CN110650749A - 使用可溶性cd24进行神经保护和髓鞘再生的方法 - Google Patents
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Abstract
本发明涉及组合物及其在保护和维持少突胶质细胞以及治疗脱髓鞘病症的方法中的用途。
Description
技术领域
本发明涉及组合物及其在保护和维持少突胶质细胞以及治疗脱髓鞘病症的方法中的用途。
背景技术
髓鞘是分层的、富含脂质的结构,包裹在轴突周围,以介导沿着它们的跳跃信号传导,并为它们提供营养支持。在中枢神经系统(CNS)中,髓鞘由少突胶质细胞形成。髓磷脂是脱髓鞘疾病的靶标,包括神经免疫病症如多发性硬化症(MS)。髓鞘再生是诱导少突胶质细胞前体细胞(OPC)形成少突胶质细胞的过程,少突胶质细胞能够在中枢神经系统(CNS)的脱髓鞘轴突上产生新的髓鞘。响应于髓鞘变性,称为少突胶质细胞祖细胞(OPC)的多能实质祖细胞被激活并募集到受损区域。这是体内自然调节的过程,在健康的CNS中往往非常有效。但是在患有神经免疫病症的人中,髓鞘再生变得越来越不完全,使轴突永久脱髓鞘,容易变性,并且在许多患者中最终失败,导致更多的疾病进展。
在诸如MS之类的疾病中,髓鞘再生失败的原因仍然没有被完全理解,并且被认为是复杂的。几项研究表明,一部分慢性脱髓鞘的MS病变中含有不能分化为再生髓鞘的少突胶质细胞的OPC。少突胶质细胞通过依赖髓鞘再生的机制和不依赖髓鞘再生的机制在神经保护中起关键作用,并在涉及中枢神经系统的炎性和退行性疾病(包括MS、阿尔茨海默氏病和潜在的帕金森氏病)中提供保护(1-4)。
因此,对通过促进少突胶质细胞的保护和维持并促进髓鞘形成活性治疗脱髓鞘疾病存在大量未满足的医学需求。
发明内容
本文提供了维持少突胶质细胞,促进髓鞘形成和治疗脱髓鞘病症的方法,所述脱髓鞘病症包括涉及中枢神经系统的炎性和退行性疾病。所述方法可以包括将CD24蛋白施用于有需要的受试者。脱髓鞘病症可以是阿尔茨海默氏病、帕金森氏病、多发性硬化症、急性播散性脑脊髓炎、视神经脊髓炎谱系病症、视神经炎、横贯性脊髓炎或急性弛缓性脊髓炎。CD24蛋白可以维持少突胶质细胞。所述方法可以进一步包括施用促进少突胶质细胞转化或促进少突胶质细胞产生髓磷脂的另一种试剂。
CD24蛋白可以包含成熟的人CD24或其变体。成熟的人CD24可以包含SEQ ID NO:1或2所示的氨基酸序列。CD24蛋白可以包含人CD24的任何或全部细胞外结构域。CD24蛋白的序列可以包含CD24的信号肽序列,其可以包含SEQ ID NO:4所示的氨基酸序列。信号肽序列可以允许从表达蛋白质的细胞分泌。信号肽序列也可以是在另一跨膜或分泌的蛋白质上发现的序列,或者是由本领域已知的现有信号肽修饰的序列。CD24蛋白可以是可溶的。CD24蛋白可以被糖基化。可以使用真核蛋白表达系统产生CD24蛋白,所述真核蛋白表达系统可以包含中国仓鼠卵巢细胞系中所含的载体或复制缺陷型逆转录病毒载体。复制缺陷型逆转录病毒载体可以稳定地整合到真核细胞的基因组中。
CD24蛋白可以包含蛋白质标签,其可以在CD24蛋白的N端或C端融合。所述蛋白质可以包含哺乳动物免疫球蛋白(Ig)的一部分,其可以是人Ig蛋白的Fc区。人Ig蛋白可以包含人Ig蛋白的铰链区以及CH2和CH3结构域,并且人Ig蛋白可以是IgG1、IgG2、IgG3、IgG4或IgA。Fc区还可以包含IgM的铰链区以及CH2、CH3和CH4结构域。CD24蛋白可以包含SEQ IDNO:5、6、8、9、11或12所示的氨基酸序列。
