CN1606694A - 监测和治疗肌萎缩性侧索硬化症的方法 - Google Patents
监测和治疗肌萎缩性侧索硬化症的方法 Download PDFInfo
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Abstract
本发明提供一种监测肌萎缩性侧索硬化(ALS)症发展的方法和监测ALS治疗效果的方法,通过测定ALS患者外周血中CD14+单核细胞的HLA-DR表达水平和/或CD14+细胞群中CD16+细胞所占百分比和/或CD14+/CD16+细胞的数量来实现。本发明还涉及减少ALS患者体内循环性CD14+单核细胞和/或CD14+/CD16+细胞群和/或CD14+/CD16+细胞的方法。本发明还涉及筛选能够减少ALS患者体内HLA-DR高表达CD14+单核细胞和/或CD14+/CD16+细胞群和/或CD14+/CD16+细胞的药物的方法。
Description
相关申请
本申请要求2001年11月16日美国临时申请60/333,263的优先权。
技术领域
本发明涉及肌萎缩性侧索硬化(ALS)症和免疫功能。更具体地说,本发明涉及活化单核细胞或异常巨噬细胞,并涉及ALS发展和治疗的监测,以及ALS患者的治疗。
背景技术
肌萎缩性侧索硬化(ALS),俗称Lou Gehrig′s病,是一种神经退行性疾病,其特征在于大脑和脊索内上位和/或下位运动神经元的选择性丧失。患者表现出不同的症状,包括肌肉抽搐和痉挛,丧失对手和手臂的运动控制,手臂和腿功能残缺,衰弱和疲劳,绊倒和跌倒,无法握持,口齿不清,以及呼吸或吞咽困难。ALS最终会导致死亡。
通常,ALS在神经病理学上以脑干、脊索和脑皮层内运动神经元退化为特征。临床上,ALS的特征包括肌肉进行性衰弱、机能丧失和震颤(痉挛),并伴有僵直、反射亢进和病理性皮质脊髓束病变。
兴奋性中毒和氧化应激是参与ALS运动神经元细胞死亡的至少两项机制(Kalra等,(1999),J.Neurol.Sci.,165:S27-32)。支持兴奋性中毒参与ALS这一观点的发现之一是发现ALS患者脑脊髓液中谷氨酸水平升高,而且,患者中枢神经系统(CNS)中谷氨酸受体的数量和功能发生改变(Rothstein等,(1990)Ann.Neurol.,28:18-25;Shaw等,(1995)Neurodegeneration,4:209-216;Gredal等(1996),J.Neurol.Sci.,143:121-125;Virgo等(1995),Brain Res.,676:196-204)。氧化应激和反应性氧参与ALS的许多证据来自部分家族性ALS病例中发现了超氧化物歧化酶(SOD1)基因突变(Deng等,(1993),Science,261:1047-1051;Rosen等(1993),Nature,362:59-62)。已证明,表达人突变SOD1的转基因小鼠的运动神经元特别易受自由基的损伤(Gurney等(1994),Science,264:1772-1775),并且,在ALS患者和SOD1转基因小鼠的CNS组织中都发现了蛋白质、脂类和核酸的氧化性改变(Ferrante等(1997),J.Neurochem,69:2064-2074;Hall等(1998),J.Neurosci.Res.,53:66-77;Ferrante等(1997)Ann.Neurol.,42:326-334)。
免疫功能失调也被提出可能与ALS相关。例如,在ALS脊索内发现有证据表明发生了细胞介导的应答。例如,ALS脊索内发现有辅助T淋巴细胞和细胞毒T淋巴细胞,以及表达主组织相容性糖蛋白HLA-A、B、C和HLA-DR的反应性小神经胶质细胞(McGeer等,(1991),Can.J.Neurol.Sci.,18:376-379)。ALS患者肌肉活组织样本中发现了主要由T淋巴细胞和巨噬细胞构成的细胞浸润(Troost等(1992),Clin.Neuropathol.,11:115-120)。萎缩肌肉纤维周围的T细胞和巨噬细胞大多数高水平地表达HLA-DR,显示细胞处于激活状态,并且表明这些细胞参与了ALS相关性肌肉萎缩。此外,ALS患者外围神经的神经内膜中也发现了表达HLA-DR的Schwann细胞(Olivera等(1994),Arq.Neuropsiquiatr.,52:493-500)。
ALS可通过多种测试和检查来诊断,其中包括肌肉和神经活组织检查、腰椎穿刺、X光、磁共振造影(MRI)和电诊断试验,其中许多牵涉伤害性过程或复杂的造影和分析。所以,仍需一项关于ALS疾病进程的简易测定方法以用于疾病的监测和ALS潜在治疗方法的评价。
本发明参考了在此引用的所有专利和非专利公开文献。
发明内容
本发明提供一种监测ALS治疗效果的方法,包括检测个体的外周血样品中CD14+细胞的HLA-DR表达水平和/或异常巨噬细胞的水平。
因此,本发明内容之一,比较治疗前和治疗期间外周血中CD14+细胞的HLA-DR表达水平和/或CD14+/CD16+细胞数量和/或CD14+细胞群中CD16+细胞所占百分比,由此确定ALS治疗效果,CD14+细胞的HLA-DR表达水平和/或CD14+/CD16+细胞数量和/或CD14+细胞群中CD16+细胞所占百分比趋于降低表明有效。
本发明还提供监测ALS患者病情发生、发展的方法,包括测定ALS患者外周血样品中异常巨噬细胞水平。
因此,本发明另一内容,比较病程的不同时刻外周血中CD14+细胞的HLA-DR表达水平和/或CD14+/CD16+细胞数量和/或CD14+细胞群中CD16+细胞所占百分比,由此监测ALS发展,CD14+细胞的HLA-DR表达水平和/或CD14+/CD16+细胞数量和/或CD14+细胞群中CD16+细胞所占百分比升高表明病情加重和/或发展加速。
本发明还提供减少ALS患者体内CD14+单核细胞,尤其是活化的循环性CD14+单核细胞的方法,包括给予减少CD14+单核细胞有效量的多胺类似物。
本发明还提供减少ALS患者体内活化、循环单核细胞的方法,包括给予减少活化、循环单核细胞有效量的多胺类似物。
本发明还提供减少ALS患者体内异常巨噬细胞的方法,是通过给予患者减少HLA-DR高表达CD14+细胞有效量的多肽类似物。
本发明还提供通过给予减少CD14+/CD16+细胞有效量的多胺类似物来减少ALS患者体内异常巨噬细胞的方法。
本发明还提供筛选能有效减少ALS相关CD14+单核细胞尤其是活化循环单核细胞的药物的方法。
本发明还提供筛选能有效减少ALS相关异常巨噬细胞的药物的方法,是通过检测候选药物存在和不存在时HLA-DR高表达CD14+细胞活度的差异,所述HLA-DR高表达CD14+细胞获自ALS患者血样。
本发明还提供另一种筛选能有效减少ALS相关异常巨噬细胞的药物的方法,是通过通过检测候选药物存在和不存在时CD14+/CD16+细胞活度的差异,所述CD14+/CD16+获自ALS患者血样。
本发明还提供辅助ALS诊断或预防的方法,是通过检测个体血样中CD14+的HLA-DR表达是否升高,和/或CD14+/CD16+细胞是否增加,和/或CD16+细胞在CD14+细胞群中所占百分比是否升高。某些实施例将以上异常巨噬细胞检测与一项或多项其它疾病指标相结合来诊断ALS。
本发明还提供通过检测血样中异常巨噬细胞来辅助ALS诊断的方法,所述的检测包括检测HLA-DR高表达CD14+细胞。本发明还提供通过检测血样中异常巨噬细胞来辅助ALS诊断的方法,所述的检测包括检测CD14+/CD16+细胞。
本发明某些实施例中,检测血样中有否异常巨噬细胞需在采血后12小时内完成。
附图说明
图1:ALS患者(ALS)和非ALS患者(正常对照)外周血样品中CD14+单核细胞上HLA-DR表达水平的柱形图。
图2:ALS患者(ALS)和非ALS患者(正常对照)外周血样品中CD16+细胞在CD14+细胞群中所占百分比的柱形图。
图3:收集在含肝素试管中和收集在含钙螯合剂ACD试管中的ALS患者外周血样品中CD14+单核细胞上HLA-DR表达水平的柱形图。收集在含肝素试管中非ALS患者(正常)外周血样品中的CD14+细胞HLA-DR表达水平中值以水平实线表示,该中值上、下的虚线表示标准偏差。
图4:收集在含肝素试管中和收集在含钙螯合剂ACD试管中的ALS患者外周血样品中CD16+细胞在CD14+细胞群中所占百分比的柱形图。收集在含肝素试管中非ALS患者(正常)外周血样品中的CD16+细胞在CD14+细胞群中所占百分比中值以水平实线表示,该中值上、下的虚线表示标准偏差。
图5:1μM多胺类似物处理后外周血样品中CD14+细胞杀伤百分比柱形图。图中样品取自6名ALS患者(Pt1-Pt6),一名多发性硬化症患者(MSpt),一名正常个体。
具体实施方式
