性机制的共有共同特性和会聚点。不完全清楚免疫激活是否牵涉于疾病起始之中,虽然流行病学研究已显示出在ALS之前的自身免疫性疾病,包括哮喘、腹部疾病、溃疡性结肠炎等(Turner等人,2013)。另外,在疾病的临床前模型中的研究暗示,小胶质细胞的调变显著地影响疾病进展的速率(Harms等人,2014;Boille等人,2006)。
在髓样细胞上表达的触发性受体(TREM)为包括由作图定位至人染色体6P21和小鼠染色体17的MHC基因簇所编码的免疫激活性和抑制性同工型的受体。TREM是主要在髓系细胞(包括在外周中的单核细胞、嗜中性粒细胞和树突细胞,和在中枢神经系统(CNS)中的小胶质细胞)中表达的免疫球蛋白(Ig)超家族的成员。在髓样细胞-1上表达的触发性受体(TREM1)是待被鉴定的TREM家族的第一个成员,并且它与该Ig超家族的其他受体具有有限的同源性。TREM1是一种跨膜糖蛋白,其具有:单Ig-样结构域,有着与在其信号传导伙伴DAP12上的带负电荷的天冬氨酸相互作用的带(+)电荷的赖氨酸残基的跨膜区,和缺乏任何信号传导结构域的短的胞质尾(Colona,2003)。已提出通过与其所提议的天然配体(例如,肽聚糖识别蛋白1(PGRP1)、高迁移率组B1(HMGB1)、可溶性CD177、热休克蛋白70(HSP70))的相互作用的TREM1激活诱导“头-尾”TREM1同二聚体的形成。交联触发在所募集的DAP12上的免疫受体酪氨酸基激活基元(immune receptor tyrosine-based activating motif;ITAM)的磷酸化,这通过为脾酪氨酸激酶(SYK)和其下游信号传导伙伴(包括ζ-链相关蛋白激酶70(ZAP70)、casitas b-谱系淋巴瘤(Cbl)、sevenless之子(son of sevenless;SOS)和生长因子受体结合蛋白2(GRB2))提供停靠位点而使得信号传导和功能成为可能。这些相互作用通过磷脂酰肌醇-3-激酶(PI3K)、磷脂酶-C-γ2(PLC-γ2)和ERK途径触发下游信号转导。这些事件之后接着的是钙动员、转录因子(包括包含ETS的蛋白质(ELK1)、激活的T-细胞的核因子(NFAT)、AP1、c-fos、c-Jun和NF-κB)的激活。通过与其配体相互作用或者通过TREM1与Toll-样受体和NOD-样受体(NLR)的各种成员相互作用所触发的这些途径在下游导致促炎细胞因子(MCP1、IL-8、MCSF、IL6、TNFα、IL-β等)的释放,在单核细胞和树突细胞中共刺激分子的增加,和在嗜中性粒细胞中的脱颗粒(Buchon等人,2000)。
US 2018/0318379公开了,任何抑制TREM1活性和/或表达的反义试剂、RNAi试剂、基因组编辑试剂、抗体或肽可以用于治疗具有急性或慢性中枢神经系统病症的受试者。
US 9,000,127提供了破坏TREM1与其配体相互作用的抗-TREM1抗体。所公开的抗体被提供用于治疗具有炎性疾病(例如,类风湿性关节炎和炎性肠病)的个体。
WO 2017/152102公开了与TREM1蛋白相结合并且调变或增强一种或多种TREM1活性的抗体。
虽然已进行了相当多的研究来了解ALS的机制,但是对于用于治疗、预防和/或延迟ALS的发作和/或发展的另外或备选的疗法,仍然存在明显的兴趣和需要。本发明解决了这种需要。
本发明首次证实,结合并且中和TREM1的抗体在治疗运动神经元变性状况(更特别地,ALS)中是有效的。本发明首次证实,抗-TREM1抗体在体内通过减少小胶质细胞神经元摄取和小胶质细胞迁移活性而减弱脑和脊髓炎症。
发明概述
本发明证实了TREM1的作用是在神经元变性病症例如ALS的情景下小胶质细胞适应不良性神经毒性应答的关键增强剂。特别地,TREM1调变在ALS的体外、离体和体内模型中减少小胶质细胞神经元摄取、促炎细胞因子释放和小胶质细胞/外周免疫迁移活性,并且在ALS的SOD1G93A小鼠模型中减弱脑和脊髓炎症。本发明首次证实,全身地注射中和TREM1的抗-TREM1抗体提供了足够用于减少ALS疾病表型并且取得治疗效应的其在脑和脊髓组织中的水平。
本发明提供了在有此需要的受试者中治疗运动神经元变性病症的方法,所述方法包括向所述受试者施用抗-TREM1抗体或其抗原结合片段。
本发明还提供了用于在治疗运动神经元变性病症中使用的抗-TREM1抗体或其抗原结合片段。
本发明还提供了抗-TREM1抗体或其抗原结合片段在制备用于治疗运动神经元变性病症的药物中的用途。
更特别地,所述运动神经元变性病症为肌萎缩性侧索硬化。
附图简述
在下面通过参考下述附图来描述本发明,其中:
图1显示,酵母聚糖颗粒的摄取在TREM1-/-小胶质细胞中相对于WT小胶质细胞而言减少。如在图1B中所显示的,在TREM1-/-小胶质细胞中吞噬速率的该降低是在统计学上显著的(误差棒±SEM;30分钟时间点;****p<0.0001;Student’s t-检验)。
图2显示,在伤后24小时之时向伤口区域中的小胶质细胞迁移在TREM1-/-小胶质细胞中相对于WT小胶质细胞而言是更低的。黑线指明了最初的伤口边界。如在图2B中所显示的,TREM1-/-小胶质细胞的迁移能力的该降低是在统计学上显著的(16小时和24小时时间点;误差棒±SEM;****p<0.0001;Student’s t-检验)。
图3显示,在LPS刺激后,MCP-1的水平在从TREM1-/-小胶质细胞收集的上清液中相对于WT小胶质细胞而言是显著地更低的(误差棒±SEM;**p<0.01;Student’s t-检验)。
图4显示,在伤后24小时之时向伤口区域中的BV2迁移在经抗-TREM1处理的小胶质细胞中相对于经同种型抗体或载料处理的小胶质细胞而言是更低的。黑线指明了最初的伤口边界。如在图4B中所显示的,经抗-TREM1处理的BV2小胶质细胞的迁移能力的该降低是在统计学上显著的(24小时时间点;误差棒±SEM;*p<0.05,**p<0.01;单因素ANOVA,随后为Tukey多重比较检验)。
图5显示,相对于单独的PGLYRP1或未处理的对照而言,用单独的PGN-BS或PGN-BS+PGLYRP1处理MDM增加了从来自3名不同供者的MDM的TNF-α、IL-1β、IL-6和IL-8释放(误差棒±SEM;****p<0.0001;所有供者的总体平均值的双因素ANOVA,随后为Tukey多重比较检验)。对于3名供者中的3名,IL-1β水平在PGN-BS+PGLYRP1处理后相对于单独的PGN-BS而言是更高的(误差棒±SEM;***P<0.001;所有供者的总体平均值的双因素ANOVA,随后为Tukey多重比较检验)。对于3名供者中的2名,TNF-α和IL-6水平在PGN-BS+PGLYRP1处理后相对于单独的PGN-BS而言是更高的(误差棒±SEM;***P<0.001;所有供者的总体平均值的双因素ANOVA,随后为Tukey多重比较检验)。在所有3名供者中,IL-8水平在PGN-BS和PGN-BS+PGLYRP1处理之间不是显著地不同的。
图6显示,酵母聚糖颗粒的摄取和Iba1+吞噬细胞的数目在TREM1-/-小胶质细胞中相对于WT小胶质细胞而言减少。如在(B)和(C)中所显示的,被吞噬的生物颗粒和Iba1+吞噬细胞的数目的该减少是在统计学上显著的(误差棒±SEM;n=5,对于TREM1-/-,和n=6,对于WT;n=23个总脑切片/基因型,对于TREM1-/-,和14个总脑切片/基因型,对于WT;*p<0.05;Student’s t-检验)。
图7显示,突触小体的摄取在TREM1-/-小胶质细胞中相对于WT小胶质细胞而言显著地减少(误差棒±SEM;n=3只小鼠/基因型,n=12个脑切片/基因型,*p<0.05;Student’st-检验)。
图8显示,来自TREM1-/-小鼠的小胶质细胞也显示出其形态学的惊人变化。如在图8B和8C中所显示的,形态学的该修饰由在TREM1-/-小胶质细胞中相比于WT对照而言显著地更长和更分枝化的突起来反映(误差棒±SEM;n=5只小鼠,对于TREM1-/-,和6只小鼠,对于WT;n=28个脑切片,对于TREM1-/-,和14个脑切片,对于WT;*p<0.05;Student’s t-检验)。
图9显示,经抗-TREM1治疗的SOD1-G93A小鼠显示出相比于经同种型治疗的SOD1-G93A对照而言减少的小胶质细胞增生(microgliosis)。如在(B)中所显示的,来自经抗-TREM1治疗的SOD1-G93A小鼠的小胶质细胞展示出相比于经同种型治疗的对照而言减少的吞噬摄取(小胶质细胞效力)。在经抗-TREM1治疗的SOD1-G93A小鼠中还存在减少的吞噬小胶质细胞的总数目(小胶质细胞丰度)。图9C显示了来自在图9A中的图像的腹侧角区域(n=5只SOD1小鼠/组;平均值±SEM,单因素ANOVA;*p<0.05;**p<0.01)。
图10显示,相比于经同种型治疗的SOD1-G93A对照而言,用TREM1抗体治疗SOD1-G93A小鼠降低了共刺激分子(CD40、CD80、CD86)和其他激活标志物(CD68、CSFR1)的水平(误差棒±SEM;n=6只小鼠/治疗;**p<0.01,***p<0.001;****p<0.0001;Student’st-检验,用错误发现率(false discovery rate;FDR)方法)。如在图10B中所显示的,许多共刺激分子和其他激活标志物在经抗-TREM1治疗的SOD1-G93A小鼠中相比于经同种型治疗的SOD1-G93A对照而言显著地减少(箭头表示在经抗-TREM1治疗的SOD1-G93A小鼠中的显著变化)。
图11显示,经t-分布随机邻域嵌入(t-Distributed Stochastic NeighborImbedding;tSNE)分析和经平均的数据显示,在经抗-TREM1治疗的SOD1-G93A小鼠中,在脑和脾中分别21.57%和28.80%的所有免疫细胞对于抗-TREM1抗体来说是阳性的。
图12显示了:(A)小鼠和人TREM1的3D图示,其具有在小鼠TREM1结构(左)和人TREM1(中)上突显的MAB1187表位。还显示了在人TREM1上的PGLYRP1表位(右边的结构)。(B)人和小鼠TREM1序列比对,具有突显的和加有下划线的MAB1187(上面和中间)和PGLYRP1(下面)的表位。
发明详述
定义
在本文中所使用的术语“抗体”一般涉及完整(全)抗体,即其包含两条全长重链和轻链的成分。所述抗体可以进一步包含额外的结合结构域,例如按照在WO 2007/024715中所公开的分子DVD-Ig,或者在WO2011/030107中所描述的所谓的(FabFv)2Fc。因此,在本文中所使用的抗体包括二价、三价或四价全长抗体。在抗体可变区中的残基常规地按照由Kabat等人所设计的系统来进行编号。该系统阐明在Kabat等人,1987,Sequences ofProteins of Immunological Interest,US Department of Health and HumanServices,NIH,USA(以下“Kabat等人(同上)”)中。在本说明书中使用该编号系统,除非另有说明。
Kabat残基命名不总是与氨基酸残基的线性编号直接地对应。实际的线性氨基酸序列可以比在严格的Kabat编号中包含更少或额外的氨基酸,其相应于基本可变结构域结构的结构组分的缩短或插入,无论是构架区还是互补性决定区(CDR)。可以通过将在抗体的序列中与在“标准的”经Kabat编号的序列中的具有同源性的残基进行比对来对于给定抗体确定残基的正确的Kabat编号。
如在本文中所使用的,术语“抗原结合片段”可以包括常规的抗原结合片段结构,例如Fab片段、经修饰的Fab、Fab′或F(ab')2片段。抗体可以被诸如下列的酶切割为片段:木瓜蛋白酶(以产生两个Fab片段和一个Fc片段)和胃蛋白酶(以产生一个F(ab')2片段和一个pFc'片段)。所述抗原结合片段也可以包含非常规结构(即,包含以备选样式的抗体的抗原结合部分,其包括通过保留抗原结合能力而模仿抗原结合片段活性的多肽)。在这一点上,抗原结合片段包括结构域抗体或纳米抗体,例如基于VH、VL、VHH和VNAR的结构,单链抗体(scFv)、肽体(peptibody)或肽-Fc融合物,以及二聚体和多聚体抗体样分子例如双链、三链和四链抗体,或微型抗体(miniAb),其包含不同的由与寡聚化结构域相连接的scFv组成的样式。多特异性抗原结合片段的例子包括分别在国际专利申请公开号WO2009040562、WO2010035012、WO2011/08609、WO2011/030107和WO2011/061492(它们都特此通过提及而合并,相关于它们的关于抗原结合部分的讨论)中所描述的Fab-Fv、Fab-dsFv、Fab-Fv-Fv、Fab-scFv-scFv、Fab-Fv-Fc和Fab-dsFv-PEG片段。可以将Fab或Fab’缀合至PEG分子或人血清白蛋白。多特异性抗原结合片段的一个进一步的例子包括串联连接的VHH片段。一种备选的抗原结合片段包含与两个scFv或dsscFv相连接的Fab,每个scFv或dsscFv结合相同或不同的靶标(例如,一个scFv或dsscFv结合治疗靶标,和一个scFv或dsscFv通过结合例如白蛋白而增加半寿期)。这样的抗原结合片段描述在国际专利申请公开号WO2015/197772(其特此通过提及而合并,以其整体,和特别地相关于抗原结合片段的讨论)中。抗原结合片段和产生它们的方法是本领域中众所周知的,参见例如Verma等人,1998,Journal ofImmunological Methods,216,165-181;Adair和Lawson,2005.Therapeuticantibodies.Drug Design Reviews—在线2(3):209-217。也被考虑用于在本公开内容的情景下进行使用的多特异性抗体或其抗原结合片段的例子包括二价、三价或四价抗体,双-scFv,双链抗体,三链抗体,四链抗体,双抗体(bibody),和三抗体(tribody)(参见例如,Holliger和Hudson,2005,Nature Biotech 23(9):1126-1136;Schoonjans等人,2001,Biomolecular Engineering,17(6),193-202)。