附图说明
图1A示出了全长CD24融合蛋白CD24Fc(在本文中也称为CD24Ig)的氨基酸组成(SEQ ID NO:5)。带下划线的26个氨基酸是CD24的信号肽(SEQ ID NO:4),其在分泌期间从表达所述蛋白质的细胞中被切除,因此从所述蛋白质的加工形式(SEQ ID NO:6)中缺失。序列的粗体部分是融合蛋白中使用的成熟CD24蛋白的细胞外结构域(SEQ ID NO:2)。为了避免免疫原性,成熟CD24蛋白中通常存在的最后一个氨基酸(A或V)已从构建体中删除。非带下划线的非粗体字母是IgG1 Fc的序列,包括铰链区以及CH1和CH2结构域(SEQ ID NO:7)。图1B示出了CD24VFc的序列(SEQ ID NO:8),其中成熟的人CD24蛋白(粗体)是SEQ ID NO:1的缬氨酸多态性变体。图1C示出了CD24AFc的序列(SEQ ID NO:9),其中成熟的人CD24蛋白(粗体)是SEQ ID NO:1的丙氨酸多态性变体。图1B和1C中融合蛋白的各个部分如图1A中所标记,并且变体缬氨酸/丙氨酸氨基酸带双下划线。
图2示出了来自小鼠(SEQ ID NO:3)和人(SEQ ID NO:1)的成熟CD24蛋白之间的氨基酸序列变异。潜在的O-糖基化位点以粗体显示,N-糖基化位点用下划线标出。
图3.CD24IgG1(CD24Fc)药代动力学的WinNonlin区室建模分析。空心圆代表3只小鼠的平均值,线是预测的药代动力学曲线。图3A.静脉内注射1mg CD24IgG1。图3B.皮下注射1mg CD24IgG1(CD24Fc)。图3C.通过曲线下面积(AUC)、半衰期和最大血液浓度测量的血液中抗体总量的比较。注意,总体而言,皮下注射的AUC和Cmax约为静脉内注射的80%,尽管差异在统计上并不显著。
图4.CD24-Siglec G(10)相互作用可区分PAMP和DAMP。图4A.宿主对PAMP的响应不受CD24-Siglec G(10)相互作用的影响。图4B.CD24-Siglec G(10)相互作用可能通过Siglec G/10相关的SHP-1抑制宿主对DAMP的响应。
图5.CD24Fc与髓磷脂相关糖蛋白(MAG)的体外结合
图6.人CD24融合蛋白在小鼠EAE中的治疗功效。如图4的图例所述,用MOG肽使C57BL/6j小鼠免疫。免疫后14-21天,将EAE评分在2.5至3.5之间的小鼠随机分为三组,并通过每隔一天注射5次CD24融合蛋白(每次注射200或50μg)或对照蛋白(每次注射200μg)来处理。显示的数据是临床评分的平均值和标准误差。*P<0.05,**P<0.01。总体而言,当施用200μg融合蛋白时,观察到了显著的治疗效果(P=0.0083)。在两个独立的实验中观察到治疗效果,每组总共有7-12只小鼠。
图7.CD24Fc防止被MOG引发的T细胞自身免疫破坏。在第0天,用含MOG肽的CFA使六周龄雌性C57BL/6小鼠免疫。免疫后第7天,当大多数小鼠没有临床症状时,通过每隔一天腹膜内注射对照人IgG Fc或CD24Fc(200μg/注射/小鼠)来处理小鼠,共注射5次,如箭头所示。每天检查小鼠以对临床症状评分。所示数据为每组9只和10只小鼠的平均值和SEM。(P=0.0019,Fisher的PLSD检验)。在另一个实验中已经再现了治疗效果。
图8.鉴定小鼠中CD24Fc的最小有效剂量。用MOG使C57BL/6小鼠免疫,并用CD24Fc处理,如在图4的图例中详述。第一个月的累积疾病评分用于计算由CD24Fc引起的抑制百分比。IgG1Fc处理组的评分用作基线。对数曲线拟合用于计算最小有效剂量。