我们发现,与非ALS患者外周血样品中的单核细胞相比,ALS患者外周血样品中的循环单核细胞通常被活化和/或分化异常(与“活化循环单核细胞”和“异常巨噬细胞”同义)。我们还发现了这些细胞的增殖。由此,我们发现了监测ALS症发展和/或活性的方法以及监测抗ALS药物疗效的方法。我们的发现还为治疗性干预指示了一个潜在的重要靶标,因为这些异常细胞至少介导ALS症的症状之一。
ALS患者外周血中存在活化单核细胞或异常巨噬细胞通常反映为CD14表达和HLA-DR总水平提高和/或CD14和CD16细胞表达,通常不伴有可测的T细胞活化。
我们还发现,用抗增殖药物例如多胺类似物处理ALS患者的外周血单核细胞可减少患者外周血中的活化CD14+单核细胞(或异常巨噬细胞)。
所以,本发明提供监测治疗前、期间和/或之后,或无治疗情况下ALS症发展情况的方法,该方法是通过测定ALS患者的生物样品尤其是血样中异常巨噬细胞的水平。本发明还提供通过在给药之前、期间或之后测定ALS患者的生物样品尤其是血样中异常巨噬细胞的水平来监测抗ALS药物或发案疗效的方法。本发明还提供减少ALS患者体内活化CD14+单核细胞的方法,该方法单用或与其它治疗方法联合可延迟和/或缓解ALS一种或多种症状。如后文所述,减少ALS患者体内活化CD14+单核细胞的药物优选多胺类似物。
定义
本文中,“巨噬细胞”和“单核细胞”同义,根据本领域常识,“单核细胞”一般用于描述表达CD14细胞表面标志的循环单核细胞,此类细胞在组织中归为巨噬细胞。
本文中,“异常巨噬细胞”或“活化循环单核细胞”或“活化单核细胞”同义,指表达CD14(即CD14+),高水平表达HLA-DR即II类主组织相容性抗原,和/或表达CD16(CD16+)的单核细胞。通常,异常巨噬细胞存在于外周血中,但也可能存在于其它生物样品中。通常,在ALS患者中,此类异常巨噬细胞不伴有可测的T细胞活化。
本文中,“有异常巨噬细胞存在”一般表示检测到一定水平的异常巨噬细胞。通常,异常巨噬细胞(或活化单核细胞)的水平表现为CD14+细胞群中的HLA-DR表达水平和/或CD16+细胞在CD14+细胞群中所占百分比和/或CD14+/CD16+细胞数量,但是也可采用反映单核细胞活化、分化和/或增殖的其它指标。一般认为,无需测定绝对值甚至相对值,观察到可测异常巨噬细胞即已足够。
“肌萎缩性侧索硬化”或“ALS”是本领域标准术语,在此表示一种进行性神经退行性疾病,它影响到上位运动神经元(脑中的运动神经元)和/或下位运动神经元(脊索中的运动神经元),造成运动神经元死亡。“ALS”在此包括所有本领域已知的ALS型,其中包括但不限于经典ALS(即影响上位运动神经元又影响下位运动神经元),原发性侧索硬化(PLS,只影响上位运动神经元),进行性延髓性麻痹(PBP或延髓性发病,ALS的一种,一般由吞咽、咀嚼和说话困难开始),进行性肌肉萎缩(PMA,一般只影响下位运动神经元)和家族性ALS(一种遗传性ALS)。
“增殖性巨噬细胞”是本领域标准术语,在此表示正在分裂的巨噬细胞。正常巨噬细胞是终极分化细胞,不具备进一步分裂的能力。在本发明中,“增殖性巨噬细胞”能够进一步分裂,或者处于细胞周期的某一中间阶段。检测增殖性巨噬细胞的方法参见后文。
本文中,检测“有否增殖性巨噬细胞存在”表示测定增殖性巨噬细胞的水平。一般认为,无需测定绝对值甚至相对值,观察到可测的增殖性巨噬细胞即已足够。
“个体”指脊椎动物,优选哺乳动物,尤其是人。哺乳动物包括但不限于畜养动物、比赛用动物、啮齿动物、灵长动物和宠物。“ALS个体”或“ALS患者”指表现出ALS相关症状因而被诊断或被疑患有ALS的个体。“非ALS患者”指没有被诊断或被疑患有ALS的个体。ALS及其诊断方法是本领域已知的,本文亦对其进行了论述。
本文中,“生物样品”包括采自某个体,可用于诊断或监测试验的多种类型的样品,包括生物来源的血液或其它液体样品,固体组织样品,例如组织活检样本或组织培养物或其衍生所得的细胞,以及其子代。该术语还包括采集后已经过处理的样品,例如经药物处理、经增溶或对某些成分例如蛋白质或聚核苷酸进行了富集。“生物样品”包括临床样品,也包括培养细胞、细胞上清液、细胞裂解液,血清,血浆,生物液和组织样品。通常,所述样品来自或就是外周血,所以可称为“血样”。有时,可事先利用例如玻璃或树脂粘附富集血液中的巨噬细胞。
“血样”即源自血液最好是外周血(或循环血)的生物样品。血样可以是例如全血、血浆或血清。
本文中,“辅助诊断”的方法表示辅助临床确定ALS型或性质的方法,其本身可能足以也可能尚不足以确诊。所以,辅助诊断ALS的方法可包括检测个体生物样品中异常巨噬细胞水平和/或测定个体生物样品中CD14+细胞HLA-DR表达水平的步骤,所述生物样品以外周血样品为佳。各种实施方式中,生物样品尤其是外周血样品中异常巨噬细胞水平可通过测定CD16+细胞在CD14+细胞群中所占百分比和/或CD14+/CD16+细胞数量来测定。
ALS的“发生”或“发展”在此表示疾病最初的显现和/或其后的发展。ALS的发展可用标准临床技术来检测和评价,例如神经和肌肉组织活检和CNS扫描技术,例如MRI。然而,发展也包括无法测知的疾病发展。就本发明而言,发生或发展指疾病状态的生物学过程。“发生”包括发生、复发和发作。本文中,ALS“发作”或“发生”包括初次发生和/或复发。
本文中,“延迟ALS的发生”指阻碍、减缓、稳定和/或推迟疾病的发生。延迟时间的长度各不相同,取决于患者的病史和/或临床状态。对本领域技术人员来说显而易见的是,充分或显著延迟包括有效避免个体发展成为可测的疾病。“延迟”疾病发展的方法,与不采用该方法相比,可在给定时间框内减缓病情。虽然这种认定可能根据既往病例,但上述比较通常依赖于对数量达到统计学意义的个体进行的临床研究。“延迟发展”可表示,与不给药相比,不良临床征兆的减轻和/或减少,和/或病程的减缓或延长。该术语还包括但不限于:症状减轻,病情缓解,病情稳定(即,不恶化),疾病发展被延迟或减缓和可测或非可测的(全面或部分)痊愈。
本文中,“有效量”(的药物)指可产生所需的和/或良性效果的量。有效量可一次或分多次给予。一些实施方式中,所谓有效量指足以降低ALS患者体内异常巨噬细胞水平的量。“足以降低异常巨噬细胞水平的量”以将该水平降低25%以上的为佳,50%以上、甚至75%以上,更甚至90%以上更好。这样的降低会引起良好的随同效应,例如病情减轻、消退、稳定、好转、减缓或延迟,延迟和/或甚至避免疾病发生。
另一些实施方式中,“足以降低CD14+细胞HLA-DR表达水平的量”优选使HLA-DR表达水平降低25%以上的量,50%以上、甚至75%以上、更甚至90%更好。这样的降低会引起良好的随同效应,例如病情减轻、消退、稳定、好转、发展减缓或延迟,延迟和/或甚至避免疾病发生。
本文中,降低“异常巨噬细胞水平”表示降低异常巨噬细胞或活化单核细胞的数量和/或降低CD14+细胞群的HLA-DR表达水平。各种实施方式中,异常巨噬细胞水平可通过测定生物样品中CD16+细胞在CD14+细胞群中所占百分比和/或CD14+/CD16+细胞数量来确定。一般认为,不必测定绝对值甚至相对值,观察异常巨噬细胞的相对水平即可。
本文中,“药物”指生物来源或化学来源的化合物,例如简单或复杂的有机或无机分子,肽,蛋白质或寡核苷酸。大量化合物可以各种不同的核心结构为基础人工合成,例如寡聚物,例如寡聚肽和寡核苷酸,以及合成有机化合物,这些也包括在“药物”中。此外,化合物可来自各种天然来源,例如植物或动物提取物等。所述药物包括但不限于多胺类似物。所述药物可以单用,也可以联用。
“调节”巨噬细胞增殖表示与不给药相比改变了增殖的速度。例如,用多胺类似物“调节”巨噬细胞增殖表示,与不给予干扰天然多胺与DNA之间相互作用(包括但不限于干扰多胺生物合成路径,干扰亚精胺、天然多胺与DNA相互作用的竞争物、抑制剂的胞内浓度,干扰多胺代谢等)的药物例如多胺类似物相比,改变了增殖速度。较好的是,“调节”巨噬细胞增殖表示增殖速度改变25%以上,50%以上、甚至75%以上、更甚至90%以上更好。通常,就本发明而言,“调节”巨噬细胞增殖表示,与不给药相比,降低个体内巨噬细胞增殖速度。然而,例如,在治疗过程中,可能希望相对先前的测得值提高增殖速度。调节幅度可通过测定巨噬细胞的增殖来评价,后文对此有所论述,而且,这通常涉及在巨噬细胞群中检测增殖标记,或检测特定物质例如BrdU或3H-胸苷的吸收(它们可提供增殖的定量指标)。而且,有可能的是,如果巨噬细胞增殖是遗传变异(例如转位、缺失或插入)所致,则上述改变可采用标准技术例如RFLP(限制性片段长度多态性)来检测。
多胺或多胺类似物的“靶标”指直接或间接与多胺或多胺类似物相互作用的物质,例如DNA、RNA和/或生物膜。