术语“嵌合抗体”或功能性嵌合抗原结合片段在本文中被定义为具有源自或相应于在一个物种中发现的序列的恒定抗体区域和源自另一个物种的可变抗体区域的抗体分子。优选地,所述恒定抗体区域源自或相应于在人中发现的序列,并且所述可变抗体区域(例如,VH、VL、CDR或FR区)源自在非人动物(例如小鼠、大鼠、兔子、猴或仓鼠)中发现的序列。
如在本文中所使用的,术语“人源化抗体分子”或“人源化抗体”是指这样的抗体分子,其中所述重链和/或轻链包含一个或多个嫁接到接受者抗体(例如,人抗体)的重链和/或轻链可变区构架中的来自供者抗体(例如,非人抗体,例如鼠类单克隆抗体)的CDR(包括,如果希望,一个或多个经修饰的CDR)。关于综述,参见Vaughan等人,NatureBiotechnology,16,535-539,1998。在一个实施方案中,不是整个CDR被转移,而是来自在本文中上面所描述的CDR中的任一个的特异性决定残基中的仅一个或多个被转移至人抗体构架(参见例如,Kashmiri等人,2005,Methods,36,25-34)。在一个实施方案中,仅来自在本文中上面所描述的CDR中的一个或多个的特异性决定残基被转移至人抗体构架。在另一个实施方案中,仅来自在本文中上面所描述的CDR中的每一个的特异性决定残基被转移至人抗体构架。
人源化抗体(其包括经CDR嫁接的抗体)为具有一个或多个来自非人物种的互补性决定区(CDR)和来自人免疫球蛋白分子的构架区的抗体分子(参见例如US 5,585,089;WO91/09967)。将会意识到的是,可以仅需要转移CDR的特异性决定残基,而非整个CDR(参见例如,Kashmiri等人,2005,Methods,36,25-34)。人源化抗体可以任选地进一步包含一个或多个源自CDR所源于的非人物种的构架残基。后者经常被称为供者残基。
在本文中所使用的术语“IgG”或“IgG免疫球蛋白”或“免疫球蛋白G”或“IgG抗体”涉及属于实质上由免疫球蛋白γ基因编码的抗体类别的多肽。更具体而言,IgG包含亚类或同种型IgG1、IgG2、IgG3和IgG4。IgG抗体为由两条重链和两条轻链组成的多结构域四聚体蛋白质。IgG重链由从N-末端至C-末端以VH-CH1-CH2-CH3(分别是指重链可变结构域、重链恒定结构域1、重链恒定结构域2和重链恒定结构域3)的次序相连接的四个免疫球蛋白结构域组成。IgG轻链由从N-末端至C-末端以VL-CL(分别是指轻链可变结构域和轻链恒定结构域)的次序相连接的两个免疫球蛋白结构域组成。
如在本文中所使用的,术语“同种型”是指由重链恒定区基因编码的抗体类别(例如,IgG1、IgG2、IgG3或IgG4抗体)。更特别地,术语“同种型”是指IgG抗体类别。
在抗体和抗原结合片段的情景下,术语“分离的”是指实质上没有其他的具有不同结合特异性的抗体或抗原结合片段的抗体或其抗原结合片段。此外,抗-TREM1抗体或抗原结合片段可以实质上没有其他细胞材料和/或化学品。
在本文中所使用的术语“效应分子”包括例如抗肿瘤试剂,药物,毒素,在生物学上有活性的蛋白质,例如酶,其他抗体或抗原结合片段,合成或天然出现的聚合物,核酸及其片段,例如DNA、RNA和其片段,放射性核素,特别是放射性碘化物,放射性同位素,螯合金属,纳米颗粒,和报道基团,例如荧光化合物或可以通过NMR或ESR光谱法检测的化合物。
如在本文中所使用的,“TREM1多肽”或“TREM1蛋白”是指野生型序列和天然出现的变体序列两者。TREM1是主要在髓系细胞(包括但不限于,巨噬细胞、树突细胞、单核细胞、皮肤的朗格汉斯细胞、库普弗细胞、破骨细胞、嗜中性粒细胞和小胶质细胞)上表达的234个氨基酸的免疫球蛋白样受体膜蛋白。在一些情况下,TREM1与DAP12形成受体信号传导复合体。在一些情况下,TREM1可以磷酸化DAP12并且通过其进行信号传导。TREM1的任何片段或变体在术语“TREM1多肽”或“TREM1蛋白”的范围之内。
本发明的TREM1蛋白包括但不限于哺乳动物TREM1蛋白、人TREM1蛋白(Uniprot登录号Q9NP99;SEQ ID NO:1)、小鼠TREM1蛋白(Uniprot登录号Q9JKE2;SEQ ID NO:2)、大鼠TREM1蛋白(Uniprot登录号D4ABU7;SEQ ID NO:3)、恒河猴TREM1蛋白(Uniprot登录号F6TBB4;SEQ ID NO:4)。
多核苷酸或多肽的“片段”这一术语是指任何通过比参照序列短(例如由于末端或内部缺失)而不同于参照多核苷酸或多肽序列的多核苷酸或多肽。例如,变体可以是可变mRNA剪接的结果。可变mRNA剪接可以导致基因表达的组织特异性模式,这通过生成可以被翻译成具有不同功能和调控特性的不同蛋白质产物的多种形式的mRNA。
在本文中所使用的术语“变体”是指分别不同于参照多核苷酸或多肽的多核苷酸或多肽。变体和参照多肽可以在氨基酸序列方面相差一个或多个置换、添加、缺失、融合和截短,其可以以任何组合存在。
“衍生物”或“变体”通常包括其中在序列中出现的氨基酸不是天然出现的氨基酸而是其结构类似物的那些。在抗体的情景下,在序列中所使用的氨基酸也可以是经衍生的或经修饰的,例如经标记的,从而提供了不被显著地不利地影响的抗体的功能。
衍生物和变体可以在抗体的合成期间或者通过产生后修饰,或者当抗体以重组形式时,通过使用已知的位点定向诱变、随机诱变或酶切割和/或核酸连接技术来制备。
如在本文中所使用的,术语“同一性”表明,在所比对的序列中的任何特定位置处,在序列之间氨基酸残基是相同的。
同一性程度可以容易地进行计算(Computational Molecular Biology,Lesk,A.M.,编者,Oxford University Press,New York,1988;Biocomputing.Informatics andGenome Projects,Smith,D.W.,编者,Academic Press,New York,1993;ComputerAnalysis of Sequence Data,Part 1,Griffin,A.M.和Griffin,H.G.,编者,HumanaPress,New Jersey,1994;Sequence Analysis in Molecular Biology,von Heinje,G.,Academic Press,1987;Sequence Analysis Primer,Gribskov,M.和Devereux,J.,编者,MStockton Press,New York,1991;从NCBI可得的BLASTTM软件(Altschul,S.F.等人,1990,J.Mol.Biol.215:403-410;Gish,W.&States,D.J.1993,Nature Genet.3:266-272;Madden,T.L.等人,1996,Meth.Enzymol.266:131-141;Altschul,S.F.等人,1997,Nucleic AcidsRes.25:3389-3402;Zhang,J.&Madden,T.L.1997,Genome Res.7:649-656)。
当抗体以优先或高亲和力与它对于其来说特异性的(选择性的)蛋白质相结合但不实质上与其他蛋白质相结合或以低亲和力与其他蛋白质相结合时,抗体“特异性地结合”或“特异性地识别”或“特异于”该蛋白质。抗体的选择性可以通过测定所述抗体是否与其他相关蛋白质相结合(如上面所讨论的)或者它是否在它们之间作出区分来进一步研究。在本文中所使用的“特异性的”意欲指这样的抗体,其仅识别它所特异于的抗原;或者这样的抗体,其对于它所特异于的抗原具有显著更高的结合亲和力,相比于与它非特异于的抗原的结合而言(例如,至少5、6、7、8、9、10倍更高的结合亲和力)。结合亲和力可以通过诸如在WO2014/019727中所描述的BIAcore的技术来进行测量。
“特异性的(选择性的)”将会被理解为所述抗体与目的蛋白质相结合,而与任何其他分子没有显著的交叉反应性。交叉反应性可以通过任何合适的方法例如BIAcore来进行评估。如果抗体以它与目的蛋白质相结合的强度的至少大约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或100%与其他分子相结合,那么该抗体的交叉反应性可以被认为是显著的。
在抗体的情景下,术语“调变(modulating)”是指结合其靶抗原并且调变(例如,减少/抑制或激活/诱导)抗原功能的抗体。例如,在TREM1的情况下,调变性抗体调变配体与TREM1结合和/或一种或多种TREM1活性。
术语“中和抗体”描述了能够抑制或减弱其靶标(靶蛋白质)的生物学信号传导活性的抗体或其抗原结合片段。
如在本文中所使用的,在抗体和抗原结合片段的情景下,术语“阻断”是指这样的抗体和抗原结合片段,其阻止其他结合剂与那个抗原结合,例如封阻所述受体,但将会也包括其中所述抗体或其抗原结合片段结合表位,其引起例如构象改变,这意味着天然配体不再与所述受体相结合。
如在本文中所使用的,“在药学上可接受的载体”包括任何和所有在生理学上相容的溶剂、分散介质、包衣、抗细菌和抗真菌试剂、等渗试剂和吸收延迟试剂等。所述载体可以适合于肠胃外施用途径,例如静脉内、肌内、真皮内、眼内、腹膜内、皮下、脊柱或其他肠胃外施用途径,例如通过注射或输注。备选地,所述载体可以适合于非肠胃外施用,例如局部、表皮或粘膜施用途径。所述载体可以适合于口服施用。取决于施用途径,可以将所述调变剂包覆在材料中以保护所述化合物免于酸和其他可能使所述化合物失活的天然条件的作用。
“在药学上可接受的赋形剂”(载料、添加剂)为可以适度地施用给受试哺乳动物并且提供有效剂量的所使用的活性成分的那些惰性物质。将这些物质添加至制剂以稳定所述抗体的物理、化学和生物学结构。所述术语还是指可能被需要来到达适合于所意欲的施用方式的等渗制剂的添加剂。
“受试者”、“个体”或“患者”在本文中可互换使用,其是指脊椎动物,优选地哺乳动物,更优选地人。哺乳动物包括但不限于鼠类、大鼠、猿猴、人、农场动物、运动用动物和宠物。
在本文中所使用的术语“运动神经元疾病”是指主要(但不是必需仅仅)影响运动神经元、神经肌肉输入或在神经肌肉接头处的信号传输的疾病。上面所指的运动神经元疾病包括但不限于:肌萎缩性侧索硬化(ALS)、重症肌无力(MG)、脊髓性肌萎缩(SMA)或沙-马-图病(CMT)。
术语“预防”等是指在完全或部分防止疾病或其症状方面获得预防效应。因此,预防包括终止疾病在可能易患所述疾病但还未被诊断为具有所述疾病的受试者中出现。
术语“治疗”等是指获得所希望的药理学和/或生理学效应。所述效应可以在关于疾病和/或归因于该疾病的不良效应的部分或完全治愈方面是治疗性的。因此,治疗包括:(a)抑制所述疾病,即停止其发展;和(b)缓解所述疾病,即引起所述疾病的消退。
在治疗性应用中,向已经罹患上面所描述的病症或状况的受试者以足以治愈、减轻或部分停止所述状况或者一个或多个其症状的量施用抗体和抗原结合片段。这样的治疗性治疗可以导致疾病症状严重度的下降,或者无症状时期的频率或持续时间的增加。将足够能够完成此的量定义为“治疗有效量”。
在本文中所使用的术语“肠胃外施用”意指除了肠和局部施用之外的其他施用方式,通常通过注射。
如在本文中所使用的,“全身施用”意指施用入身体的循环系统(包括心血管和淋巴系统)中,从而影响整个身体而不是特定的部位例如胃肠道(经由例如口服或直肠施用)和呼吸系统(经由例如鼻内施用)。全身施用可以例如通过施用到肌肉组织中(肌内)、施用到真皮中(真皮内、经皮或真皮上)、施用到皮肤下面(皮下)、施用到粘膜下面(粘膜下)、施用到静脉中(静脉内)等来施行。
抗-TREM1抗体和其抗原结合片段
本发明证实,结合并且中和TREM1的抗体和其结合片段可以用于治疗其中小胶质细胞功能受到影响的疾病。这样的功能在运动神经元变性病症中(特别是在ALS中)是重要的。特别有用的是抑制一种或多种TREM1活性的抗体和其抗原结合片段。更特别地,抗体和抗原结合片段阻止TREM1与一种或多种其天然配体相互作用。
如在本文中所描述的,用于在本发明中使用的抗体包含具有全长重链和轻链的完整抗体分子。备选地,本发明使用抗原结合片段。
优选地,所述抗-TREM1抗体和其抗原结合片段为分离的抗体和其抗原结合片段。