图9.SJL模型中复发性缓解型EAE的CD24Fc处理。在第0天,用含PLP肽的CFA使六周龄雌性SJL小鼠免疫。免疫后第7天,当大多数小鼠没有临床症状时,通过每隔一天腹膜内注射对照人IgG Fc或CD24 Ig(200μg/注射/小鼠)来处理小鼠,共注射5次(第7、9、11、13和15天)。每天检查小鼠以对临床症状评分。所示数据为每组中14只或15只小鼠的平均值和SEM。P=0.0039,Fisher的PLSD检验。SJL模型中的治疗效果已重复3次。由于在涉及此模型的某些实验中IgGFc加剧了疾病评分(从而增强了治疗效果),因此在此模型中使用了GMP级媒剂(PBS)。
图10.未处理和EAE小鼠的CNS中CD24Fc的浓度。通过将200μgMOG35-55肽在含有400μg结核分枝杆菌的完全弗氏佐剂(CFA)中皮下免疫接种到8-10周龄雌性C57BL/6小鼠中来诱发EAE。免疫后立即静脉内注射200ng百日咳毒素,并在48小时后再次注射。在EAE诱导后的第11天,给小鼠静脉内施用1mg CD24Fc。年龄匹配的未处理雌性C57BL/6小鼠也静脉内接受了相同量的CD24Fc。24小时后,从两组小鼠中收集脑脊髓液(CSF),并通过夹心ELISA测量CNS中的CD24Fc浓度。在这项研究中,将来自施用PBS的未处理小鼠的脑脊髓液用作阴性对照。
图11.Cd24或Siglecg的靶向突变会增加少突胶质细胞对铜宗(Cuprizone,CPZ)治疗的敏感性。图11A.分析了胼胝体组织切片的位置。图11B.WT、Cd24-/-和Siglecg-/-小鼠的前囟-1脑区域中oligo-2染色的代表性图像。在8周龄时,在处死前,给小鼠喂食含有0.2重量%CPZ的食物2至5周。将另外的动物保持在含CPZ的饮食中5周,接着再允许恢复(从饮食中去除CPZ)10天,然后处死。对照组保持正常饮食。用磷酸盐缓冲盐水(PBS),然后用冷的含4%多聚甲醛的PBS经贲门灌注小鼠。取出大脑,在4%多聚甲醛中固定过夜,然后转移至冷冻保护溶液中。在Leica滑动切片机上切割冠状冷冻切片(30μm,自由漂浮)。将自由漂浮的切片用PBS冲洗,并在室温下用5%正常驴或山羊血清阻断1小时。然后,将切片与抗Oligo2抗体(EMD Millipore,目录号Ab9610,以1:2000稀释度使用)在室温下培育2小时,然后与fluor 555偶联的驴抗兔IgG二抗(Invitrogen,目录号A-31572)在室温下培育1小时。随后,将切片洗涤,用DAPI染色,固定在载玻片上,并盖上Fluoromount-G盖玻片。图11C.关于CPZ对WT、Cd24-/-和Siglecg-/-脑的前囟-1区少突胶质细胞数量的影响的摘要数据。显示的数据代表两个独立的实验。使用学生t检验确定P值。数据显示为平均值和标准偏差。图11D.单次全身施用CD24Fc(10mg/小鼠)后,CSF和血清中检测到的CD24Fc浓度。这些数据代表两个独立的实验,N=4。数据显示为平均值和标准偏差。图11E.治疗性实验的研究时间线。图11F.单剂量CD24Fc处理(10mg/小鼠)后2周或4周,前囟-1中Oligo 2+细胞的数量。显示的数据代表两个独立的实验。P值由学生t检验确定。N=4。数据显示为平均值和标准偏差。所有统计分析均使用GraphPad Prism软件进行。数据显示为平均值和标准偏差。