“烷基”指直链、支链、环状饱和脂族基团或其组合,其中含指定数量的碳原子,若不指定,则至多12个碳原子。“直链烷基”或“线型烷基”指既非环状又无支链的烷基,常称为“正烷基”。烷基的例子包括但不限于:甲基,乙基,正丙基,异丙基,丁基,正丁基,异丁基,仲丁基,叔丁基,戊基,正戊基,己基,庚基,辛基,壬基,癸基,十一烷基,十二烷基,新戊基,环丙基,环丁基,环戊基,环己基和金刚烷基。环状基团可由单环构成,例如环庚基,由多个稠环构成,例如金刚烷基或降冰片烷基。优选的烷基包括C1-12,C1-10,C1-8,C1-6,C1-4,C1-2,C3-4和C4烷基。
“取代烷基”表示被一取代或多取代的烷基,取代基例如卤素(氟、氯、溴、碘),烷氧基,酰氧基,氨基,羟基,巯基,羧基,苄氧基,苯基,苄基,氰基,硝基,硫代烷氧基,羧基醛(carboxaldehyde),羧基烷氧基(carboxalkoxy)和酰胺基,或可用保护基适当封闭的官能团。取代烷基的例子包括但不限于-CF3,-CF2-CF3,以及其它全氟和全卤基团。
“羟基烷基”指被一个-OH基团取代的具有所述碳原子数的烷基。因此,“C3线型羟基烷基”指-CH2CH2CHOH-,-CH2CHOHCH2-和-CHOHCH2CH2-。
“烯基”指含有至少一个双键(-C=C-)的不饱和脂族基团,包括直链、支链或环状及其组合,具有指定碳原子数,若无指定,则至多12个碳原子。烯基例如但不限于:-CH2-CH=CH-CH3和-CH2-CH2-环己烯基,其中的乙基可连接在任一可能价态的环己烯基部分上。“炔基”指含有至少一个三键(-C C-)的不饱和脂族基团,包括直链、支链或环状及其组合,具有指定碳原子数,若无指定,则至多12个碳原子。“烃链”或“烃基”指直链、支链或环状烷基、烯基或炔基的各种组合。“取代烯基”、“取代炔基”和“取代烃链”或“取代烃基”指被一个或多个取代基取代的代表性基团,取代基例如但不限于卤素,烷氧基,酰氧基,氨基,羟基,巯基,羧基,苄氧基,苯基,苄基,氰基,硝基,硫代烷氧基,羧基醛(carboxaldehyde),羧基烷氧基(carboxalkoxy)和酰胺基,或可用保护基适当封闭的官能团。
“芳基”或“Ar”表示具有单环(例如苯基)或多个稠环(例如萘基或蒽基)的取代和非取代芳香族碳环。“取代芳基”指被一个或多个取代基取代的芳基,取代基例如烷基,烯基,炔基,烃链,卤素,烷氧基,酰氧基,氨基,羟基,巯基,羧基,苄氧基,苯基,苄基,氰基,硝基,硫代烷氧基,羧基醛(carboxaldehyde),羧基烷氧基(carboxalkoxy)和酰胺基,或可用保护基适当封闭的官能团。
“杂烷基”、“杂烯基”和“杂炔基”指含有指定数量碳原子(若无指定,则至多12个碳原子),在其主链、支链或环状链中含有一个或多个杂原子的烷基、烯基和炔基。所述杂原子包括但不限于N,S,O和P,优选N和O。杂烷基、杂烯基和杂炔基可通过杂原子(如果价态允许)或通过碳原子与分子的其余部分相连。杂烷基例如但不限于:-O-CH3-,-CH2-CH2-O-CH3,-S-CH2-CH2-CH3,-CH2-CH(CH3)-S-CH3,-CH2-CH2-NH-CH2-CH2-,1-乙基-6-丙基哌啶子基,2-乙基硫代苯基和吗啉代。杂烯基例如但不限于:-CH=CH-NH-CH(CH3)-CH2-。“杂芳基”指含有单环(如吡啶基、硫代苯基或呋喃基)或多个稠环(如咪唑基、中氮茚基或苯并噻吩基),且环内含有至少一个杂原子如N、O、P或S的芳香族碳环基团。除非另作说明,杂烷基、杂烯基、杂炔基和杂芳基含有1至5个杂原子和1至12个碳原子。“取代杂烷基”、“取代杂烯基”、“取代杂炔基”和“取代杂芳基”指被一个或多个取代基取代的杂烷基、杂烯基、杂炔基和杂芳基,取代基例如但不限于烷基,烯基,炔基,烃链,卤素,烷氧基,酰氧基,氨基,羟基,巯基,羧基,苄氧基,苯基,苄基,氰基,硝基,硫代烷氧基,羧基醛(carboxaldehyde),羧基烷氧基(carboxalkoxy)和酰胺基,或可用保护基适当封闭的官能团。取代杂烷基例如但不限于氮原子上或碳原子上被苯基或苄基取代并通过碳原子或氮原子以可能的价态与分子其余部分相连的哌嗪基,-NH-SO2-苯基,-NH-(C=O)O-烷基,-NH-(C=)O-烷基-芳基和-NH-(C=)-烷基。只要化学上允许,取代基可位于杂原子和碳原子上。如果化学上允许,杂原子可以是氧化形式的。
“烷芳基”指与一个、两个或三个芳基相连的具有指定碳原子数的烷基。
“烃氧基”指具有指定碳原子数(若无指定则至多12个)的与氧原子相连的烷基、烯基、炔基或烃链。烃氧基例如但不限于甲氧基、乙氧基和叔丁氧基。
“链烷酸酯(或盐)”指离子化羧酸基团,例如乙酸酯(盐)(CH3C(=O)-O(-l)),丙酸酯(盐)(CH3CH2C(=O)-O(-l))等。“链烷酸烷酯”指与烷氧基酯化的羧酸,例如乙酸乙酯(CH3C(=O)-O-CH2CH3)。“ω-卤代链烷酸烷酯”指距离羧基最远的链烷酸酯碳原子上具有一个卤原子的链烷酸烷酯;因此,ω-溴代丙酸乙酯指3-溴丙酸乙酯,ω-氯正丁酸甲酯指4-氯正丁酸甲酯,等等。
“卤素”在此指Cl,Br,F或I取代基。
以上定义中,优选C1-12,C1-10,C1-8,C1-6,C1-4,C1-2(如果化学上允许),C3-4和C4基团。
“保护基”指表现出以下特性的化学基团:1)选择性地与指定官能团反应,并以良好的得率生成对所处反应亦即保护所针对的反应来说稳定的被保护基团;2)可选择性地从被保护基团上去除从而得到所需的官能团;和3)可用与原先存在或在所经历的反应中生成的其它官能团相容的试剂去除且得率良好。合适的保护基的例子可参考Greene等(1991),“有机合成中的保护基”,第三版(John Wiley&Sons,Inc.,NewYork)。氨基保护基包括但不限于均三甲苯磺酰基(Mts),苄氧基羰基(CBz或Z),叔丁氧基羰基(Boc),叔丁基二甲基甲硅烷基(TBS或TBDMS),9-芴基甲基氧基羰基(Fmoc),甲苯磺酰基,苯磺酰基,2-吡啶基磺酰基,或合适的光敏性保护基,例如6-硝基藜芦基氧基羰基(Nvoc),硝基胡椒基,芘基甲氧基羰基,硝基苄基,二甲基二甲氧基偶苯酰,5-溴-7-硝基二氢吲哚基等。羟基保护基包括但不限于Fmoc,TBS,光敏性保护基(例如硝基藜芦基氧基甲基醚(Nvom)),Mom(甲氧基甲基醚)和Mem(甲氧基乙氧基甲基醚),NPEOC(4-硝基苯乙基氧基羰基)和NPEOM(4-硝基苯乙基氧基甲基氧基羰基)。
“多胺类似物”指结构与多胺类似但不相同的有机阳离子,所述多胺例如精胺和/或亚精胺以及它们的前体,二胺腐胺。“多胺”指各种由氨基酸生物合成的脂族直链胺;Marton等(1995),Ann.Res.Pharm.Toxicol.,35:55-91中对几种多胺进行了论述。尸胺和腐胺是二胺,分别由赖氨酸或鸟氨酸脱羧而得。通过添加氨基丙基,腐胺可转化为亚精胺,亚精胺继而转换为精胺。该基团由S-腺苷甲硫氨酸脱羧而得。
“构象限制”指多胺类似物中至少两个氨基在空间构型上彼此锁闭或限制。两个氨基的相对移动可能因为在两个相邻氮原子之间引入一个环状或非饱和基团(例如三碳、四碳、五碳、六碳环,或双键或三键,例如碳碳双键或三键)而受到限制,所述相邻氮原子不在所述受构象限制基团内。由于空间位阻限制构象灵活性,但结构上促进抗增殖效果的基团也可用于构象限制。“受构象限制”的多胺类似物可包含至少两个彼此构象受到限制的氨基,还可包含构象不受限制的其它氨基。灵活分子,例如精胺和BE-444,可能具有多种构象,因而是非构象限制的。在多胺和多胺类似物中,不论构象限制与否,所述氨基都是脂族而非芳族氨基。
本发明的方法
本发明提供监测ALS治疗的方法,包括检测个体外周血样品中的CD14+细胞的HLA-DR表达水平和/或异常巨噬细胞水平和/或CD16+细胞在CD14+细胞群中所占百分比和/或CD14+/CD16+细胞数量。本发明还提供监测ALS患者ALS发生或发展的方法,包括测定个体外周血样品中的异常巨噬细胞水平,和/或CD14+细胞的HLA-DR表达水平,和/或CD16+细胞在CD14+细胞群中所占百分比,和/或CD14+/CD16+细胞数量。本发明还提供减少ALS患者体内CD14+单核细胞尤其是活化循环单核细胞的方法。本发明还提供筛选可减少ALS患者体内CD14+单核细胞尤其是活化循环单核细胞的药物的方法。
CD14+细胞的HLA-DR表达水平升高,和/或CD14+/CD16+细胞增加,和/或CD16+细胞在CD14+细胞群中所占百分比升高与ALS相关,因此,监测这些水平可指示治疗方法的最初反应性和/或效果以及合适的剂量。一般认为,监测治疗表示在不同时刻例如治疗期间采集生物样品,并彼此比较,与对照比较,和/或与理想值比较。实施例之一中,监测治疗包括测定外周血中CD14+细胞的HLA-DR表达水平。另一实施例中,监测治疗包括测定血样尤其是外周血中HLA-DR高表达CD14+细胞的水平。另一实施例中,监测治疗包括测定血样尤其是外周血中CD16+细胞在CD14+细胞群中所占百分比。另一实施例中,监测治疗包括测定血样尤其是外周血中CD14+/CD16+细胞数量。另一实施例中,治疗期间和/或之后测定的异常巨噬细胞水平(不同实施方式中分别为HLA-DR高表达CD14+细胞,CD16+细胞在CD14+细胞群中所占百分比,和/或CD14+/CD16+细胞数量)与对照和/或理想值比较。另一实施例中,监测治疗还包括监测异常巨噬细胞增殖。