抗原结合片段和产生它们的方法是本领域中众所周知的,参见例如Verma等人,1998,Journal of Immunological Methods,216,165-181;Adair和Lawson,2005.Therapeutic antibodies.Drug Design Reviews—在线2(3):209-217。也被考虑用于在本公开内容的情景下进行使用的多特异性抗体或其抗原结合片段的例子包括二价、三价或四价抗体,双-scFv,双链抗体,三链抗体,四链抗体,双抗体,和三抗体(参见例如,Holliger和Hudson,2005,Nature Biotech 23(9):1126-1136;Schoonjans等人,2001,Biomolecular Engineering,17(6),193-202)。
可以通过下述方式来获得针对TREM1多肽而生成的抗体,其中动物的免疫接种是必需的:向动物(优选地非人动物)施用所述多肽,其中使用众所周知和常规的实验方案,参见例如Handbook of Experimental Immunology,D.M.Weir(编者),第4卷,BlackwellScientific Publishers,Oxford,England,1986。许多温血动物例如兔子、小鼠、大鼠、绵羊、牛、骆驼或猪可以进行免疫接种。然而,小鼠、兔子、猪和大鼠通常是最合适的。
也可以使用单淋巴细胞抗体方法来生成用于在本发明中使用的抗体,通过克隆和表达从就特定抗体的产生而选择的单个淋巴细胞生成的免疫球蛋白可变区cDNA,例如通过由Babcook,J.等人,1996,Proc.Natl.Acad.Sci.USA 93(15):7843-7848l;WO92/02551;WO2004/051268;和国际专利申请号WO2004/106377所描述的方法。
更特别的抗-TREM1抗体为单克隆抗体。在一个特别的实施方案中,抗-TREM1抗体或其抗原结合片段对于TREM1来说是特异性的。
单克隆抗体可以通过本领域中已知的任何方法来制备,例如杂交瘤技术(Kohler&Milstein,1975,Nature,256:495-497)、三源杂交瘤技术、人B-细胞杂交瘤技术(Kozbor等人,1983,Immunology Today,4:72)和EBV-杂交瘤技术(Cole等人,Monoclonal Antibodiesand Cancer Therapy,第77-96页,Alan R Liss,Inc.,1985)。
在一个实施方案中,根据本公开内容的抗体或片段是人源化的。更特别地,所述抗-TREM1抗体或其抗原结合片段为人的、人源化的或嵌合的抗体或其抗原结合片段。
适宜地,根据本发明的人源化抗体或其抗原结合片段具有这样的可变结构域,其包含人接受者构架区以及所述CDR中的一个或多个,和任选地进一步包含一个或多个供者构架残基。因此,在一个实施方案中提供了与TREM1相结合的人源化抗体,其中所述可变结构域包含人接受者构架区和非人供者CDR。
当嫁接CDR或特异性决定残基时,考虑到所述CDR所源自的供者抗体的类别/类型,可以使用任何合适的接受者可变区构架序列,包括小鼠、灵长类动物和人构架区。
如果希望,可以将用于在本发明中使用的抗体与一个或多个效应分子相缀合。将会意识到的是,所述效应分子可以包含单个效应分子,或者两个或更多个此类分子,其如此地相连接以便形成可以被附接至本发明的抗体的单个部分。当希望获得与效应分子相连接的抗体、片段时,这可以通过标准的化学或重组DNA操作程序来制备,其中所述抗原结合片段直接地或经由偶联试剂连接至所述效应分子。用于将此类效应分子缀合至抗体的技术是本领域中众所周知的(参见,Hellstrom等人,Controlled Drug Delivery,第2版,Robinson等人,编者,1987,第623-53页;Thorpe等人,1982,Immunol.Rev.,62:119-58;和Dubowchik等人,1999,Pharmacology and Therapeutics,83,67-123)。特别的化学操作程序包括例如,在WO 93/06231、WO 92/22583、WO 89/00195、WO 89/01476和WO 03/031581中所描述的那些。备选地,当所述效应分子为蛋白质或多肽时,所述连接可以通过使用重组DNA操作程序来取得,例如如在WO 86/01533和EP0392745中所描述的。
抗体或其抗原结合片段包含结合结构域。结合结构域通常将会包含6个CDR,其中三个来自重链和三个来自轻链。在一个实施方案中,所述CDR在构架中并且一起形成可变区。因此,在一个实施方案中,抗体或其抗原结合片段为特异于TREM1的结合结构域,其包含轻链可变区和重链可变区。
可以在本发明中使用的人构架的例子为KOL、NEWM、REI、EU、TUR、TEI、LAY和POM(Kabat等人,同上)。例如,KOL和NEWM可以用于重链,REI可以用于轻链,和EU、LAY和POM可以用于重链和轻链两者。备选地,可以使用人种系序列;这些在http://vbase.mrc- cpe.cam.ac.uk/处可得。
在本发明的一种人源化抗体中,所述接受者重链和轻链并不必需需要源自相同的抗体,并且可以(如果希望)包含具有源自不同链的构架区的复合链。
更特别地,所述抗-TREM1抗体或其抗原结合片段包含人重链恒定区和人轻链恒定区。
更特别地,所述抗-TREM1抗体为全长抗体。更特别地,所述抗-TREM1抗体是IgG同种型的。更特别地,所述抗-TREM1抗体选自由IgG1、IgG4组成的组。
本发明的抗体分子的恒定区结构域(如果存在)可以通过考虑所提出的所述抗体分子的功能和特别是可能被需要的效应子功能来进行选择。例如,所述恒定区结构域可以是人IgA、IgD、IgE、IgG或IgM结构域。特别地,可以使用人IgG恒定区结构域,特别是IgG1和IgG3同种型的,当所述抗体分子意欲用于治疗性用途并且需要抗体效应子功能时。备选地,可以使用IgG2和IgG4同种型,当所述抗体分子意欲用于治疗目的并且不需要抗体效应子功能时。将会意识到的是,也可以使用这些恒定区结构域的序列变体。例如,可以使用其中在位置241处的丝氨酸已被变为脯氨酸的IgG4分子,如在Angal等人,Molecular Immunology,1993,30(1),105-108中所描述的。本领域技术人员还将会理解,抗体可以经历各种各样的翻译后修饰。这些修饰的类型和程度常常取决于用于表达抗体的宿主细胞系以及培养条件。此类修饰可以包括在下列方面的变动:糖基化、甲硫氨酸氧化、二酮哌嗪形成、天冬氨酸异构化和天冬酰胺脱酰胺。一种时常发生的修饰为归因于羧肽酶的作用的羧基末端碱性残基(例如,赖氨酸或精氨酸)的丢失(如在Harris,RJ.Journal of Chromatography,705:129-134,1995中所描述的)。因此,抗体重链的C-末端赖氨酸可以是不存在的。
在一个实施方案中,所述抗-TREM1抗体或其抗原结合片段以至少100mM、50mM、30nM的亲和力与TREM1相结合。
抗体或其抗原结合片段的亲和力以及抗体或其抗原结合片段抑制结合的程度可以由本领域普通技术人员来进行测定,使用常规技术,例如由Scatchard等人(Ann.KY.Acad.Sci.51:660-672(1949))所描述的那些,或者通过表面等离子体共振(SPR),其使用诸如BIAcore的系统。对于表面等离子体共振,将靶分子固定化在固相上并且暴露于在沿着流动池运行的流动相中的配体。如果发生配体与经固定化的靶标相结合,那么局部折光指数就发生变化,从而导致SPR角的变化,其可以通过检测反射光的强度的变化来实时地进行监测。可以分析SPR信号的变化速率,以产生关于结合反应的缔合和解离阶段的表观速率常数。这些值之比给出表观平衡常数(亲和力)(参见例如,Wolff等人,Cancer Res.53:2560-65(1993))。
本发明的抗体和抗原结合片段抑制一种或多种TREM1活性。这样的抑制导致在实施例中所描述的效应,特别是对于小胶质细胞功能和迁移以及不同标志物的水平的效应。本发明的抗体和其抗原结合片段可以阻断TREM1(阻断性抗体和其抗原结合片段),或者干扰TREM1与其他蛋白质相互作用,所述其他蛋白质为例如其天然配体,例如肽聚糖识别蛋白1(PGLYRP1)、高迁移率组B1(HMGB1)、可溶性CD177、热休克蛋白70(HSP70)。在一个优选的实施方案中,所述抗-TREM1抗体或其抗原结合片段阻断或阻止TREM1与PGLYRP1相互作用。
涉及抗体(特别是关于结合亲和力和特异性以及活性)的在本文中的公开内容也可应用于抗原结合片段和抗体样分子。将会意识到的是,抗原结合片段也可以以单克隆的、嵌合的、人源化的、完全人的、多特异性的、双特异性的等为特征,并且关于这些术语的讨论也涉及抗原结合片段。
在一个实施例中,所述抗体和其抗原结合片段与由SEQ ID NO:1所定义的TREM1相结合。备选地,所述抗体或其抗原结合片段与由SEQ ID NO:1所定义的TREM1多肽或者任何其变体或片段(更特别地,任何其天然出现的变体或片段)相结合。特别地,所述抗体或其抗原结合片段与和SEQ ID NO:1的氨基酸序列至少80%同一的多肽序列相结合。
上述的抗体和其抗原结合片段仅为了参考和示例目的进行描述,而并不限制本发明的范围。
抑制TREM1的所述抗-TREM1抗体或其抗原结合片段降低共刺激分子(例如,CD40、CD80、CD86)和激活标志物(例如,CD68、CSFR1)的水平。在一个特别的实施方案中,它们降低CD40、CD80、CD86、CD68和CSFR1中的一个或多个的水平。
所述抗体或其抗原结合片段还抑制小胶质细胞的迁移。小胶质细胞的迁移可以通过使用刮擦伤口测定法(scratch wound assay)来进行测量。这样的测定法通常用于测量细胞迁移。
如通过本发明所证实的,所述抗-TREM1抗体或其抗原结合片段还显示出在小胶质细胞中的吞噬速率的降低。
在一个特别的实施方案中,所述抗-TREM1抗体或其抗原结合片段与包含一个或多个从I45、M46、K47、N50、Q71、R72、P73、T75、R76、P77、S78、S92和E93中选择的残基的在小鼠TREM1上的表位相结合,其中所述残基编号根据SEQ ID NO:2。
虽然这些残基是对于小鼠TREM1的特定序列而提供的,但是技术人员可以通过使用常规技术而容易地将这些残基的位置外推至其他相应的TREM1多肽(例如,人或大鼠的)。因此,本发明还提供了与包含在这些其他TREM1序列之内的相应的残基的表位相结合的抗体。
更特别地,在本发明的一个实施方案中,所述抗-TREM1抗体或其抗原结合片段与包含一个或多个从L45、E46、K47、S50、E71、R72、P73、K75、N76、S77、H78、D92和H93中选择的残基的在人TREM1上的表位相结合,其中所述残基编号根据SEQ ID NO:1。
在一个特别的实施方案中,所述抗-TREM1抗体或其抗原结合片段阻止TREM1与PGLYRP1相互作用。
为了筛选与特定表位相结合的抗体,可以进行常规的交叉阻断测定法,例如在Antibodies,Harlow和Lane(Cold Spring Harbor Press,Cold Spring Harb.,NY)中所描述的那种。其他方法包括丙氨酸扫描突变体、肽印迹(Reineke(2004)Methods Mol Biol248:443-63)或肽切割分析。另外,可以采用诸如抗原的表位切除、表位提取和化学修饰的方法(Tomer(2000)Protein Science 9:487-496)。此类方法是本领域中众所周知的。
抗体表位也可以通过X-射线晶体学分析来进行测定。因此,本发明的抗体可以通过结合至TREM1的抗体的X-射线晶体学分析来进行评估。
抗-TREM1抗体和其抗原结合片段的体外和离体用途
本发明提供了抑制小胶质细胞的吞噬能力和/或小胶质细胞的迁移能力的体外或离体方法,所述方法包括使小胶质细胞与结合并且中和TREM1的抗体或其抗原结合片段相接触并且一起进行温育。更特别地,所述抗-TREM1抗体或其抗原结合片段阻止TREM1与一种或多种其天然配体相互作用。在一个优选的实施方案中,所述抗-TREM1抗体或其抗原结合片段阻止TREM1与PGLYRP1相互作用。
通常将细胞温育足以允许抗-TREM1抗体或其抗原结合片段与TREM1相结合并且引起生物学效应的时间。
牵涉抗-TREM1抗体或其抗原结合片段的方法可以用于取得生物学效应,如在本文的实施例中所描述的。
抗-TREM1抗体和其抗原结合片段的治疗性用途
本发明证实了TREM1的作用是在神经元变性病症例如ALS的情景下小胶质细胞适应不良性神经毒性应答的关键增强剂。特别地,TREM1抑制在ALS的体外、离体和体内模型中减少小胶质细胞神经元摄取、促炎细胞因子释放和小胶质细胞/外周免疫迁移活性,并且在ALS的SOD1G93A小鼠模型中减弱脑和脊髓炎症,如在本文的实施例中所描述的。在ALS中的TREM1抑制可以通过取消小胶质细胞的、外周免疫异常的和神经毒性的激活来终止或减弱疾病进展。
本发明提供了在有此需要的受试者中治疗或预防运动神经元变性病症的方法,所述方法包括向所述受试者施用结合并且中和TREM1的抗体或其抗原结合片段。这样的抗-TREM1抗体或其抗原结合片段以治疗有效量进行施用。特别地,这样的治疗或预防通过减少小胶质细胞神经元摄取和降低小胶质细胞迁移活性来取得。
本发明还提供了用于在治疗运动神经元变性病症中使用的结合并且中和TREM1的抗体或其抗原结合片段。