图12示出了通过治疗人受试者中PK可评估人群的平均血浆CD24Fc浓度(±SD)的图。PK=药代动力学;SD=标准偏差。
图13示出了针对PK可评估人群的CD24Fc Cmax与剂量的剂量比例图。
图14示出了针对PK可评估人群的CD24Fc AUC0-42d与剂量的剂量比例图。
图15示出了针对PK可评估人群的CD24Fc AUC0-inf与剂量的剂量比例图。
具体实施方式
发明人惊奇地发现,CD24的可溶形式对于维持少突胶质细胞和治疗与脱髓鞘相关的神经免疫病症非常有效。该作用可以通过与损伤相关的分子模式来介导。模式识别涉及由病原体相关和组织损伤相关分子模式(分别称为PAMP和DAMP)触发的炎症反应。不受理论的束缚,对DAMP的加剧的宿主反应可能在炎性和自身免疫性疾病的发病机理中起作用。已发现在动物模型中,DAMP促进炎性细胞因子和自身免疫性疾病的产生,并因此发现DAMP的抑制剂如HMGB1和HSP90减轻类风湿性关节炎(RA)(4-6)。已显示TLR、RAGE-R、DNGR(由Clec9A编码)和Mincle是负责介导由多种DAMP引发的炎症的受体(2,7-14)。
发明人已经证明CD24-Siglec G相互作用区分针对DAMP与PAMP的先天免疫(15,16)。Siglec蛋白是膜相关的免疫球蛋白(Ig)超家族成员,其识别多种含唾液酸的结构。大多数Siglec具有与SHP-1、-2和Cbl-b相关的细胞内免疫酪氨酸抑制基序(ITIM),以控制炎症反应的关键调节因子。CD24被确定为Siglec小鼠的Siglec G和人类的Siglec 10的第一个天然配体(15)。Siglec G通过SHP-1/2信号传导机制与唾液酸化的CD24相互作用,以抑制TLR介导的宿主对DAMP(如HMGB1)的反应(15),这对于SLE发病机理至关重要(2)。SiglecG还与Cbl缔合以触发RIG-I降解,从而抑制了I型干扰素反应(17),这是人类狼疮发病机理中的关键因素。
另外,发明人已经证明CD24负调节宿主对由于组织或器官损伤而释放的细胞DAMP的反应,并且至少两种重叠的机制可以解释这种活性。首先,CD24与几种DAMP结合,包括HSP70、HSP90、HMGB1和核仁素,并抑制宿主对这些DAMP的反应。为此,假定CD24可能捕获炎症刺激,以防止与其受体TLR或RAGE相互作用。其次,CD24通过与其受体Siglec G的相互作用为宿主对组织损伤的反应提供了强有力的负调节。为了实现该活性,CD24可以通过Siglec G结合并刺激信号传导,其中与Siglec G相关的SHP1触发负调节。这两种机制可能共同起作用,因为具有任一基因的靶向突变的小鼠都具有更强的炎症反应。实际上,当用HMGB1、HSP70或HSP90刺激时,从CD24-/-或Siglec G-/-小鼠的骨髓中培养的DC产生较高水平的炎性细胞因子。就发明人所知,CD24是能够抑制由DAMP触发的炎症的唯一抑制性DAMP受体,并且目前尚无专门针对宿主对组织损伤的炎症反应的药物。此外,在类风湿性关节炎、多发性硬化症和移植物抗宿主病的小鼠模型中,外源可溶性CD24蛋白减轻DAMP介导的自身免疫性疾病。
人CD24是由CD24基因中的240个碱基对的开放阅读框编码的GPI锚定的小分子(28)。在这80个氨基酸中,前26个构成信号肽,而后23个用作裂解信号,以允许GPI尾部附着。因此,成熟的人CD24分子仅具有31个氨基酸。这31个氨基酸之一是人类群体中多态的。在开放阅读框的核苷酸170处C到T的转变导致丙氨酸(A)被缬氨酸(V)取代。由于该残基紧邻切割位点的N端,并且由于置换是非保守的,因此这两个等位基因可能在细胞表面以不同的效率表达。实际上,用cDNA进行转染研究表明CD24v等位基因在细胞表面更有效地表达(28)。与此相一致,CD24v/v PBL表达更高水平的CD24,尤其是在T细胞上。