为了监测ALS治疗,采自接收治疗的患者的样品和/或治疗结束后采集的样品中的异常巨噬细胞水平通常与治疗前采自该患者的样品中的水平和/或在治疗期间另一不同时刻采自患者的样品中的水平相比较。例如,治疗期间所采样品中异常巨噬细胞水平相比治疗前样品中的或治疗早期样品中的降低,一般表明ALS治疗有效。
实施方式之一中,为了监测ALS治疗,异常巨噬细胞水平通过测定血样尤其是外周血样品中CD14+细胞的HAL-DR表达水平来评价。例如,比较治疗前和治疗期间外周血中CD14+细胞的HAL-DR表达水平,由此确定治疗的效果,HAL-DR表达水平趋于下降表明治疗有效。
实施方式之一中,为了监测ALS治疗,异常巨噬细胞水平通过测定血样尤其是外周血样品中CD16+细胞在CD14+细胞群中所占百分比来评价。例如,比较治疗前和治疗期间外周血中CD16+细胞在CD14+细胞群中所占百分比,由此确定治疗的效果,CD16+细胞在CD14+细胞群中所占百分比趋于下降表明治疗有效。
实施方式之一中,为了监测ALS治疗,异常巨噬细胞水平通过测定血样尤其是外周血样品中CD16+/CD14+细胞数量来评价。例如,比较治疗前和治疗期间外周血中CD16+/CD14+细胞数量,由此确定治疗的效果,CD16+/CD14+细胞趋于减少表明治疗有效。
在ALS患者中,检测生物样品尤其是外周血样品中CD14+细胞的HAL-DR表达水平,和/或CD16+细胞在CD14+细胞群中所占百分比,和/或CD16+/CD14+细胞数量还有助于监测疾病的发生或发展。因此,本发明还提供监测ALS患者疾病发生或发展的方法,包括检测个体外周血样品中CD14+细胞的HAL-DR表达水平,和/或CD16+细胞在CD14+细胞群中所占百分比,和/或中CD16+/CD14+细胞数量,和/或异常巨噬细胞水平。较好的是,所述个体“患有”ALS(诊断为患有,表现出一种或多种临床症状)。
因为CD14+细胞的HLA-DR表达水平升高和/或CD14+/CD16+细胞增加和/或CD16+细胞在CD14+细胞群中所占百分比升高与ALS相关,监测这些水平可指示疾病发生或发展过程中的变化。一般认为,检测ALS患者通常表示在数周、数月和/或数年内在不同时刻采集生物样品,然后彼此比较,与对照比较和/或与理想值比较。另一实施方式中,监测疾病发展还包括检测异常巨噬细胞增殖。在对ALS的监测中,CD14+细胞的HLA-DR表达水平升高和/或CD14+/CD16+细胞增加和/或CD16+细胞在CD14+细胞群中所占百分比升高通常表明病情加重和/或发展加快。
对于那些ALS的高危疑患个体,测定其生物样品CD14+细胞的HLA-DR表达水平和/或CD16+细胞在CD14+细胞群中所占百分比和/或CD14+/CD16+细胞数量有助于警示该个体和/或医生。所以,本发明还提供监测ALS高危疑患的方法,包括测定该疑患生物样品中CD14+细胞的HLA-DR表达水平和/或CD16+细胞在CD14+细胞群中所占百分比和/或CD14+/CD16+细胞数量。较好的是,该个体表现出一种或多种ALS相关临床症状,或有发生ALS的“危险性”(具有ALS高发遗传背景、家族史或接触到诱发ALS的因素)。在对ALS高危疑患的监测中,CD14+细胞的HLA-DR表达水平升高和/或CD14+/CD16+细胞增加和/或CD16+细胞在CD14+细胞群中所占百分比升高通常表明ALS症状发生可能性升高。
一般认为,除非特例,监测高危个体表示在数周、数月和/或数年内在不同时刻采集生物样品,然后彼此比较,与对照比较和/或与理想值比较。实施方式之一中,监测高危个体包括检测样品中CD14+细胞的HLA-DR表达水平和/或CD16+细胞在CD14+细胞群中所占百分比和/或测定外周血中CD14+/CD16+细胞数量。另一实施方式中,监测高危疑患包括监测异常巨噬细胞的增殖。
就监测治疗、监测疾病发展或监测高危疑患而言,可将样品中CD14+细胞的HLA-DR表达水平和/或CD16+细胞在CD14+细胞群中所占百分比和/或CD14+/CD16+细胞数量与性别和/或年龄相当的健康个体或非ALS患者的平均值或中值相比。或者,可将测得的上述指标同一个体不同时刻测得值综合所得平均值或中值比较。ALS样品中CD14+细胞的HLA-DR表达水平和/或CD16+细胞在CD14+细胞群中所占百分比和/或CD14+/CD16+细胞数量与非ALS样品之间的差异或改变通常与疾病的发展或活性相关。例如,CD14+细胞的HLA-DR表达水平升高和/或CD14+/CD16+细胞增加和/或CD16+细胞在CD14+细胞群中所占百分比升高通常与ALS加重相关。
与一种或多种其它疾病指标一起,检测CD14+细胞的HLA-DR表达水平和/或CD16+细胞在CD14+细胞群中所占百分比和/或CD14+/CD16+细胞数量有助于诊断或预告ALS。不同的诊断包括诊断各种与ALS相关或者导致ALS或者由其所致的状况,最后由主治医师确诊。所以,本发明包括协助ALS诊断的方法。此类方法一般包括检测ALS疑患个体血样中的CD14+细胞的HLA-DR表达水平和/或CD16+细胞在CD14+细胞群中所占百分比和/或CD14+/CD16+细胞数量。
为了检测HLA-DR表达水平是否升高,需测定同一ALS个体大量CD14+细胞上HLA-DR表达水平的平均值或中值。可计算血样(或其它生物样品)中HLA-DR分子数/细胞作为HLA-DR表达水平。更常见的是计算样品中CD14+细胞群的HLA-DR检测标记(例如荧光度)/细胞作为HLA-DR表达水平。可将所得值与同一个体不同时刻和/或不同状态(例如治疗前,不同剂量,等等)下测得的HLA-DR水平相比较。
一些实施方式将HLA-DR水平与非ALS标准个体CD14+细胞群HLA-DR表达水平的平均值或中值比较,所述非ALS标准个体例如一个或多个非ALS个体。HLA-DR表达水平比非ALS标准个体高约1.4倍表示ALS个体内HLA-DR表达水平升高。通常,比非ALS标准个体的HLA-DR表达水平高约1.5倍、1.6倍、1.7倍、1.8倍、1.9倍、2.0倍、5.0倍或10倍都表示ALS个体内HLA-DR表达水平升高。
由CD14+单核细胞表达的HLA-DR即II类主组织相容性抗原的表达水平可用多种已知方法来检测,例如普通流式细胞计数法,参见Current Protocols ofImmunology(J.E.,Coligan等,1999)。已知方法,包括普通流式细胞计数法,还可用来测定细胞包括CD14+细胞上的CD16+表达。通常,可用针对某一种或多种抗原的一种或多种抗体对个体血样中的细胞就所述一种或多种抗原进行染色,所述抗体包括抗CD14抗体,抗CD16抗体和抗HLA-DR抗体。当分析细胞一种以上抗原的表达时,可同时或先后用抗原特异性抗体染色细胞。或者,可将表达某特定抗原的细胞从不表达该抗原的细胞中分离出来,然后对分离出的细胞群就其它抗原的表达进行染色。所述抗原特异性抗体可直接用荧光团标记,或采用与抗抗体抗体(例如第二抗体)偶联的荧光团间接标记。与抗原特异性抗体反应并荧光标记后,用流式细胞计数仪,例如Becton Dickinson FACScan,分析细胞。可根据流式细胞计数仪所得数据定量测定CD14+细胞HLA-DR表达水平,参见实施例1。还可根据流式细胞计数结果测定细胞上CD14+和CD16+的共表达。
也可用其它已知技术测定CD14+单核细胞的HLA+DR表达水平。例如,将CD14+细胞与其它血细胞和血液组分分离,例如采用基于抗体的细胞电子分选技术,参见例如Current Protocols of Immunology(J.E.,Coligan等,1999)。分离出的CD14+细胞的HLA-DR表达水平可通过分析细胞的mRNA和/或蛋白质来测定。可用各种已知技术测定CD14+细胞内的HLA-DR RNA,例如S1核酶分析,核糖核酸酶蛋白质试验,引物延伸试验,RNA印迹分析(例如Northern和/或斑点杂交)和定量RT-PCR,参见例如Current Protocols in Molecular Biology(F.M.Ausubel等,1987)。可用各种已知技术定量测定CD14+细胞中和/或表面的HLA-DR蛋白,这包括但不限于定量免疫试验,例如放射免疫试验、免疫荧光试验、酶免疫试验、化学发光试验,ELISA或Western印迹试验,参见例如Current Protocols ofImmunology(J.E.,Coligan等,1999)。以上技术还可用来检测CD14+单核细胞内或细胞上的CD16表达。