特别地,如通过实施例所证实的,所述抗-TREM1抗体或其抗原结合片段通过减少小胶质细胞神经元摄取和降低小胶质细胞迁移活性来在被诊断为具有神经元变性病症的受试者中减弱脑和脊髓炎症。
因此,本发明提供了在被诊断为具有神经元变性病症的受试者中减弱脑和脊髓炎症的方法,所述方法包括向所述受试者施用结合并且中和TREM1的抗体或其抗原结合片段。
在另外一个实施方案中,本发明提供了用于在被诊断为具有神经元变性病症的受试者中减弱脑和脊髓炎症中使用的结合并且中和TREM1的抗体或其抗原结合片段。
特别地,脑和脊髓炎症的此类减弱通过减少小胶质细胞神经元摄取和降低小胶质细胞迁移活性来取得。
更特别地,所述运动神经元变性病症为肌萎缩性侧索硬化(ALS)。在一个特别的实施方案中,ALS以在超氧化物歧化酶1基因(SOD1)中的突变为特征。
药学组合物
可以在药学组合物中提供抗-TREM1抗体或其抗原结合片段。所述药学组合物通常将会是无菌的,并且可以另外包含在药学上可接受的辅助剂和/或载体。
由于结合并且中和TREM1的抗体在治疗和/或预防在本文中所描述的病症或状况中是有用的,因此本发明还提供了药学组合物,其包含结合并且中和TREM1的抗体或其抗原结合片段,以及与之相组合的一种或多种在药学上可接受的载体、赋形剂或稀释剂。
特别地,作为包含一种或多种在药学上可接受的赋形剂、稀释剂或载体的药学组合物来提供所述抗体或其抗原结合片段。
除了在治疗上有活性的成分外,这些组合物还可以包含在药学上可接受的赋形剂、载体、稀释剂、缓冲剂、稳定剂或其他本领域技术人员熟知的材料。此类材料应当是无毒的,并且不应当干扰所述活性成分的功效。
还提供了组合物(包括药学制剂),其包含有:抗体,或者包含编码抗体的序列的多核苷酸。在某些实施方案中,组合物包含一种或多种结合并且中和TREM1的抗体,或者一种或多种包含编码一种或多种结合并且中和TREM1的抗体的序列的多核苷酸。这些组合物可以进一步包含合适的载体,例如在药学上可接受的赋形剂和/或辅助剂,包括缓冲剂,它们本领域中众所周知的。
本发明的抗体的药学组合物通过将具有所希望的纯度的此类抗体与一种或多种任选的在药学上可接受的载体相混合来制备,以冻干制剂或水溶液的形式。
上面提及的技术和实验方案的例子可以在Remington'sPharmaceuticalSciences,第20版,2000,pub.Lippincott,Williams&Wilkins中找到。
在药学上可接受的载体通常在所采用的用量和浓度下对于受者来说是无毒的,并且包括但不限于:缓冲剂,例如磷酸盐、柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(例如,氯化十八烷基二甲基苄基铵;六甲氯铵;苯扎氯铵;苄索氯铵;苯酚,丁醇或苄醇;对羟基苯甲酸烷基酯,例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;儿茶酚;雷琐酚;环己醇;3-戊醇;和间甲酚);低分子量(少于大约10个残基)多肽;蛋白质,例如血清白蛋白、明胶或免疫球蛋白;亲水聚合物,例如聚乙烯吡咯烷酮;氨基酸,例如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合试剂,例如EDTA;糖类,例如蔗糖、甘露糖醇、海藻糖或山梨糖醇;成盐抗衡离子,例如钠;金属络合物(例如,Zn-蛋白质络合物);和/或非离子型表面活性剂,例如聚乙二醇(PEG)。在本文中的示例性的在药学上可接受的载体进一步包括间质药物分散试剂,例如可溶性中性活性透明质酸酶糖蛋白(sHASEGP),例如人可溶性PH-20透明质酸酶糖蛋白,例如rHuPH20(Baxter International,Inc.)。某些示例性的sHASEGP和使用方法(包括rHuPH20)描述在US 2005/0260186和2006/0104968中。在一个方面,sHASEGP与一种或多种另外的糖胺聚糖酶例如软骨素酶相组合。
示例性的冻干抗体制剂描述在US 6,267,958中。水性抗体制剂包括在US 6,171,586和WO2006/044908中所描述的那些,后者制剂包含组氨酸-乙酸盐缓冲液。
可以将活性成分包载在微胶囊中,其例如通过凝聚技术或通过界面聚合来制备,例如分别为羟甲基纤维素或明胶微胶囊和聚(甲基丙烯酸甲酯)微胶囊,在胶体药物递送系统(例如,脂质体、白蛋白微球、微乳状液、纳米颗粒和纳米胶囊)中或在粗滴乳状液中。此类技术公开在Remington's Pharmaceutical Sciences,第16版,Osol,A.编者(1980)中。
也可以制备持续释放制备物。持续释放制备物的合适例子包括包含抗体的固体疏水聚合物的半渗透性基质,所述基质处于成形物品例如薄膜或微胶囊的形式。
待用于体内施用的制剂通常是无菌的。无菌状态可以容易地实现,例如经由通过无菌过滤膜进行过滤。
示例性的冻干抗体制剂描述在US6,267,958中。水性抗体制剂包括在US6,171,586和WO2006/044908中所描述的那些,后者制剂包含组氨酸-乙酸盐缓冲液。
所述药学组合物可以包含一种或多种在药学上可接受的盐。
在药学上可接受的载体包括水性载体或稀释剂。可以在本发明的药学组合物中使用的合适的水性载体的例子包括水、缓冲水和盐水。其他载体的例子包括乙醇,多元醇(例如,甘油、丙二醇、聚乙二醇等),和其合适的混合物,植物油例如橄榄油,和可注射有机酯例如油酸乙酯。在许多情况下,将会希望的是,在所述组合物中包括等渗试剂,例如,糖类,多元醇例如甘露糖醇、山梨糖醇,或氯化钠。
药学组合物典型地必须是无菌的并且在制备和储存条件下是稳定的。所述组合物可以被配制为溶液、微乳状液、脂质体或其他适合于高药物浓度的有序结构。
在一个实施方案中,所述抗-TREM1抗体是唯一的活性成分。在另一个实施方案中,抗-TREM1抗体与一种或多种另外的活性成分相组合。备选地,所述药学组合物包含作为唯一的活性成分的本发明的抗体,并且可以将它与其他试剂、药物或激素相组合地(例如,同时地、顺次地或分开地)独个地施用给患者。
所述载体或其他材料的精确性质可以取决于施用途径,例如口服、静脉内、皮肤或皮下、鼻、肌内和腹膜内途径。例如,固体口服形式可以包含(与活性物质一起):稀释剂,例如乳糖、右旋糖、蔗糖、纤维素、玉米淀粉或马铃薯淀粉;润滑剂,例如硅石、滑石、硬脂酸、硬脂酸镁或钙和/或聚乙二醇;粘合试剂,例如淀粉、阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素或聚乙烯吡咯烷酮;解聚试剂,例如淀粉、藻酸、藻酸盐或羟乙酸淀粉钠;泡腾混合物;染料;甜味剂;润湿剂,例如卵磷脂、聚山梨酯、硫酸月桂酯;和通常,在药学制剂中所使用的无毒并且在药理学上无活性的物质。此类药学制备物可以以已知的方式来制备,例如通过混合、颗粒化、片剂化、包糖衣或包薄膜衣过程。
口服制剂包含这样的经常采用的赋形剂,例如药物级的甘露糖醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。这些组合物采取溶液、悬浮液、片剂、丸剂、胶囊、持续释放制剂或粉剂的形式,并且包含10%至95%,优选地25%至70%的活性成分。当所述药学组合物被冻干时,可以在施用之前重构经冻干的材料,例如悬浮液。重构优选地在缓冲液中实施。
用于静脉内施用或输注的溶液可以包含例如无菌水作为载体,或者优选地,它们可以以无菌、水性、等渗盐水溶液的形式。
优选地,所述药学组合物包含人源化抗体。
治疗有效量和用量确定
可以向患者适宜地施用所述抗-TREM1抗体和药学组合物以鉴定所需要的治疗有效量。对于任何抗体,所述治疗有效量最初可以在细胞培养测定法中或者在动物模型中(通常在啮齿类动物、兔子、狗、猪或灵长类动物中)进行估计。所述动物模型也可以用于确定合适的浓度范围和施用途径。然后,这样的信息可以用于确定关于在人中施用的有用的剂量和途径。
对于人受试者的精确的治疗有效量将会取决于疾病状态的严重度,受试者的总体健康状态,受试者的年龄、体重和性别,饮食、施用的时间和频次,药物组合,反应敏感性,和对于疗法的耐受性/应答。组合物可以方便地以每剂包含预先确定量的本公开内容的活性试剂的单位剂量形式来呈现。关于在本文中所描述的实施方案中的任一个的剂量范围和用药方案包括但不限于:范围为1mg-1000mg单位剂量的用量。
抗体或药学组合物的合适的用量可以由有技能的医师来确定。在所述药学组合物中所述活性成分的实际用量水平可以变化,以便获得对于取得对于特定患者、组合物和施用方式的所希望的治疗应答来说有效的而对于患者没有毒性的所述活性成分的量。所选择的用量水平将会取决于各种各样的药物代谢动力学因素,包括所采用的特定组合物的活性,施用途径,施用时间,所采用的特定化合物的排泄速率,治疗的持续时间,与所采用的特定组合物相组合地进行使用的其他药物、化合物和/或材料,所治疗的患者的年龄、性别、体重、状况、总体健康状态和既往病史,和在医学领域中众所周知的类似因素。
合适的剂量可以例如在大约0.01μg/kg至大约1000mg/kg待治疗的患者的体重,典型地大约0.1μg/kg至大约100mg/kg待治疗的患者的体重的范围内。
可以调整给药方案以提供最佳的所希望的应答(例如,治疗应答)。例如,可以施用单剂量,可以随时间施用几个分开的剂量,或者可以如通过治疗情况的紧急性所指示的来按比例地减小或增加剂量。在本文中所使用的用量单位形式是指适合作为用于待治疗的受试者的单一用量的在物理上分散的单位;每个单位包含经计算以产生所希望的治疗效应的预先确定量的活性化合物,以及与之相联合的所需要的药学载体。
药学组合物或制剂的施用
抗体或药学组合物可以通过使用本领域中已知的各种各样方法中的一种或多种方法经由一种或多种施用途径来进行施用。如技术人员将会意识到的,施用途径和/或方式将会取决于所希望的结果而变化。对于所述抗体或药学组合物的施用途径的例子包括静脉内、肌内、真皮内、眼内、腹膜内、皮下、脊柱或其他肠胃外施用途径,例如通过注射或输注。备选地,所述抗体或药学组合物可以经由非肠胃外途径(例如,局部、表皮或粘膜施用途径)来进行施用。所述抗体或药学组合物可以是用于口服施用的。
用于施用的合适形式包括适合于肠胃外施用的形式,例如通过注射或输注,例如通过推注或连续输注,以静脉内、可吸入或皮下形式。当所述产品是用于注射或输注时,它可以采取在油性或水性载料中的悬浮液、溶液或乳状液的形式,并且它可以包含另外的试剂,例如悬浮试剂、防腐剂、稳定试剂和/或分散试剂。备选地,根据本发明的抗体或其抗原结合片段可以处于干的形式,其用于在使用前用合适的无菌液体进行重构。也可以制备适合于在注射前溶解或悬浮在液体载料中的固体形式。
优选地,全身地施用结合并且中和TREM1的抗体或其抗原结合片段。更特别地,以皮下方式或以静脉内方式施用这样的抗体或抗原结合片段。
一旦配制好,就可以向所述受试者直接施用所述药学组合物。
制品和试剂盒
还提供了试剂盒,其包含结合并且中和TREM1的抗体和其抗原结合片段以及使用说明书。所述试剂盒可以进一步包含一种或多种另外的试剂,例如在上面所讨论的另外的治疗性或预防性试剂。
在某些实施方案中,所述制品或试剂盒包括包含一种或多种本发明的抗体或者在本文中所描述的组合物的容器。在某些实施方案中,所述制品或试剂盒包括包含编码一种(或多种)所述抗体的核酸或者在本文中所描述的组合物的容器。在一些实施方案中,所述试剂盒包括产生在本文中所描述的抗体的细胞系的细胞。
因此,在本文中提供了结合并且中和TREM1的抗体或其抗原结合片段在制备药物中的用途,所述药物用于治疗运动神经元变性病症。
本发明还提供了结合并且中和TREM1的抗体或其抗原结合片段在制备药物中的用途,所述药物用于在被诊断为具有神经元变性病症的受试者中减弱脑和脊髓炎症。
在某些实施方案中,所述制品或试剂盒包括容器和在所述容器上或与所述容器相联的标签或包装附页。合适的容器包括例如瓶、小瓶、注射器、IV溶液袋等。所述容器可以从各种各样的材料(例如,玻璃或塑料)来制成。所述容器容纳本身的或者与另一种对于治疗、预防和/或诊断来说有效的组合物相组合的组合物,并且可以具有无菌进入口。在所述组合物中的至少一种试剂为本发明的抗体。所述标签或包装附页指明,所述组合物用于治疗运动神经元变性病症。
更特别地,所述运动神经元变性病症为肌萎缩性侧索硬化(ALS)。在一个特别的实施方案中,ALS以在超氧化物歧化酶1基因(SOD1)中的突变为特征。
应当注意的是,上面提及的实施方案举例说明而非限制本发明,并且本领域技术人员将会能够设计许多备选实施方案而不背离权利要求书的范围。在所述权利要求书中,置于括号之间的任何参考符号不应当被解释为限制了所述权利要求。
实施例
实施例1.TREM1敲除在体外调变小胶质细胞吞噬