发明人发现,Cd24或Siglecg的靶向突变形成了一个轴,该轴选择性地调节了对DAMP的先天性炎症反应,从而保护了小鼠免受铜宗诱导的少突胶质细胞损失。发明人还发现,已知在体内刺激Siglec G信号传导并抑制炎症反应的CD24蛋白(CD24Fc)的全身施用保护少突胶质细胞免于长期暴露于铜宗。因此,宿主对细胞损伤的反应积极参与少突胶质细胞的损失,并提供了一种在病理条件下维持少突胶质细胞的新方法。
因此,本文描述的方法可用于提供神经保护,以减轻、最小化或治疗涉及中枢神经系统的炎性和退行性疾病。特别地,本文描述的方法可用于治疗神经免疫病症,包括多发性硬化症(MS)、急性播散性脑脊髓炎(ADEM)、视神经脊髓炎谱系病症(NMOSD)、视神经炎(ON)和横贯性脊髓炎(TM),其可能是急性弛缓性脊髓炎(AFM)。
1.定义.
本文所使用的术语仅出于描述特定实施例的目的,而无意于进行限制。如在说明书和所附权利要求书中所用,除非上下文另外明确规定,否则单数形式“一(a/an)”和“所述”包括复数指示物。
为了在此列举数值范围,明确考虑了它们之间具有相同精确度的每个中间数字。例如,对于6-9的范围,除了6和9外,还涵盖数字7和8;对于6.0-7.0的范围,明确涵盖了数字6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9和7.0。
“肽”或“多肽”是氨基酸的连接序列,并且可以是天然的、合成的或天然的或合成的修饰或组合。
“基本上相同”可以意指第一和第二氨基酸序列在1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、55、60、65、70、75、80、85、90、95、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290或300个氨基酸的区域上为至少60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%或99%。
当提到保护动物免受疾病侵害时,“治疗(treatment/treating)”是指预防、抑制、遏制或完全消除疾病。预防疾病涉及在疾病发作之前向动物施用本发明的组合物。抑制疾病涉及在诱发疾病之后但在其临床出现之前向动物施用本发明的组合物。遏制疾病涉及在疾病的临床出现后向动物施用本发明的组合物。
“变体”可以意指通过氨基酸的插入、缺失或保守取代而在氨基酸序列上不同,但是保留至少一种生物活性的肽或多肽。“生物活性”的代表性实例包括与toll样受体结合并被特异性抗体结合的能力。变体也可以意指具有与保留至少一种生物活性的氨基酸序列的参照蛋白质基本上相同的氨基酸序列的蛋白质。氨基酸的保守取代,即用具有相似特性(例如,亲水性、带电区域的程度和分布)的不同氨基酸取代氨基酸,在所属领域中被认为通常涉及微小的变化。如所属领域所理解的,这些微小的变化可以部分地通过考虑氨基酸的亲水指数来鉴定。Kyte等人,《分子生物学杂志(J.Mol.Biol.)》157:105-132(1982)。氨基酸的亲水指数是基于对其疏水性和电荷的考虑。所属领域已知具有相似亲水指数的氨基酸可以被取代并且仍然保留蛋白质功能。