分析前,待分析生物样品需保持在合适的条件下,从而确保样品中可能存在的异常巨噬细胞在分析时可被测出。一些实施方式中,在容器中(可以是采集时所用的容器)用足量的非螯合钙将待分析生物样品中的细胞维持在保存培养基中,直至分析。但这并不表示不可以有钙螯合剂存在或不可以有被螯合钙存在。例如,一些实施方式中,钙螯合剂与待分析生物样品中的细胞共存,但其含量低到不至于干扰凝血。亦即,一些实施方式中,必须避免待分析细胞接触其量足以干扰凝血的钙螯合剂。一些实施方式中,待分析生物样品中的细胞维持在没有钙螯合剂的条件下。例如实施例2,没有钙螯合剂存在下,ALS样品中的CD14+/CD16+百分比比非ALS样品中的高4倍。但是,生物样品中的钙螯合剂使得ALS样品中的可测CD4+/CD16+细胞降低到了非ALS样品中的水平。即,在这些外周血样品中,钙螯合剂的存在影响了CD14+/CD16+细胞数作为ALS指标的可用性。
一些实施方式中,CD14、CD16和/或HLA-DR表达的测定在采集生物样品的当日进行(即“当日”分析)。另一些实施方式中,测定CD14、CD16和/或HLA-DR表达在采集生物样品的次日进行(即“次日”分析)。一些实施方式中,测定CD14、CD16和/或HLA-DR表达约在采血后96、72、60、48、36、24、18、12、6、4或2小时内进行。一些实施方式中,所述待分析生物样品是血液,优选外周血。一些实施方式中,外周血被采集在含有肝素的容器内。
一些实施方式将CD14+/CD16+细胞数量和/或CD16+细胞在CD14+细胞中所占百分比与非ALS标准例如一名或多名非ALS个体的生物样品中CD14+/CD16+细胞水平的平均值或中值相比较。样品中CD16+细胞在CD14+细胞中所占百分比和/或CD14+/CD16+细胞数量比非ALS标准约高1.5、1.6、1.7、1.8、1.9、2.0、3.0、4.0、5.0或10倍表示ALS个体内CD14+/CD16+细胞增加。
通常,可在ALS个体或ALS疑患个体中测得上述异常巨噬细胞,同时不会测到伴随CD14+单核细胞HLA-DR表达水平升高和/或CD14+/CD16+细胞增加和/或CD16+细胞在CD14+细胞群中所占百分比升高而发生的T细胞活化或T细胞活化水平降低。T细胞活化可用已知方法和标准来评价。例如,T细胞活化水平可通过测定细胞上的特定细胞活化标记例如CD4、CD8和/或CD38的表达,或通过检测表达这些标记的细胞来测定。如实施例1,将ALS个体外周血中的T细胞群,表现为CD4/CD38和CD8/CD38细胞群,与正常(非ALS)个体的相比较。
如上所述,有时,HLA-DR高表达的CD14+细胞群包括增殖性巨噬细胞。而且,有时,CD14+/CD16+细胞群中包括增殖性巨噬细胞。增殖性巨噬细胞可用多种方法来检测。本发明一些实施方式中,检测异常巨噬细胞增殖是对外周血白细胞制备物中的全体循环巨噬细胞进行的。另一些实施方式中,增殖检测是对固定组织中的巨噬细胞进行的,通常在组织切片上进行。增殖性巨噬细胞可通过分析细胞增殖标记例如PCNA、Ki67或溴脱氧尿苷(BrdU)或3H-胸苷摄入来检测。这些标记与仅确认“活化”巨噬细胞(与增殖性巨噬细胞相反)的例如CD69和CD25不同。可对代表巨噬细胞的细胞亚群进行进一步鉴定,例如检测CD14、CD68、CD16或非特异性酯酶等特定细胞特异性标记。检测这些细胞类型和/或增殖标记可采用本领域的标准方法,例如染色和FACS分选和分析。此类方法可参见实施例3。也可以根据其它特征例如细胞密度(例如以PERCOLLTM梯度测定)来鉴别增殖性巨噬细胞。此类测定方法可利用本领域标准技术凭经验来建立。
本发明提供筛选能降低ALS患者体内异常巨噬细胞水平的药物的方法。例如,为了粗筛可有效降低ALS相关异常巨噬细胞水平的药物,可分离ALS患者的外周血细胞。测定样品中异常巨噬细胞的水平和/或活度,用候选药物处理细胞样品,然后将结果与非处理细胞相比。例如,处理后样品中异常巨噬细胞水平和/或活度比非处理样品低,表明候选药物能够有效降低ALS患者体内的异常巨噬细胞水平和/或活度。对患者给药后,通过比较治疗前后的异常巨噬细胞水平来测定候选药物的效果,异常巨噬细胞趋于减少表示有效。不同的实施方式中,测定异常巨噬细胞水平包括检测样品中的HLA-DR高表达CD14+单核细胞水平和/或CD14+/CD16+细胞数量和/或CD16+细胞在CD14+细胞群中所占百分比。通常,评价细胞活度例如CD14+细胞活度的方法和试剂是本领域所熟知的。
本发明提供筛选能减少ALS患者体内CD14+单核细胞尤其是活化CD14+单核细胞和/或HLA-DR高表达CD14+单核细胞和/或减少CD14+/CD16+细胞和/或降低CD16+细胞在CD14+细胞群中所占百分比的药物的方法。ALS患者体内例如CD14+细胞减少的标志包括但不限于生物样品中细胞活度降低和/或细胞数量减少。例如,为了粗筛能够有效减少ALS相关CD14+单核细胞的药物,分离ALS患者的外周血细胞。测定样品中的CD14+单核细胞数量,用候选药物处理样品,将结果与非处理细胞相比较。例如,处理后样品中CD14+单核细胞比非处理样品少表明候选药物有效。给药后,比较治疗前后CD14+单核细胞尤其是活化CD14+单核细胞水平,CD14+单核细胞趋于减少表示有效。、
本发明提供减少ALS患者体内CD14+单核细胞尤其是活化CD14+单核细胞的方法,包括给予减少CD14+单核细胞尤其是活化CD14+单核细胞和/或HLA-DR高表达CD14+单核细胞和/或CD14+/CD16+细胞和/或CD16+细胞在CD14+细胞群中所占百分比有效量的多胺类似物、其盐或其被保护衍生物。“减少CD14+单核细胞有效量”最好能使CD14+单核细胞减少约25%、50%、75%甚至90%。这样的减少可能会引发良好的伴随效应,例如疾病减轻、缓解、稳定、好转、发展减缓和/或延迟,疾病发生或发展的延迟甚至避免。
另一实施方式中,给予ALS患者的是调节巨噬细胞增殖有效量的含多胺类似物或其被保护衍生物的组合物。
本发明方法所用的化合物可取其游离碱或游离酸的形式(即化合物的非盐游离形式)。此外,化合物的任何药学上认可的盐均可采用。药学上认可的盐即保留游离化合物的生物活性且无其它不良生物学或其它效果的盐。碱性化合物的盐可通过与酸反应来制备。无机酸例如盐酸、氢溴酸、硫酸、硝酸和磷酸。有机酸例如甲酸、乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、磺酸和水杨酸。还可制备碱性化合物与氨基酸的盐,例如天冬氨酸盐和谷氨酸盐。酸性化合物的盐可通过与碱反应来制备。酸性化合物的无机盐包括但不限于碱金属和碱土金属盐,例如钠盐、钾盐、镁盐、钙盐;铵盐;铝盐。酸性化合物的有机盐包括但不限于普鲁卡因、二苄基胺、N-乙基哌啶、N,N′-二苄基乙二胺和三乙基胺。还可制备酸性化合物与氨基酸的盐,例如赖氨酸盐。
本发明还可采用化合物的立体异构体,包括对映体和非对映体,以及立体异构体的混合物,包括但不限于外消旋物。除非在结构式中明示立体化学特征,一个结构式通常涵盖所有可能的立体异构体。
就本发明而言,适合多胺给药的个体是已确诊患ALS或被认为极有可能发生ALS的个体。“危发”或“高危”个体指具有特殊且明显的发生ALS危险性的个体。“危发”或“高危”个体在接收本发明方法处理前可能有、可能没有可测疾病,可能已经或尚未表现出可测疾病。“高危”(或“危发”)表示个体具有一种或多种所谓危险因素,即一些与疾病发生相关的可测指标。具有一种或多种所述危险因素的个体比没有此类因素的个体更可能发生疾病。此类因素包括但不限于遗传因素(包括家族史和遗传标记)。一般认为,通常只要有一项危险因素就有高危险性。医生,作为本领域熟练技术人员,能够确定是否对危发个体进行某种药物的治疗。
另一实施方式中,本发明提供调节ALS个体巨噬细胞增殖的方法,包括给予含有干扰多胺与增殖性巨噬细胞靶标例如DNA、RNA和/或视网膜相互作用有效量的药物的组合物。干扰多胺与增殖性巨噬细胞靶标相互作用的药物可以是干扰以下任一方面的药物:天然多胺的合成和/或代谢、胞内浓度调节和/或功能(即与DNA的相互作用)。
减少CD14+单核细胞的药物
本发明部分实施方式中,降低异常巨噬细胞水平(即,ALS患者体内HAL-DR高表达CD14+单核细胞和/或CD14+/CD16+单核细胞和/或CD16+细胞在CD14+细胞群中所占百分比)是用多胺类似物实现的。另一些实施方式中,任何可降低异常巨噬细胞增殖的药物均可采用。此类抗增殖药物是本领域已知的。就多胺类似物而言,包括它们的立体异构体、盐和被保护衍生物。
多胺类似物
本发明所用多胺类似物包括结构式1、2、3、4和5所示化合物及其立体异构体、盐和被保护衍生物:
其中,R1,R2,R4,R6和R7各自选自:H,烷基和芳基,R3和R5是烷基;
其中,R1,R2,R4,R6,R8和R9各自选自:H,烷基和芳基,R3,R5和R7是烷基;
其中,R1,R2,R4,R6,R8,R10和R11各自选自:H,烷基和芳基,R3,R5,R7和R9是烷基;