通过使用缀合有pH-敏感型荧光探针的酵母聚糖吞噬测定法来评价TREM1敲除对于小胶质细胞的吞噬能力的效应。为了分离初级小胶质细胞,首先从出生后第7-8天TREM1-/-小鼠(Charles River)和B6NTac野生型(WT)匹配对照(Taconic)中分离出前脑。小心地移除脑脊膜,并且按照制造商的说明书使用木瓜蛋白酶解离系统(PapainDissociation System)(Worthington)来解离脑。将匀浆物通过40μm细胞粗滤器(Falcon)进行过滤,并且重悬浮在完全培养基中。然后,将单细胞悬浮液转移到T75瓶中并且在37℃下在5% CO2中温育7天。通过在37℃下以200rpm将瓶摇动一个小时来从混合的神经胶质细胞培养物中分离出小胶质细胞,将其重悬浮在具有20ng/ml的无载体巨噬细胞集落刺激因子(M-CSF;ThermoFisher)的完全培养基中,并且使其以20,000个细胞/孔的密度在96-孔平板(Greiner)中生长7天。然后,将细胞与缀合有的酵母聚糖生物颗粒(12.5μg/ml/孔;ThermoFisher)一起温育30分钟。在所述测定法期间使用InCell Analyzer 6000系统(GE Healthcare Life Sciences)来获取图像,其中使用InCellDeveloper Toolboxv1.9来进行细胞分割和颗粒计数。
如在图1A中所显示的,酵母聚糖颗粒的摄取在TREM1-/-小胶质细胞中相对于WT小胶质细胞而言显著地减少。
实施例2.TREM1敲除在体外降低小胶质细胞的迁移能力
TREM1敲除对于小胶质细胞的迁移能力的效应通过使用刮擦伤口迁移测定法来进行评价。为了分离初级小胶质细胞,首先从出生后第7-8天TREM1-/-小鼠(Charles River)和B6NTac野生型(WT)匹配对照(Taconic)中分离出前脑。小心地移除脑脊膜,并且按照制造商的说明书使用木瓜蛋白酶解离系统(Papain Dissociation System)(Worthington)来解离脑。将匀浆物通过40μm细胞粗滤器(Falcon)进行过滤,并且重悬浮在完全培养基中。然后,将单细胞悬浮液转移到T75瓶中并且在37℃下在5% CO2中温育7天。通过在37℃下以200rpm将瓶摇动一个小时来从混合的神经胶质细胞培养物中分离出小胶质细胞,将其重悬浮在具有20ng/ml的无载体巨噬细胞集落刺激因子(M-CSF;ThermoFisher)的完全培养基中,并且使其以30,000个细胞/插件的密度在2-孔培养插件24-孔平板(Ibidi)中生长7天。将细胞在37℃下在5% CO2中进行温育直至达到大约80%汇合。然后,小心地移出培养插件,随后用新鲜的完全培养基洗涤细胞单层并且使用EVOS数字倒置光学显微镜对刮擦区域进行成像。小胶质细胞迁移到刮擦区域中的程度通过使用ImageJ来进行定量。
如在图2A中所显示的,在伤后24小时之时向伤口区域中的小胶质细胞迁移在TREM1-/-小胶质细胞中相对于WT小胶质细胞而言是显著地更低的。
实施例3.TREM1敲除在体外降低在经LPS刺激的小胶质细胞中的MCP-1水平
为了评价TREM1敲除对于小胶质细胞分泌趋化信号的能力的效应,在脂多糖(LPS)刺激后测量MCP-1(CCL-2)(调节单核细胞/巨噬细胞的迁移和浸润的关键趋化因子)的水平。为了分离初级小胶质细胞,首先从出生后第7-8天TREM1-/-小鼠(Charles River)和B6NTac野生型(WT)匹配对照(Taconic)中分离出前脑。小心地移除脑脊膜,并且按照制造商的说明书使用木瓜蛋白酶解离系统(Papain Dissociation System)(Worthington)来解离脑。将匀浆物通过40μm细胞粗滤器(Falcon)进行过滤,并且重悬浮在完全培养基中。然后,将单细胞悬浮液转移到T75瓶中并且在37℃下在5% CO2中温育7天。通过在37℃下以200rpm将瓶摇动一个小时来从混合的神经胶质细胞培养物中分离出小胶质细胞,将其重悬浮在具有20ng/ml的无载体巨噬细胞集落刺激因子(M-CSF;ThermoFisher)的完全培养基中,并且使其以30,000个细胞/孔的密度在96-孔平板(Greiner)中生长7天。用1μg/ml的来自大肠杆菌(Escherichia coli)(O55:B5;Sigma-Aldrich)的LPS处理小胶质细胞24小时,并且收集上清液用于MCP-1水平的分析(MesoScale Discovery)。
如在图3中所显示的,在LPS刺激后,MCP-1的水平在从TREM1-/-小胶质细胞收集的上清液中相对于WT小胶质细胞而言是显著地更低的。
实施例4.抗-TREM1抗体在体外降低小胶质细胞的迁移能力
TREM1抗体调变小胶质细胞的迁移能力的能力通过使用刮擦伤口测定法来进行评价。将BV2小胶质细胞在增湿的培养箱中在37℃下在5% CO2中在完全培养基中进行维持:补充有10%胎牛血清(FBS;ThermoFisher)和1%青霉素/链霉素(P/S;ThermoFisher)的DMEM GlutaMAX(ThermoFisher)。以30,000个细胞/插件的密度将BV2小胶质细胞接种在2-孔培养插件24-孔平板(Ibidi)中。将细胞在37℃下在5% CO2中进行温育直至达到大约80%汇合。然后,小心地移出培养插件,随后用新鲜的完全培养基洗涤细胞单层。然后,用同种型(IgG2A,MAB006,R&D Systems)或抗小鼠TREM1(MAB1187,R&D Systems)抗体处理细胞,并且使用EVOS数字倒置光学显微镜对刮擦区域进行成像。小胶质细胞迁移到刮擦区域中的程度通过使用ImageJ来进行定量。
如在图4中所显示的,在伤后24小时之时向伤口区域中的BV2迁移在经抗-TREM1抗体处理的小胶质细胞中相对于经同种型抗体或载料处理的小胶质细胞而言是更低的。
实施例5.使用天然TREM1配体的TREM1激活诱导从单核细胞来源的巨噬细胞释放促炎细胞因子
为了评估使用所提出的天然TREM1配体的TREM1激活对于促炎细胞因子的释放的效应,用来自枯草芽孢杆菌(Bacillus subtilis)的肽聚糖(PGN-BS)和肽聚糖识别蛋白1(PGLYRP1)刺激人单核细胞来源的巨噬细胞(MDM)。为了生成MDM,首先通过白细胞去除法从健康人供者中分离出单核细胞。将细胞重悬浮在补充有40ng/ml的无载体巨噬细胞集落刺激因子(M-CSF;Thermo Fisher)的完全培养基(DMEM Glutamax+10% FBS+1% P/S)中并且在增湿的培养箱中在37℃下在5% CO2中在24-孔平板(Falcon)中以5×105个细胞/ml的密度培养7天。然后,如下将MDM处理24小时:未处理的对照、PGN-BS(3μg/ml;InvivoGen)、PGLYRP1(1μg/ml;R&D Systems)和PGN-BS+PGLYRP1。然后,收集上清液用于TNF-α、IL-1β、IL-6和IL-8水平的分析(MesoScale Discovery和R&D Systems Quantikine试剂盒)。
如在图5中所显示的,相对于单独的PGLYRP1或未处理的对照而言,用单独的PGN-BS或PGN-BS+PGLYRP1处理MDM增加了从来自3名不同供者的MDM的TNF-α、IL-1β、IL-6和IL-8释放。对于所有3名供者,IL-1β水平在PGN-BS+PGLYRP1处理后相对于单独的PGN-BS而言是更高的。对于3名供者中的2名,TNF-α和IL-6水平在PGN-BS+PGLYRP1处理后相对于单独的PGN-BS而言是更高的。在所有3名供者中,IL-8水平在PGN-BS和PGN-BS+PGLYRP1处理之间不是显著地不同的。
实施例6.TREM1敲除调变离体小胶质细胞吞噬
在离体急性小鼠脑切片中通过使用缀合有pH-敏感型荧光探针的酵母聚糖吞噬测定法来测量TREM1敲除对于小胶质细胞的吞噬能力的效应。解剖来自5只TREM1-/-小鼠(Charles River)和6只B6NTac野生型(WT)匹配对照(Taconic)的脑,并且使用振动切片机VT1200S切成300μm厚的矢状切片。允许切片在冰冷的人工脑脊液(A-CSF)胆碱缓冲液(其连续地用碳合气(95% O2、5% CO2)进行冒泡)中平衡1小时。然后,将它们转移到培养箱中并且在37℃下温育另外一个小时。将100μl的缀合有的酵母聚糖生物颗粒(ThermoFisher)放置在脑切片的顶部。在1小时温育后,洗涤脑切片,在4%低聚甲醛中固定1小时,并且通过与抗-Iba1(小胶质细胞标志物;Synaptic Systems)一起温育48小时来进行免疫染色。然后,将切片与抗兔的缀合有Alexa-488的二抗(ThermoFisher)一起温育3小时,并且使用DAPI(细胞核标志物;ThermoFisher)进行对比染色。然后,基于共聚焦LSM 880(Zeiss)成像以及随后的颗粒摄取的手动定量来进行离体小胶质细胞吞噬活性和形态学的定量。使用Fiji软件通过使用定制脚本来评估小胶质细胞形态学。
如在图6A中所显示的,酵母聚糖颗粒的摄取和Iba1+吞噬细胞的数目在TREM1-/-小胶质细胞中相对于WT小胶质细胞而言显著地减少。
实施例7.TREM1敲除减少离体突触小体摄取
在离体急性小鼠脑切片中评价TREM1敲除对于小胶质细胞吞噬新鲜分离的大鼠突触小体的能力的效应。从3月龄Sprague-Dawley大鼠(Charles River)中解剖出脑,置于10个体积的冰冷的HEPES缓冲蔗糖(0.32M蔗糖,4mM HEPES pH 7.4)中,并且使用Dounce匀浆器进行匀浆。将匀浆物在4℃下以1000×g旋转离心10分钟,以去除粒状核级分(P1)。将所得的上清液以15,000×g旋转离心20分钟以产生粗制突触小体粒状沉淀(P2),将其重悬浮在10个体积的HEPES缓冲蔗糖中。在以10,000×g离心另外15分钟后,将经洗涤的粗制突触小体级分(P2’)铺放到4ml的1.2M蔗糖上并且以230,000×g离心15分钟。收集中间相,铺放到4ml的0.8M蔗糖上,并且以230,000×g(SW40 Ti转子,Beckman Optima L-90K)离心15分钟以产生突触小体粒状沉淀。通过在室温和温和搅动下温育2小时,在0.1M碳酸钠(pH 9.0)中将经纯化的突触小体与基于pH-敏感型罗丹明的Red琥珀酰亚胺酯(ThermoFisher,P36600)相缀合。通过用HBSS进行多轮的洗涤和离心来去除未结合的然后将缀合有/>的突触小体重悬浮在具有5% DMSO的HBSS中并且储存在-80℃下直至使用。
如在图7A和7B中所显示的,突触小体的摄取在TREM1-/-小胶质细胞中相对于WT小胶质细胞而言显著地减少。
实施例8.TREM1敲除调变离体小胶质细胞形态学
还评价了TREM1敲除对于小胶质细胞形态学的效应。如在图8A中所显示的,来自TREM1-/-小鼠的小胶质细胞也显示出其形态学的惊人变化。如在图8B和8C中所显示的,形态学的该修饰由在TREM1-/-小胶质细胞中相比于WT对照而言显著地更长和更分枝化的突起来反映。
实施例9.抗-TREM1抗体在SOD1-G93A小鼠中减少脊髓小胶质细胞吞噬
通过使用从SOD1-G93A小鼠中分离的离体急性脊髓切片来在ALS小鼠模型中评价TREM1抗体对于小胶质细胞的吞噬能力的效应。用同种型(IgG2A,MAB006,R&D Systems)抗体或抗小鼠TREM1(MAB1187,R&D Systems)抗体对SOD1-G93A小鼠(100日龄;Jackson)进行注射(两次I.P.注射,相隔48小时)。在第二次注射后24小时,收集脊髓并且立即用于离体切片生成。选择覆盖胸部和腰部区域两者的脊髓区段,从脑脊膜中取出,并且浸入填充有低熔点琼脂糖溶液(Sigma)的模子中。在凝固(在4℃下1分钟)后,使用振动切片机VT1200S切成300μm厚的脊髓切片。允许切片在冰冷的人工脑脊液(A-CSF)胆碱缓冲液(其连续地用碳合气(95% O2、5% CO2)进行冒泡)中平衡1小时。然后,将它们转移到培养箱中并且在37℃下温育另外一个小时。将100μl的缀合有的酵母聚糖生物颗粒(ThermoFisher)放置在脊髓切片的顶部。在一小时温育后,洗涤脊髓切片,在4%低聚甲醛中固定1小时,并且通过与抗-Iba1(小胶质细胞标志物;Synaptic Systems)一起温育48小时来进行免疫染色。然后,将切片与抗兔的缀合有Alexa-488的二抗(ThermoFisher)一起温育3小时,并且使用DAPI(细胞核标志物;ThermoFisher)进行对比染色。然后,基于共聚焦LSM 880(Zeiss)成像以及随后的颗粒摄取的手动定量来进行离体小胶质细胞吞噬活性和形态学的定量。
如在图9A中所显示的,经抗-TREM1治疗的SOD1-G93A小鼠显示出相比于经同种型治疗的SOD1-G93A对照而言减少的小胶质细胞增生。如在图9B中所显示的,来自经抗-TREM1治疗的SOD1-G93A小鼠的小胶质细胞展示出相比于经同种型治疗的对照而言减少的吞噬摄取(小胶质细胞效力)。在经抗-TREM1治疗的SOD1-G93A小鼠中还存在减少的吞噬小胶质细胞的总数目(小胶质细胞丰度)。图9C显示了来自在9A中的图像的腹侧角区域。
实施例10.TREM1的抑制在SOD1-G93A小鼠中降低共刺激分子和激活标志物的水平