一方面,亲水指数为±2的氨基酸被取代。氨基酸的亲水性也可用于揭示使蛋白质保留生物功能的取代基。在肽的情况下考虑氨基酸的亲水性可以计算该肽的最大局部平均亲水性,这是一种有用的量度,据报道与抗原性和免疫原性很好地相关。美国专利号4,554,101,通过引用完全并入本文。如所属领域所理解的,具有相似亲水性值的氨基酸的取代可以使肽保留生物活性,例如免疫原性。可用亲水性值彼此在±2之内的氨基酸进行取代。氨基酸的疏水性指数和亲水性值均受该氨基酸的特定侧链影响。与该观察结果一致,与生物功能相容的氨基酸取代应理解为取决于氨基酸的相对相似性,尤其是那些氨基酸的侧链,如疏水性、亲水性、电荷、大小和其他属性所显示。
2.CD24
本文提供了CD24蛋白,其可以包含成熟的CD24或其变体。成熟的CD24对应于CD24的细胞外结构域(ECD)。成熟的CD24可以来自人或另一种哺乳动物。如上所述,成熟的人CD24蛋白长31个氨基酸,通常在其C端具有可变的丙氨酸(A)或缬氨酸(V)残基:
SETTTGTSSNSSQSTSNSGLAPNPTNATTK(V/A)(SEQ ID NO:1)
C端缬氨酸或丙氨酸可能具有免疫原性,可以从CD24蛋白中省略,从而降低其免疫原性。因此,CD24蛋白可能包含缺少C端氨基酸的人CD24的氨基酸序列:
SETTTGTSSNSSQSTSNSGLAPNPTNATTK(SEQ ID NO:2)
尽管来自小鼠和人的成熟CD24蛋白的氨基酸序列有相当大的序列变异,但它们在功能上是等效的,因为已显示人CD24Fc在小鼠中具有活性。人CD24ECD的氨基酸序列显示出与小鼠蛋白的某些序列保守性(39%同一性;Genbank登录号NP_033976)。然而,不出人意料的是,同一性百分比不会更高,因为取决于物种,CD24 ECD的长度仅为27-31个氨基酸,并与其某些受体如Siglec10/G的结合是通过糖蛋白的唾液酸和/或半乳糖介导的。人Siglec-10(GenBank登录号AF310233)的细胞外结构域与其鼠同系物Siglec-G(GenBank登录号NP_766488)受体蛋白之间的氨基酸序列同一性为63%(图2)。由于小鼠和人CD24之间的序列保守性主要在C端和丰富的糖基化位点,因此使用CD24蛋白可以耐受成熟CD24蛋白的显著变异,特别是如果这些变异不影响保守的C端的残基或不影响小鼠或人CD24的糖基化位点。因此,CD24蛋白可能包含成熟鼠CD24的氨基酸序列:
NQTSVAPFPGNQNISASPNPTNATTRG(SEQ ID NO:3)。
人CD24 ECD的胺基酸序列显示出与食蟹猕猴蛋白(52%同一性;UniProt登录号UniProtKB-I7GKK1)具有相比与小鼠更多的序列保守性。同样,鉴于同一性百分比不会更高,因为在这些物种中ECD的长度仅为29-31个氨基酸,以及糖残基在与其受体的结合中的作用,这并不出人意料。猕猴Siglec-10受体的氨基酸序列尚未确定,但人和恒河猴Siglec-10(GenBank登录号XP_001116352)蛋白之间的氨基酸序列同一性为89%。因此,CD24蛋白还可以包含成熟猕猴(或恒河猴)CD24的氨基酸序列:
TVTTSAPLSSNSPQNTSTTPNPANTTTKA(SEQ ID NO:10)
CD24蛋白可能是可溶的。CD24蛋白可进一步包含N端信号肽,以允许从表达该蛋白的细胞分泌。信号肽序列可以包含氨基酸序列MGRAMVARLGLGLLLLALLLPTQIYS(SEQ ID NO:4)。或者,信号序列可以是任何在其他跨膜或分泌的蛋白质上发现的那些信号序列,或者是由所属领域已知的现有信号肽修饰的那些信号序列。