其中,R1和R5各自选自:甲基,乙基,正丙基和异丙基;
R2,R3和R4各自选自:C1-6烷基,C2-6烯基,C3-6环烷基,C1-6烷基-C3-6环烷基-C1-6烷基,C3-10芳基和C1-6烷基-C3-10芳基-C1-6烷基;R6,R7,R8和R9各自选自:H,甲基和乙基。
其中,R1和R6各自选自:甲基,乙基,正丙基和异丙基;
R2,R3,R4和R5各自选自:C1-6烷基,C2-6烯基,C3-6环烷基,C1-6烷基-C3-6环烷基-C1-6烷基,C3-10芳基和C1-6烷基-C3-10芳基-C1-6烷基;
R7,R8,R9和R10各自选自:H,甲基和乙基。
一些实施方式中,多胺类似物包括如下结构3化合物:其中R3,R5,R7和R9各自是(CH2)x基团,其中x是2至6的整数,R4,R6和R8是氢原子。
一些实施方式中,多胺类似物包括如下结构3化合物:其中R3,R5,R7和R9各自是(CH2)x基团,其中x是2至6的整数,R4,R6和R8是氢原子,R1和R10是烷基,R2和R11是氢原子。
一些实施方式中,多胺类似物包括如下结构3化合物:其中R3,R5,R7和R9各自是(CH2)x基团,其中x是2至6的整数,R4,R6和R8是氢原子,R1和R10是烷基,R2和R11是氢原子,该多胺类似物的分子量低于500。
一些实施方式中,化合物包括如下结构4化合物:
其中R6,R7,R8和R9是H;
其中,R1和R5是乙基;
其中,R6,R7,R8和R9是H,且,R1和R5是乙基;和/或
其中,R2和R4各自选自C1-6烷基,且R3选自:C1-6烷基,C2-6烯基,C3-6环烷基,C1-6烷基-C3-6环烷基-C1-6烷基,C3-10芳基和C1-6烷基-C3-10芳基-C1-6烷基。
本发明可用的多胺类似物还包括结构式6所示化合物及其立体异构体、盐和被保护衍生物:
其中,R4是C2-6正烯基,C3-6环烷基,C3-6环烯基,或C3-6芳基;
R3和R5各自选自:单键,C1-6烷基,或C1-6烯基;
R2和R6各自选自:C1-6烷基,C1-6烯基或C3-6环烷基,C3-6环烯基,或C3-6芳基;
R1和R7各自选自:H,C1-6烷基或C2-6烯基;
R8,R9,R10和R11是H。
一些实施方式的结构式6化合物中,R1和R7各自选自C1-6烷基或C2-6烯基。
本发明可用的多胺类似物还包括结构式7所示化合物及其立体异构体、盐和被保护衍生物:
其中,R4是C1-6正烯基或C1-6支链烷基;
R3和R5各自选自:单键或C1-6烷基;
R2和R6各自选自:C1-6烷基,C1-6烯基,C3-6环烷基,C3-6环烯基或C3-6芳基;
R1和R7各自选自:H,C1-6烷基或C2-6烯基;而且
R8,R9,R10和R11是H。
一些实施方式的结构式7化合物中,R1和R7各自选自C1-6烷基或C2-6烯基,R4是C1-6饱和正烃基或C1-6饱和支链烃基,R3和R5各自选自:单键或C1-6饱和正烃基。
一些实施方式中,多胺类似物中的各氮原子分别是仲胺、叔胺、季铵基团。
一些实施方式中,本发明所用多胺类似物是构象限制的。
有关环多胺化合物和环多胺类似物可参见WO02/10142。这些环多胺化合物中,一个或多个脂族氮原子构成酰氨基的一部分。
本发明所用多胺类似物包括表现为能够调节细胞内天然多胺水平的化合物。除理论之外,可能的机制包括多胺合成路径中的竞争;多胺分解代谢物例如SSAT上调;影响多胺代谢等。
本发明尤其关注以下多胺类似物:
1,11-二(乙基)降精胺(norspermine)(1,11-二(乙基氨基)-4,8-二氮杂十一烷;BE-3-3-3);
1,8-二(乙基)亚精胺(BES);
1,12-二(乙基)精胺(BESm;DESPM(N1,N12-二乙基精胺;SunPharm);
1,14-二(乙基氨基)-5,10-二氮杂十四烷(BE-4-4-4)(二乙基高精胺(homospermine),N1,N14-二乙基高精胺;DEHOP或DEHSPM;SunPharm);
二乙基降精胺(DENOP;SunPharm);
1,19--二(乙基氨基)-5,10,15-三氮杂十九烷(BE-4-4-4-4);
四盐酸N-乙基-N′-(2-(3′-乙基氨基-丙基氨基甲基)-顺-环丙基甲基-丙烷1,3-二胺(SL-11037),S′LIL,Madison,Wisconsin提供;
四盐酸N-乙基-N′-(2-(3′-乙基氨基-丙基氨基甲基)-反-环丁基甲基-丙烷1,3-二胺(SL-11038),S′LIL
四盐酸N-乙基-N′-(2-(3′-乙基氨基-丙基氨基甲基)-反-环丙基甲基-丙烷1,3-二胺(SL-11044),S′LIL
四盐酸N,N′-二(3-乙基氨基丙基)-顺-丁-2-烯-1,4-二胺(SL-11047,S′LIL)及其对应的反式异构体(见WO95/18091);
(5,10,15,20,25,30,35,40-八氮杂四十四-22-烯-1,44-二胺,N,N′-二乙基,十盐酸,(22E)-)(SL-11144),S′LIL,化学摘要编号No.304911-07-7;
(5,10,15,20,25,30,35,40-八氮杂四十四-22-烯-1,44-二胺,N,N′-二乙基,十盐酸,(22Z)-)(SL-11150),S′LIL,化学摘要编号No.304911-08-8。
SL-11037,SL-11038,SL-11044,SL-11047,SL-11144和SL-11150的结构如下所示:
此外,美国专利5,889,061,5,880,161和5,541,230,WO00/66587,WO00/66175和WO02/10142所述多胺类似物也可用于本发明。
支链或非支链多胺类似物包括但不限于:BE4444(1,19-二(乙基氨基)-5,10,15-三氮杂十九烷);BE-333(N1,N11-二乙基降精胺;DENSPM;1,11-二(乙基氨基)-4,8-二氮杂十一烷;thermine;Warner-Parke-Davis);BE-33(N1,N17-二乙基降亚精胺(norspermidine));BE-34(N1,N8-二乙基亚精胺);BE-44(N1,N9-二乙基高精胺);BE-343-(N1,N12-二乙基精胺);二乙基精胺-N1-N12;DESPM);BE-343-(N,N′-二(3-乙基氨基)丙基)-1,7-庚二胺,Merrel-Dow);BE-444(N1,N14-二乙基高精胺;二乙基高精胺-N1-N14);BE-3443(1,17-二(乙基氨基)-4,9,14-三氮杂十七烷),BE-4334(1,17-二(乙基氨基)-5,9,13-三氮杂十七烷);1,12-Me2-SPM(1,12-二甲基精胺);WO98/17624和美国专利5,889,061所述各种多胺类似物;和WO00/66587和WO00/66175所述新多胺类似物,包括但不限于以下代号的化合物:SL-11027,SL-11028,SL-11029,SL-11033,SL-11034,SL-11037,SL-11038,SL-11043,SL-11044,SL-11047,SL-11048,SL-11050,SL-11090,SL-11091,SL-11092,SL-11093,SL-11094,,SL-11098,SL-11099,SL-11100,SL-11101,SL-11102,SL-11103,SL-11104,SL-11105,SL-11108,SL-11114,SL-11118,SL-11119,SL-11121,SL-11122,SL-11123,SL-11124,SL-11126,SL-11127,SL-11128,SL-11129,SL-11130,SL-11132,SL-11133,SL-11134,SL-11136,SL-11137,SL-11141,,SL-11144,SL-11150,SL-11201和,SL-11202。其它多胺类似物是已知的,参见例如O′Sullivan等(1997),Bioorg.Med.Chem.,5:2145-2155;和Mukhopadhyaya等(1995)Exp.Parasit.,81:39-46;和美国专利4,935,449。
除此之外,也可使用上述化合物的立体异构体、盐或被保护衍生物。本发明还包括用有效量的任一上述化合物、其立体异构体、盐或被保护衍生物(或包含有效量上述物质的组合物)降低ALS相关性异常巨噬细胞的数量或增殖的方法(或用于治疗,或用于延迟ALS的发展)。本发明还包括以上多胺类似物、其立体异构体、盐或被保护衍生物用于制备治疗ALS的组合物(即药物)的用途。
任一上述化合物、其立体异构体、盐或被保护衍生物(或包含有效量上述物质的组合物)可体外使用也可体内使用。体外,即将合适的生物样品(例如血样,富集或未富集异常巨噬细胞群)与所述组合物接触。体内,即根据制造商/供应商的说明书进行所述组合物的给药。通常,多胺类似物通过皮下或静脉注射给药,也可口服。