通过使用质谱细胞计量术(mass cytometry)方法来评估在SOD1-G93A小鼠中TREM1抗体对于脑炎症的效应。用同种型(IgG2A,MAB006,R&D Systems)抗体或抗小鼠TREM1(MAB1187,R&D Systems)抗体对SOD1-G93A小鼠(100日龄)进行注射(两次I.P.注射,相隔48小时)。在第二次注射后24小时,将小鼠麻醉并且用1X HBSS(10U/ml肝素)灌注5分钟。将前脑收集在冰冷的1X HBSS中,并且按照制造商的说明书使用木瓜蛋白酶解离系统(Worthington)来进行解离。将单细胞悬浮液进行过滤,重悬浮于在HBSS中的30%Percoll中,并且以500×g无制动地离心15分钟以去除髓磷脂。将细胞粒状沉淀用Maxpar细胞染色缓冲液(Fluidigm)进行洗涤,然后用加有稀有金属标签的抗体的混合物(Fluidigm,下面列出的标志物)染色1小时(100μl最终染色体积/样品)。将细胞在Maxpar细胞染色缓冲液中洗涤3次,并且于在PBS中的4% PFA(从16%甲醛制备的,ThermoFisher)中进行固定。在4℃下将Maxpar DNA嵌入剂(50nM,Fluidigm)与细胞一起温育过夜以鉴定活/死细胞。在PBS中洗涤两次后,将细胞在Maxpar H2O(Fluidigm)中进行洗涤并且以800×g离心5分钟。然后,将细胞重悬浮在Maxpar H2O中,并且向样品添加金属同位素珠粒标准品(EQ Four ElementCalibration Beads,Fluidigm)用于数据标准化。在CyTOF Helios质谱细胞计量仪(Fluidigm)上分析单细胞悬浮液,其中以大约500个事件/秒获取事件。使用Cytobank软件(Cytobank Inc.)来分析数据。
如在图10A中所显示的,相比于经同种型治疗的SOD1-G93A对照而言,用TREM1抗体治疗SOD1-G93A小鼠降低了共刺激分子(CD40、CD80、CD86)和其他激活标志物(CD68、CSFR1)的水平。如在图10B中所显示的,许多共刺激分子和其他激活标志物在经抗-TREM1治疗的SOD1-G93A小鼠中相比于经同种型治疗的SOD1-G93A对照而言显著地减少(箭头表示在经抗-TREM1治疗的SOD1-G93A小鼠中的显著变化)。
实施例11.在SOD1-G93A小鼠中抗-TREM1抗体的脑穿透
通过使用质谱细胞计量术方法来评估在SOD1-G93A小鼠中抗-TREM1抗体的脑穿透程度。用经生物素化的同种型(IgG2A,IC006B,R&D Systems)抗体或经生物素化的抗小鼠TREM1(BAM1187,R&DSystems)抗体对SOD1-G93A小鼠(100日龄)进行注射(两次I.P.注射,相隔48小时)。在第二次注射后24小时,将小鼠麻醉并且用1X HBSS(10U/ml肝素)灌注5分钟。将前脑和脾收集在冰冷的1XHBSS中。按照制造商的说明书使用木瓜蛋白酶解离系统(Worthington)解离脑。将单细胞悬浮液进行过滤,重悬浮于在HBSS中的30% Percoll中,并且以500×g无制动地离心15分钟以去除髓磷脂。将脾进行机械匀浆,过滤,并且使用红细胞裂解缓冲液(ThermoFisher)来去除红细胞污染物。将细胞粒状沉淀用Maxpar细胞染色缓冲液(Fluidigm)进行洗涤,然后用抗生物素(1D4-C5,Fluidigm)染色1小时(100μl最终染色体积/样品)。将细胞在Maxpar细胞染色缓冲液中洗涤3次,并且于在PBS中的4% PFA(从16%甲醛制备的,ThermoFisher)中进行固定。在4℃下将Maxpar DNA嵌入剂(50nM,Fluidigm)与细胞一起温育过夜以鉴定活/死细胞。在PBS中洗涤两次后,将细胞在MaxparH2O(Fluidigm)中进行洗涤并且以800×g离心5分钟。然后,将细胞重悬浮在Maxpar H2O中,并且向样品添加金属同位素珠粒标准品(EQ Four Element Calibration Beads,Fluidigm)用于数据标准化。在CyTOF Helios质谱细胞计量仪(Fluidigm)上分析单细胞悬浮液,其中以大约500个事件/秒获取事件。使用Cytobank软件(Cytobank Inc.)来分析数据。
如在图11中所显示的,tSNE经平均的数据显示,在经抗-TREM1治疗的SOD1-G93A小鼠中,在脑和脾中分别21.57%和28.80%的所有免疫细胞对于抗-TREM1抗体来说是阳性的。
实施例12.MAB1187的表位及其在人TREM1中的等价物的确定
制备了37个小鼠TREM1 IgV结构域(SEQ ID NO:2的位置21-136)突变体克隆的阵列。所述克隆中的每一个具有2个紧密靠近的被突变为丙氨酸的表面残基,并且使其融合至人Fc。除了所述突变体克隆外,还包括野生型克隆。突变体小鼠TREM1阵列克隆(包括野生型)的序列显示在表1中。
上述克隆中的每一个被表达为Fc融合蛋白,并且被捕获在用抗人Fc抗体进行包被的传感器上。该融合蛋白由TREM1 IgV结构域和随后的与人Fc结构域相融合的三联丙氨酸连接体组成,从而确保TREM1将会以二价样式呈现。随后,将所述传感器浸泡在抗体溶液中,并且通过使用生物层干涉量度学(Bio-Layer Interferometry;BLI)仪器(octet RED384,ForteBio)来监测结合动力学。
一旦所有突变体TREM1 Fc克隆已经加载在传感器尖头(38个使用的尖头/轮)上,就将传感器浸泡在包含抗体(对于其表位需要鉴定)的溶液中。通过监测所述抗体与这些突变体中的每一个的结合动力学并且将它们与针对野生型蛋白质的动力学进行比较,我们可以推断出表位。关于克隆的ab解离常数的下降指明,经突变的残基对于抗体结合来说是重要的并且因此是其表位的一部分。
将上述小鼠TREM1阵列加载在38个抗人Fc传感器上,并且用于监测R+D单克隆抗体MAB1187的动力学。结果显示在表2中。
使用上述方法,已经确定了如下表位:残基I45、M46、K47、N50、Q71、R72、P73、T75、R76、P77、S78、S92和E93(所述位置相应于SEQ ID NO:2)。
使用Clustal omega(也可以使用pyMol,其做结构比对)比对了小鼠和人TREM1序列。已经鉴定了下面的在人TREM1中的相应的表位残基(所述位置相应于SEQ ID NO:1):L45、E46、K47、S50、E71、R72、P73、K75、N76、S77、H78、D92和H93。
图12A显示了小鼠和人TREM1的3D图示,其具有在小鼠TREM1结构和人TREM1上的MAB1187表位。还显示了在人TREM1上的PGLYRP1表位(右边的结构)。人和小鼠TREM1的序列比对(具有MAB1187和PGLYRP1的表位)表明,MAB1187以阻止TREM1与PGLYRP1配体结合的方式与TREM1相结合。
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实施例13.MAB1187的结合动力学
在25℃下在Biacore T200仪器上通过表面等离子体共振来测量Mab1187与小鼠TREM1结合的动力学。
将山羊抗大鼠IgG,Fc片段特异性抗体(F(ab)’2片段,Jackson ImmunoResearch112-005-071),通过胺偶联化学固定化在CM5传感器芯片上,至大约10000RU的水平。用相同的胺偶联化学处理参照池,但不使其与所述抗体相接触。在胺偶联完成后,使所有随后的溶液连续地流过参照池和样品池,并且在在整个运行期间从样品池中减去参考池的应答。
每个分析循环由下列组成:将大约250RU的MAB1187捕获至抗-Fc表面,注射分析物180秒(在25℃下以30μl/分钟的流速),解离分析物600秒,随后为表面再生(50mM HCl的60秒注射,5mM NaOH的30秒注射,和50mM HCl的进一步的60秒注射)。以在HBS-EP+运行缓冲液(GE Healthcare)中的3-倍系列稀释以300nM至3.7nM的浓度注射小鼠TREM-1分析物(内部,加有his标签的)。包括了缓冲液空白注射以减去仪器噪声和漂移。
使用Biacore T200评价软件(3.0版),通过使用1:1结合模型来测定动力学参数。将RI(表示整体偏移(bulk shift))和Rmax(表示完全结合的复合物的信号)的拟合参数均设定为使用局部拟合。MAB1187显示出具有26nM的对于小鼠TREM1的亲和力。动力学参数汇总于表3中。
表3.MAB1187与小鼠TREM1结合的动力学参数
ka(1/Ms) | kd(1/s) | KD(nM) | n= |
2.0E+05 | 5.1E-03 | 26 | 1 |
实施例14.在SOD1-G93A小鼠中抗-TREM1抗体的脑穿透
还评估了在SOD1-G93A小鼠中抗-TREM1抗体的脑穿透程度,其中通过质谱法检测液相色谱法(LCMS/MS)来对所述抗体进行定量。以30mg/kg用抗-TREM1抗体(#MAB1187,克隆174031,R&Dsystems)以腹膜内方式对SOD1-G93A小鼠(15周龄)及其非转基因同窝出生幼仔对照进行注射(n=3只动物/基因型)。在抗体注射后48小时从侧尾静脉中将用于血浆分离的血液收集在包含凝血激活剂的microvette管(CB 300,16.440,Sarstedt)中。通过使血液在室温下凝固30-60分钟并且随后在4℃下以2000g离心10分钟来获得血清。收集上清液,在干冰上缓慢冷冻,并且储存于-80℃直至进一步使用。之后,用0.1ml的未稀释的戊巴比妥(Dolethal,Vetoquinol)来使动物麻醉并且用补充有0.2%肝素的HBSS以6ml/分钟经心脏灌注5分钟。快速解剖脊髓和脑半球,在液氮中闪冻,并且储存于-80℃直至进一步使用。
制备样品用于使用全裂解测定法的分析。首先将脑和脊髓样品在PBS缓冲液中稀释2倍,然后用Precellys匀浆器(Bertin Instruments)仪器以4500rpm混合2次,持续30秒。将25μL的每个样品等分到micronic管中,以及校准标准品、质量控制样品和空白。然后,向每个管添加30μL的内部标准工作溶液,其通过在33/67H2O/ACN中稀释储备溶液来制备。因此,使用7μL的TCEP来使样品变性并且将其在室温下温育30分钟。之后,使用7μL的碘乙酰胺来使样品烷基化并且将其在室温和避光条件下温育30分钟。向每个管添加170μL/孔的混合物,其由7μL的L-半胱氨酸、153μL的pH 7.9的碳酸氢铵pH 7.9缓冲液和10μL的胰蛋白酶溶液(以在乙酸中0.5mg/mL)组成。将样品在37℃下过夜温育16至21小时。然后,将样品以大约1500g离心5分钟。通过将100μL的上清液转移至包含100μL的92% H2O、5%MeOH、3%甲酸的96-孔平板来终止胰蛋白酶消化反应。通过二维LC-MS/MS来分析所述平板。仪器为来自Shimadzu的超高效液相色谱仪,其与来自Sciex的三重四极质谱仪(6500+system)相偶联。对于第一维LC,所使用的固定相为来自Waters的尺寸为2.1×100mm的BEH C4柱,而所使用的流动相为碳酸氢盐缓冲液10mM/MEOH 95/5和碳酸氢盐缓冲液10mM/MEOH 5/95。对于第二维LC,所使用的固定相为来自Waters的尺寸为2.1×100mm的BEH C18柱,而所使用的流动相为H2O+0.1%丙酸和ACN+0.1%甲酸。以MRM模式使用所述MS仪器,并且对于标识肽(signature peptide)和内部标准分别使用下面的跃迁来监测两个目的肽:615,330->654,382和421,9->513,3。数据处理在Analyst软件(Sciex)上进行。
在血清、脑或脊髓中的抗体的暴露水平方面,在SOD1-G93A小鼠和野生型小鼠之间不存在值得注意的差异。在SOD1-G93A小鼠中观察到的在腹膜内施用30mg/kg后48小时的关于抗-TREM1抗体的平均浓度在血清、脑和脊髓中分别为259μg/mL、0.826μg/g和0.874μg/g,和在野生型小鼠中在血清、脑和脊髓中分别为277μg/mL、0.998μg/g和1.114μg/g。在腹膜内施用30mg/kg后48小时观察到的抗-TREM1抗体的脑与血清浓度比在SOD1-G93A小鼠和野生型小鼠中分别为0.33%和0.38%。在腹膜内施用30mg/kg后48小时观察到的抗-TREM1抗体的脊髓与血清浓度比在SOD1-G93A小鼠和野生型小鼠中分别为0.42%和0.35%。在腹膜内施用30mg/kg后48小时观察到的抗-TREM1抗体的脑与脊髓浓度比在SOD1-G93A小鼠和野生型小鼠中分别为0.85%和0.95%,这暗示了在脑和脊髓中相似的对于抗-TREM1抗体的暴露。这些数据暗示,对于所述抗体的CNS暴露为大约0.3%的在血清中的水平,并且在SOD1-G93A小鼠和野生型小鼠之间不存在在暴露方面的差异。脑与血清比和脊髓与血清比与在啮齿动物中用其他抗体所报道的值相似。
在本文中所引用的所有参考文献,包括专利、专利申请、论文、教科书等,以及在其中所引用的参考文献(就它们尚未被引用来说),特此通过提及而以其整体合并入本文。
参考文献
Al-Chalabi和Hardiman,(2013)Nat Rev Neurol.9(11):617-28
Al-Chalabi等人,(2017)Nat Rev Neurol.13(2):96-104
Beers,D.R.等人,(2019)Lancet Neurol.18(2):211-220
Boille,S.等人,(2006)Science 312:1389-1391
Buchon,A等人,(2000)J.Immunol.164:4991-4995
Butovsky等人,(2012)J Clin Inv 122(9):3063-308