a.融合
CD24蛋白可以在其N端或C端融合至蛋白质标签,所述蛋白质标签可以包含哺乳动物Ig蛋白的一部分,其可以是人或小鼠的或来自其他物种。所述部分可以包含Ig蛋白的Fc区。Fc区可以包含Ig蛋白的铰链区、CH2、CH3和CH4结构域中的至少一个。Ig蛋白可以是人IgG1、IgG2、IgG3、IgG4或IgA,并且Fc区可以包含Ig的铰链区以及CH2和CH3结构域。Fc区可以包含人免疫球蛋白G1(IgG1)同种型SEQ ID NO:7。Ig蛋白也可以是IgM,并且Fc区可以包含IgM的铰链区以及CH2、CH3和CH4结构域。蛋白质标签可以是有助于蛋白质纯化的亲和标签,和/或增强功能性蛋白质的溶解度和回收率的溶解度增强标签。蛋白质标签还可以增加CD24蛋白的价数。蛋白质标签还可以包含GST、His、FLAG、Myc、MBP、NusA、硫氧还蛋白(TRX)、小泛素样修饰物(SUMO)、泛素(Ub)、白蛋白或骆驼Ig。制备融合蛋白和纯化融合蛋白的方法是所属领域众所周知的。
根据临床前研究,为了构建在实例中鉴定的融合蛋白CD24Fc,已经使用30个氨基酸的天然CD24分子的截短形式,其在GPI信号切割位点之前缺少最终的多态性氨基酸(即具有SEQ ID NO:2的成熟CD24蛋白)。成熟的人CD24序列与人IgG1 Fc结构域(SEQ ID NO:7)融合。全长CD24Fc融合蛋白提供在SEQ ID NO:5中(图1),而从细胞分泌的CD24Fc融合蛋白的加工版本(即,缺少被切割的信号序列)提供在SEQ ID NO:6中。与IgG1 Fc融合的成熟CD24(即具有SEQ ID NO:1的成熟CD24蛋白)的经加工的多态性变体可以包含SEQ ID NO:11或12。
b.生产
CD24蛋白可能被高度糖基化,并且可能参与CD24的功能,例如免疫细胞的共刺激以及与损伤相关分子模式分子(DAMP)的相互作用。可以使用真核表达系统制备CD24蛋白。表达系统可能需要在哺乳动物细胞如中国仓鼠卵巢(CHO)细胞中从载体表达。所述系统也可以是病毒载体,例如可用于感染真核细胞的复制缺陷型逆转录病毒载体。CD24蛋白也可以由稳定的细胞系产生,所述细胞系表达来自已经整合到细胞基因组中的载体或载体的一部分的CD24蛋白。稳定的细胞系可以从整合的复制缺陷型逆转录病毒载体表达CD24蛋白。表达系统可以是GPExTM。
c.药物组合物
CD24蛋白可以包含在药物组合物中,所述药物组合物可以包含药学上可接受量的CD24蛋白。药物组合物可以包含药学上可接受的载体。药物组合物可以包含溶剂,其可以在延长的时期内保持CD24蛋白稳定。溶剂可以是PBS,其可以在-20℃(-15至-25℃)下保持CD24蛋白稳定至少66个月。所述溶剂可能能够容纳与另一种药物组合的CD24蛋白。
可以将药物组合物配制用于肠胃外施用,包括但不限于通过注射或连续输注。用于注射的制剂可以是在油性或水性媒剂中的悬浮液、溶液或乳液形式,并且可以含有配制剂,包括但不限于悬浮剂、稳定剂和分散剂。组合物也可以粉末形式提供,以与合适的媒剂重构,所述媒剂包括但不限于无菌的无热原质水。
药物组合物也可以配制成贮库制剂,其可以通过植入或肌内注射施用。所述组合物可以用合适的聚合或疏水材料(例如,作为在可接受的油中的乳液)、离子交换树脂或作为微溶的衍生物(例如,作为微溶的盐)配制。皮下注射制剂可能与狼疮及其相关表现和并发症等适应症特别相关。
d.剂量