多胺类似物(其立体异构体、盐或被保护衍生物)的给药量取决于多项变量,例如所用具体类似物(或其立体异构体、盐或被保护衍生物),给药程序,个体状况,针对的疾病,疾病程度,剂次,剂量,是否服用其它药物。通常,用量是按照制造商的推荐量和/或根据经验确定。如果是多胺类似物(其立体异构体、盐或被保护衍生物),剂量一般约为1-300mg/m2/天,也可以是15-150mg/m2/天。一般采取间歇性给药,即,一般隔至少1至2天给予一次多胺类似物(其立体异构体、盐或被保护衍生物),然后在此后的至少1至2天内不给药,如此重复。实施方式之一中,多胺类似物每3周中有6天给药。
给药途径取决于具体的多胺类似物(或其立体异构体、盐或被保护衍生物),可以是例如口服或注射(皮下或静脉),一般采用静脉或皮下注射给药。
较好的是,将多胺类似物(或其立体异构体、盐或被保护衍生物)或其它能干扰多胺合成路径、代谢和/或精胺胞内浓度维持的药物加在合适的药物赋形剂中给药。药物赋形剂属于本领域常识,可参见Remington:The Science and Practice ofPhamacy,第20版,Mack Publishing(200)。多胺类似物还可以与促进药物向巨噬细胞传递或提高药物对巨噬细胞特异性的其它物质一同给药。例如,可将药物与脂质体结合。脂质体属于本领域常识。然后,脂质体再与靶向物质例如IgGFc受体偶联。可用增强巨噬细胞吞噬作用的物质例如酵母聚糖或四氯十氧(TCDO)和/或促进其活性的物质例如MCSF、GMCSF或IL-3来提高抗增殖药物的吸收率。
根据同期药物治疗(即目标结果,个体状况和适应症),多胺类似物(或其立体异构体、盐或被保护衍生物)可单独给药,也可与其它物质和/或治疗联合。“联合”表示在其它物质或治疗之前、同时或之后给药。可与本发明药物联合给药的物质例如但不限于riluzole(RILUTEK)。食品和药物管理委员会许可的对Riluzole用于ALS治疗的研究表明它对提高ALS患者存活率具有统计学显著效果(Bensimon等(1994),New Eng.J.Med.,330:585-591;Lacomblez等(1996),Lancet347:1425-1431)。通常,ALS治疗包括以控制症状为目的的治疗。所以,可与本发明药物联用的针对ALS相关症状的物质例如但不限于巴氯芬、地西泮、苯海索和/或阿米替林。
各种多胺类似物和酶抑制剂的作用机制可在特定细胞系中测定,至少部分是通过它们消除胞内多胺聚集的能力。Kramer等(1995,Biochem.Pharmacol.,50:1433)描述了用4-氟-L-鸟氨酸监测多胺生物合成路径中的代谢通量。据测定,以氟化多胺产生速度表征的代谢通量反映了细胞的增殖状态。美国专利5,498,522描述了用SSAT作为预示剂或肿瘤应答标记。可以直接测定SSAT酶活性、SSAT酶蛋白或mRNA转录产物,或者测定与SSAT诱导相关的其它决定因子例如SSAT辅因子乙酰辅酶A(乙酰CoA)和SSAT产物N1-乙烯基精胺和N1-乙烯基亚精胺。为了进一步测定某多胺类似物给药的效果,可监测个体疾病(先兆疾病)发展和疾病(先兆疾病)生物化学和/或遗传标记。就疾病发展而言,以确立了许多ALS的定级标准(即临床功能指标),属于已知技术。
ALS相关症状属于已知技术(参见例如Rowland等(2001),N.Engl.J.Med.,344:1688-1700)。此类症状包括但不限于肌肉衰弱,肌肉力度和协调性降低,麻痹,肌肉抽搐,声音改变和/或沙哑,语言障碍,吞咽困难,易窒息,呼吸困难,肌肉挛缩,肌肉萎缩,尿频/急,以及膝盖、脚、腿肿胀。神经肌肉检查发现的ALS症状包括,例如四肢之一或附近部位(例如肩、臀)开始衰弱,肌肉震颤、痉挛、抽搐,肌萎缩,步态蹒跚,反射异常。
其它调节巨噬细胞增殖的药物
除了以上多胺类似物之外,适用于调节ALS相关性巨噬细胞的药物还包括通用的抗增殖药物(即增殖调节剂)。这些包括但不限于:红比霉素,丝裂霉素C,柔红霉素,阿霉素,5-FU,阿糖胞苷,秋水仙碱,细胞松弛素B,博来霉素,长春新碱,长春碱,氨甲蝶啉,顺铂,蓖麻毒素,相思豆毒素,白喉毒素和saporin。
其它合适的还包括抑制或干扰多胺合成路径的药物或影响多胺代谢的药物,以及影响密切调节亚精胺胞内浓度的药物。此类药物的例子之一是MGBG(二盐酸米托胍腙;XYRKAMINE;Ilex,Texas),它抑制产生多胺所必需的腺苷甲硫氨酸脱氧酶。任何干扰多胺与增殖性巨噬细胞靶标之间相互作用的药物都适用于本发明,所述靶标例如DNA、RNA和/或细胞膜。另一类适用药物是干扰多胺与DNA相互作用的药物。此类药物可以通过任一前述效应(即,干扰多胺合成路径和/或代谢,干扰精胺胞内浓度,作为竞争物等)起作用,同时影响多胺与DNA相互作用的功能。根据常识,在确定上述药物是否可用及用量时需考虑其毒理特性。
一般认为,上述药物可以并的确被认为属于多胺类似物。
关于给药和其它问题可参见前文论述。
以下实施例仅是为了说明而非限定本发明。
实施例
总的说来,本发明所用流式细胞计数法属于本领域常规技术,可参见,例如“Flow Cytometry:A Practical Approach”,第2版,M.G.Ormerod编辑,OxfordUniversity Press(1997);Handbook of Flow Cytometry Methods,J.Paul Robinson编辑,John Wiley&Sons(1993);Current Protocols in Cytometry,J.Paul Robinson编辑,John Wiley&Sons(1997年10月,定期更新);Becton Dickinson CytometrySource Book,Becton Dickinson Immunocytometry Systems(1998,定期更新)(SanJose,Calif.)。
实施例1:ALS患者外周血中的异常单核细胞检测
检查肌萎缩性侧索硬化(ALS)患者和非ALS患者外周血单核细胞(PBMC)内的共有细胞分化抗原表达。这些细胞分化抗原包括跟踪单核细胞和淋巴细胞变化的特异性抗原。15名ALS患者血样的分析结果与正常非ALS家族成员(3名)的分析结果,淋巴瘤患者(11名)的历史数据分析结果和AIDS相关性痴呆患者(2名)的分析结果相比较。参试者或其代表都表示同意参见本试验。
试验中采用了以下针对所述抗原的荧光团标记的抗体:
荧光素偶联的抗CD8(Becton Dickinson);
藻红蛋白偶联的抗HLA-DR(Becton Dickinson);
藻红蛋白偶联的抗CD38(Becton Dickinson);
多甲藻素叶绿素蛋白偶联的抗CD4(Becton Dickinson);
多甲藻素叶绿素蛋白偶联的抗IgG1(同种型对照,Becton Dickinson);
荧光素偶联的抗CD14(DAKO Corp.);
藻红蛋白偶联的抗CD16(DAKO Corp.);
藻红蛋白偶联的抗PCNA(DAKO Corp.);
藻红蛋白偶联的抗Ki67(DAKO Corp.);
荧光素偶联的抗IgG1(同种型对照,DAKO Corp.);
藻红蛋白偶联的抗IgG1(同种型对照,DAKO Corp.)。
10μL肝素化全血用一种或多种上述标记抗体室温下避光染色20分钟。加入2ml FACSLYSE溶液(Becton Dickinson,San Jose,CA)培养5分钟以裂解红细胞。细胞悬浮液以400×g离心5分钟。细胞沉淀先后用1ml FACSLYSE和1ml 0.01M的磷酸盐缓冲液(PBS)洗涤。
没有进行胞内抗原染色的细胞用1ml含1%多聚甲醛+0.1%叠氮钠的0.01MPBS固定。
进行胞内抗原染色的细胞悬浮在0.5ml“透化溶液”(Becton Dickinson)中室温培养10分钟进行透化。然后,用2ml PBS洗涤细胞,离心,重悬于0.1ml PBS中。洗涤后的细胞用胞内抗原特异性抗体室温下避光染色30分钟。用1ml PBS洗涤后,用1ml含1%多聚甲醛+0.1%叠氮钠的0.01M PBS固定。
用FACSCAN流式细胞计数仪(Becton Dickinson)进行细胞计数。用流式细胞计数仪处理至少10,000细胞/份样品以测定细胞的抗体染色情况。用CELLQUEST软件(Becton Dickinson)分析表型。
将ALS患者的CD14+单核细胞表面的II类主组织相容性抗原(HLA-DR)表达水平与非ALS个体的相比。用Becton Dickinson Quatibrite试剂盒和荧光标准品定量测定CD14+细胞上HLA-DR表达水平。测定CD14+细胞群的荧光度/细胞平均值作为HLA-DR表达水平。用非配对T试验进行统计学分析来比较非ALS个体的细胞和LAS个体的细胞。结果见表1。