Colona,M.(2003)Nat.Immunol.Rev.3:1-9
Harms,M.等人,(2014)82(10supplement)Neurology
Lincencum等人,(2010)Nat Genetics 42(5):392-9
Philips等人,(2015)Curr Protoc Pharmacol.1M 69
Turner,M.等人,(2013)Neurology.81(14):1222-1225
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His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Ala
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Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
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His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
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<212> PRT
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His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
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Val Thr Lys Gly
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<211> 116
<212> PRT
<213> 人工序列
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<223> 突变体序列
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Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
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Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
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Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
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His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
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Val Thr Lys Gly
115
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<211> 116
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<213> 人工序列
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Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
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Val Thr Gln Arg Pro Phe Ala Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
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Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 20
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
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Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
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Lys Ala Trp Gln Arg Leu Pro Ala Gly Ala Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 21
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 21
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Ala Ala Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 22
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 22
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Ala Pro Ala Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 23
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 23
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Ala Ala Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 24
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 24
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Ala Ala Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 25
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 25
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Ala Ala Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 26
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 26
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Ala Ala Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 27
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 27
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Ala Ala Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 28
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 28
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ala Ala Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 29
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 29
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val Ala Ala Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 30
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 30
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Ala Val His Met Gly Lys
50 55 60
Phe Thr Leu Ala His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 31
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 31
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Ala Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Ala Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 32
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 32
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ala Ala Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 33
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 33
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Ala Ala Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 34
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 34
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Ala Ala Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 35
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 35
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Ala Ala Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 36
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 36
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
Ala Ala Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 37
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 37
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Ala Ala Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 38
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 38
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Ala Ala Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 39
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 39
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Ala Ala Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 40
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 40
Ala Ile Val Leu Glu Ala Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe Ala Pro Val Arg Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 41
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 41
Ala Ile Val Leu Glu Glu Glu Ala Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Ala Leu Val
100 105 110
Val Thr Lys Gly
115
<210> 42
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 突变体序列
<400> 42
Ala Ile Val Leu Glu Glu Glu Arg Tyr Asp Leu Val Glu Gly Gln Thr
1 5 10 15
Leu Thr Val Lys Cys Pro Phe Asn Ile Met Lys Tyr Ala Asn Ser Gln
20 25 30
Lys Ala Trp Gln Arg Leu Pro Asp Gly Lys Glu Pro Leu Thr Leu Val
35 40 45
Val Thr Gln Arg Pro Phe Thr Arg Pro Ser Glu Val His Met Gly Lys
50 55 60
Phe Thr Leu Lys His Asp Pro Ser Glu Ala Met Leu Gln Val Gln Met
65 70 75 80
Thr Asp Leu Gln Val Thr Asp Ser Gly Leu Tyr Arg Cys Val Ile Tyr
85 90 95
His Pro Pro Asn Asp Pro Val Val Leu Phe His Pro Val Arg Leu Val
100 105 110
Val Ala Ala Gly
115
Claims (21)
1.在有此需要的受试者中治疗运动神经元变性病症的方法,所述方法包括向所述受试者全身地施用结合并且中和TREM1的抗体或其抗原结合片段。
2.结合并且中和TREM1的抗体或其抗原结合片段,其用于在治疗运动神经元变性病症中使用,其中全身地施用所述抗体或其抗原结合片段。
3.结合并且中和TREM1的抗体或其抗原结合片段在制备药物中的用途,所述药物用于全身施用以治疗运动神经元变性病症。
4.根据权利要求1至3中任一项的方法、抗体或其抗原结合片段或者用途,其中所述抗体或其抗原结合片段阻止TREM1与一种或多种其天然配体相互作用。
5.根据权利要求4的方法、抗体或其抗原结合片段或者用途,其中所述天然配体为肽聚糖识别蛋白1(PGLYRP1)。
6.根据权利要求1至4中任一项的方法、抗体或其抗原结合片段或者用途,其中所述运动神经元变性病症为肌萎缩性侧索硬化(ALS)。
7.根据权利要求5的方法、抗体或其抗原结合片段或者用途,其中所述ALS以在SOD1基因中存在突变为特征。
8.根据权利要求1至4中任一项的方法、抗体或其抗原结合片段或者用途,其中所述抗体或其抗原结合片段以皮下方式或以静脉内方式进行施用。
9.根据权利要求1至4中任一项的方法、抗体或其抗原结合片段或者用途,其中所述抗体或其抗原结合片段以至少50nM的亲和力与TREM1相结合。
10.根据权利要求1至4中任一项的方法、抗体或其抗原结合片段或者用途,其中所述治疗减少小胶质细胞神经元摄取。
11.根据权利要求1至4中任一项的方法、抗体或其抗原结合片段或者用途,其中所述治疗抑制小胶质细胞的迁移。
12.根据权利要求11的方法、抗体或其抗原结合片段或者用途,其中所述迁移通过使用刮擦伤口测定法来进行测量。
13.根据权利要求1至4中任一项的方法、抗体或其抗原结合片段或者用途,其中所述抗体或其抗原结合片段降低在小胶质细胞中的吞噬速率。
14.根据权利要求1至4中任一项的方法、抗体或其抗原结合片段或者用途,其中所述抗体或其抗原结合片段为单克隆抗体或其抗原结合片段。
15.根据权利要求1至4中任一项的方法、抗体或其抗原结合片段或者用途,其中所述抗体或抗原结合片段为人的、人源化的或嵌合的抗体或其抗原结合片段。
16.根据权利要求1至4中任一项的方法、抗体或者用途,其中所述抗体为全长抗体。
17.根据权利要求1至4中任一项的方法、抗体或其抗原结合片段或者用途,其中所述抗体或抗原结合片段包含人重链恒定区和人轻链恒定区。
18.根据权利要求1至4中任一项的方法、抗体或者用途,其中所述抗体是IgG同种型的。
19.根据权利要求1至4中任一项的方法、抗体或者用途,其中所述抗体为IgG1或IgG4。
20.根据权利要求1至19中任一项的方法、抗体或其抗原结合片段或者用途,其中作为包含一种或多种在药学上可接受的赋形剂、稀释剂或载体的药学组合物来提供所述抗-TREM1抗体或抗原结合片段。
21.抑制小胶质细胞的吞噬能力和/或小胶质细胞的迁移能力的体外或离体方法,所述方法包括使小胶质细胞与结合并且中和TREM1的抗体或其抗原结合片段相接触并且一起进行温育。
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PCT/EP2020/080672 WO2022089767A1 (en) | 2020-11-02 | 2020-11-02 | Use of anti-trem1 neutralizing antibodies for the treatment of motor neuron neurodegenerative disorders |
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EP (1) | EP4237081A1 (zh) |
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Family Cites Families (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8422238D0 (en) | 1984-09-03 | 1984-10-10 | Neuberger M S | Chimeric proteins |
DK336987D0 (da) | 1987-07-01 | 1987-07-01 | Novo Industri As | Immobiliseringsmetode |
GB8719042D0 (en) | 1987-08-12 | 1987-09-16 | Parker D | Conjugate compounds |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
GB8907617D0 (en) | 1989-04-05 | 1989-05-17 | Celltech Ltd | Drug delivery system |
GB8928874D0 (en) | 1989-12-21 | 1990-02-28 | Celltech Ltd | Humanised antibodies |
CA2090126C (en) | 1990-08-02 | 2002-10-22 | John W. Schrader | Methods for the production of proteins with a desired function |
GB9112536D0 (en) | 1991-06-11 | 1991-07-31 | Celltech Ltd | Chemical compounds |
GB9120467D0 (en) | 1991-09-26 | 1991-11-06 | Celltech Ltd | Anti-hmfg antibodies and process for their production |
US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
US6171586B1 (en) | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
US6908963B2 (en) | 2001-10-09 | 2005-06-21 | Nektar Therapeutics Al, Corporation | Thioester polymer derivatives and method of modifying the N-terminus of a polypeptide therewith |
AU2003285578B2 (en) | 2002-12-03 | 2010-07-15 | Ucb Pharma S.A. | Assay for identifying antibody producing cells |
US7871607B2 (en) | 2003-03-05 | 2011-01-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases |
US20060104968A1 (en) | 2003-03-05 | 2006-05-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases |
GB0312481D0 (en) | 2003-05-30 | 2003-07-09 | Celltech R&D Ltd | Antibodies |
JO3000B1 (ar) | 2004-10-20 | 2016-09-05 | Genentech Inc | مركبات أجسام مضادة . |
BRPI0615026A8 (pt) | 2005-08-19 | 2018-03-06 | Abbott Lab | imunoglobulina de domínio variável duplo e seus usos |
US8629246B2 (en) | 2007-09-26 | 2014-01-14 | Ucb Pharma S.A. | Dual specificity antibody fusions |
BRPI0918947A2 (pt) | 2008-09-26 | 2015-12-01 | Ucb Pharma Sa | proteína de fusão de anticorpo |
CN102497833B (zh) | 2009-07-14 | 2014-12-03 | 波技术视觉系统公司 | 眼科手术测量系统 |
WO2011030107A1 (en) | 2009-09-10 | 2011-03-17 | Ucb Pharma S.A. | Multivalent antibodies |
GB0920127D0 (en) | 2009-11-17 | 2009-12-30 | Ucb Pharma Sa | Antibodies |
LT2814844T (lt) | 2012-02-15 | 2017-10-25 | Novo Nordisk A/S | Antikūnai, kurie jungiasi ir blokuoja ekspresuotą ant mieloidinių ląstelių inicijuojantį receptorių 1 (trem-1) |
US9550830B2 (en) * | 2012-02-15 | 2017-01-24 | Novo Nordisk A/S | Antibodies that bind and block triggering receptor expressed on myeloid cells-1 (TREM-1) |
GB201208370D0 (en) | 2012-05-14 | 2012-06-27 | Ucb Pharma Sa | Antibodies |
GB201411320D0 (en) | 2014-06-25 | 2014-08-06 | Ucb Biopharma Sprl | Antibody construct |
EP3423493A2 (en) | 2016-03-04 | 2019-01-09 | Alector LLC | Anti-trem1 antibodies and methods of use thereof |
US20180318379A1 (en) | 2017-05-01 | 2018-11-08 | The Board Of Trustees Of The Leland Stanford Junior University | Inhibition of triggering receptor expressed on myeloid cells 1 (trem1) to treat central nervous system disorders |
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