表1:CD14+PBMC内HLA-DR的定量表达
非ALS | HLA-DR(平均值) | ALS | HLA-DR(平均值) |
正常 | 525 | GH | 2425 |
正常 | 979 | AJ | 1327 |
正常 | 1409 | WC | 887 |
淋巴瘤 | 735 | DF | 1011 |
淋巴瘤 | 520 | BC | 3140 |
淋巴瘤 | 520 | BS | 2863 |
淋巴瘤 | 810 | DP | 1871 |
淋巴瘤 | 664 | FV | 1371 |
淋巴瘤 | 573 | GC | 2146 |
淋巴瘤 | 1887 | ML | 1221 |
淋巴瘤 | 2192 | FS | 789 |
AIDS痴呆 | 236 | PK | 1662 |
AIDS痴呆 | 1263 | GD | 813 |
淋巴瘤(转移后) | 823 | DK | 1235 |
淋巴瘤(转移后) | 822 | SR | 1181 |
淋巴瘤(转移后) | 1585 | ||
平均值 | 973 | 1596(P≤0.01) |
如表1所示,ALS患者的CD14+细胞表面的HLA-DR表达水平显著高于非ALS个体。根据定量测定,细胞表面的HLA-DR表达高出64%,具有统计学显著性(P≤0.01)。
通常,当单核细胞活化并分化为组织巨噬细胞时会高水平表达HLA-DR,非受激循环单核细胞只低水平地表达HLA-DR。因此,以上数据表明ALS患者体内的循环单核细胞被普遍活化并且正在分化为巨噬细胞。
如前所述,在采血后的次日(“次日”细胞)分析肝素化血样的细胞标记表达。用增殖标记,即增殖细胞核抗原(PCNA)和Ki67活性,检测ALS患者和非ALS个体的单核细胞增殖。用抗CD14和抗PCNA或抗Ki67染色PBMC,并如上所述进行分析。结果见表2。
表2:CD14+PBMC内的抗原表达
标记或抗原 | ALS | 非ALS |
侧散 | 386 | 361 |
%CD14/HLA-DR | 93 | 93 |
%CD14/CD16 | 29 | 23 |
%CD14/PCNA | 35 | 32 |
%CD14/Ki67 | 2.48 | 0.4 |
如表2所示,ALS患者的PCNA活性在正常范围内。但是,ALS患者体内的Ki67阳性CD14+细胞似乎增多。Ki67和PCNA在细胞周期的多个不同阶段表达。因此,ALS患者CD14+细胞的Ki67活性表明这些细胞进行有丝分裂。
还对PBMC进行了T淋巴细胞标记分析,结果见表3。
表3:CD14+PBMC内的淋巴细胞抗原表达
抗原 | ALS | 非ALS |
%CD4 | 45 | 41(28-52) |
%CD8 | 21 | 29(16-45) |
CD4/CD8 | 2.57(1.2-6.1)* | 1.37(0.7-3.0) |
%CD4/CD38 | 24 | 19 |
CD4/CD38的中值 | 11 | 4 |
%CD8/CD38 | 11 | 9 |
CD8/CD38的中值 | 2 | 1 |
*P≤0.01
如表3所示,对PBMC的T淋巴细胞标记分析没有发现任何表明T淋巴细胞活化的证据。CD4和CD8水平都正常。根据CD4/CD38和CD8/CD38活性之比测定的淋巴细胞活化状态也正常,表明免疫系统内的这一组分普遍正常。
另一实验中,20名ALS患者的血样分析结果与20名正常非ALS个体的进行比较。在采血的当日(“当日”细胞)如上所述对肝素化全血进行细胞标记表达分析。图1显示当日血样CD14+单核细胞上的HLA-DR表达水平。图2显示当日血样中共表达CD16的CD14+细胞的百分比。
如图1所示,ALS患者CD14+单核细胞的HLA-DR表达水平显著高于非ALS个体。图2显示,ALS患者的CD14+细胞群中CD16+细胞百分比显著高于非ALS个体。
总而言之,ALS患者的PBMC中的CD14+细胞表现出表面标记的改变,这些改变表明细胞活化、分化和增殖异常。例如,虽然没有发现淋巴细胞活化状态的重大变化,但是单核细胞表现出了活化迹象。
实施例2:血液采集条件对ALS患者异常循环性巨噬细胞鉴定的影响
对7份抽入含肝素试管的ALS患者血样和抽入含钙螯合剂柠檬酸葡萄糖的试管(ACD管)的血样如前所述进行细胞标记表达分析。同时,在采血当日,对10份抽入含肝素管的正常非ALS个体的血样也如前所述进行细胞标记表达分析。
图3显示采集在肝素管中的ALS血样中的CD14+单核细胞上的HLA-DR表达水平与采集在ACD管中的比较。图4显示采集在肝素管中的ALS血样中共表达CD16的CD14+单核细胞百分比与采集在ACD管中的比较。图3和图4中,采集在肝素管中的正常样品的中值用水平实线表示,中值以上和以下的虚线表示标准偏差。
如图3和图4所示,当血样中存在钙螯合剂时,同日分析的ALS血样中的HLA-DR表达水平和CD16+/CD14+细胞百分比都降至正常值。用EDTA作为螯合剂时获得相似结果。这表明,细胞培养基中的钙螯合剂造成ALS的异常巨噬细胞特征丢失;还表明,足量非螯合钙对于检测将ALS样品区别于对照的两项重要巨噬细胞活化参数来说是必需的。
实施例3:多胺类似物对于ALS患者CD14+单核细胞的作用
在密度1.087的Percoll(Pharmacia,Piseataway,NJ)上分层叠加肝素化全血,从中分离出外周血单核细胞(PBMC),然后以800×g离心。收集Percoll/血浆界面的细胞,用0.01M磷酸盐缓冲液(PBS)洗涤。然后,将分离所得细胞悬浮在加有10%胎牛血清的RPMI 1640培养基中,浓度约为1×106细胞/ml。将细胞分装到聚乙烯培养管中,1ml/管。在3根培养管中加入多胺类似物,例如SL-11047,最终浓度分别为1.0,0.1和0.01mM。第4管,作为对照,不加任何药物。全部培养管放入增湿培养箱中,37℃,5%二氧化碳,培养5天。
第5天,从培养箱中取出细胞,用PBS洗涤,重悬于PBS,0.1ml/管。用荧光素偶联的抗CD14(DAKO Corp.,Carpenteria,CA)室温下避光染色20分钟以检测单核细胞。另取一份平行样品,以对照即荧光素偶联的IgG1(同种型抗体对照,DAKO Corp.)染色,作为阴性染色对照。用PBS洗涤细胞,用1ml含1%多聚甲醛+0.1%叠氮钠的PBS固定细胞。用FACSCAN流式细胞计数仪(Becton Dickison,San Jose,CA)和CELLQUEST软件(Becton Dickison)处理至少20,000细胞/管来鉴定CD14+单核细胞。将药物处理管的CD14+单核细胞数与非处理对照比较,并计算减少50%所需的药物剂量(ED50)。
对6名ALS患者,1名多发性硬化症(MS)患者和1名正常(非ALS)对照的CD14+循环单核细胞进行上述实验。该实验中,同一个体的细胞加或不加多胺类似物SL-11047培养6天,然后测定CD14+细胞存活率。图5显示各份细胞样品在1.0μM SL-11047存在下的被杀细胞百分比。该实验显示,ALS患者的CD14+循环单核细胞对多胺类似物的杀伤易感性比正常个体或MS患者明显高得多,这可能是因为多胺类似物对ALS患者循环性CD14+单核细胞中的异常巨噬细胞群所具有的杀伤力。所以,多胺类似物有望用于减少ALS患者的异常巨噬细胞。
Claims (7)
1.一种辅助ALS疾病诊断的方法,包括在个体血样中检测异常巨噬细胞,所述检测包括检测HLA-DR高表达CD14+细胞或CD14+/CD16+细胞。
2.如权利要求1所述的方法,所述检测包括检测HLA-DR高表达CD14+细胞。
3.如权利要求1所述的方法,所述检测包括检测CD14+/CD16+细胞。
4.如权利要求1所述的方法,所述检测异常巨噬细胞在血样采集后12小时内进行。
5.一种筛选能够减少ALS相关性异常巨噬细胞的药物的方法,包括检测候选药物存在和不存在时HLA-DR高表达的CD14+细胞或CD14+/CD16+细胞的细胞活度差异,所述HLA-DR高表达的CD14+细胞或CD14+/CD16+细胞获自ALS患者的血样。
6.如权利要求5所述方法,检测的是HLA-DR高表达的CD14+细胞的活度。
7.如权利要求5所述方法,检测的是CD14+/CD16+细胞的活度。
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CN112424608A (zh) * | 2018-05-10 | 2021-02-26 | 卫理公会医院 | 用于疾病的预后和管理的方法 |
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JP2005511061A (ja) | 2005-04-28 |
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