CD24蛋白的剂量可以最终通过临床试验确定,以确定具有可接受的毒性和临床功效的剂量。可以通过在啮齿动物和非人类灵长类动物中的药代动力学和毒性研究来估计初始临床剂量。CD24蛋白的剂量可以是0.01mg/kg至1000mg/kg,并且可以是1至500mg/kg,这取决于所需的少突胶质细胞维持程度或所治疗的神经免疫病症以及施用途径。可以通过静脉内输注或皮下、壁内(即腔或器官壁内)或腹膜内注射来施用CD24蛋白,并且剂量可以是10-1000mg、10-500mg、10-240mg、10-120mg或10、30、60、120或240mg,其中受试者是人类。
3.治疗方法
本文提供了通过向有需要的受试者施用本文所述的CD24蛋白来维持少突胶质细胞的方法。本文进一步提供了通过向有需要的受试者施用CD24蛋白来治疗可能是脱髓鞘病症的神经免疫病症的方法。可以将CD24蛋白施用于患有神经免疫病症或脱髓鞘病症或处于罹患神经免疫病症或脱髓鞘病症的风险下的受试者。少突胶质细胞可以通过增强或改善少突胶质细胞的髓鞘形成活性而维持在受试者的中枢神经系统(CNS)中。
本文还提供了通过向有需要的受试者施用CD24蛋白来向受试者提供神经保护的方法。CD24蛋白可以为CNS中的细胞提供神经保护。神经保护可以减轻、最小化或治疗涉及中枢神经系统的炎性或退行性疾病。炎性或退行性疾病可以是多发性硬化症、阿尔茨海默氏病或帕金森氏病。
神经免疫病症可以是MS、急性播散性脑脊髓炎(ADEM)、视神经脊髓炎谱系病症(NMOSD)、视神经炎(ON)或横贯性脊髓炎(TM),其可以是急性弛缓性脊髓炎(AFM)。CD24蛋白还可用于减轻、减少或治疗神经免疫病症。
a.施用
药物组合物的施用途径可以是肠胃外的。肠胃外施用包括但不限于静脉内、动脉内、腹膜内、皮下、肌内、鞘内、关节内和直接注射。药物组合物可以施用于人类患者、猫、狗、大型动物或禽类。所述组合物可以每天施用1、2、3、4、5、6、7、8、9、10、11或12次。
b.组合治疗
本文所述的CD24蛋白可与用于促进髓鞘再生或促进少突胶质前体细胞在少突胶质细胞中转化的另一种治疗组合。此类治疗的实例包括抗Lingo-1、NDC-1308、抗EphrinB3、富马酸氯马斯汀(clemastine fumarate)、氟胺(fluorosamine)和芬戈莫德(fingolimod)。LINGO-1是由CNS产生的一种蛋白质,防止未成熟的细胞成为少突胶质细胞,而抗Lingo(奥匹奴单抗,opicinumab)可以阻断LINGO-1的作用,从而使这些细胞成熟为少突胶质细胞。NDC-1308被设计来修复脱髓鞘神经纤维的髓鞘和特异性地靶向治疗运动神经元损害。EphrinB3是一种膜结合信号传导蛋白,阻断MS中受损神经元的髓鞘再生,因此抗Ephrin旨在逆转这种阻断作用。通过防止硫酸软骨素蛋白聚糖的合成和促进少突胶质细胞功能,氟胺被认为可以增强小鼠的髓鞘再生。同样,芬戈莫德(GILENYA)是一种批准用于复发性多发性硬化症患者以预防神经炎症的药物,它也可以通过部分地独立于其抗炎特性的方式直接增强神经再生和增加髓鞘形成来帮助这些患者。
CD24蛋白可与其他治疗同时或按节律施用。如本文所用,术语“同时(simultaneous/simultaneously)”意指CD24蛋白和其他治疗在彼此的48小时、优选24小时、更优选12小时、再更优选6小时、最优选3小时或更短时间内施用。如本文所用,术语“按节律”意指在与其他治疗不同的时间并且相对于重复施用以一定频率施用药剂。
CD24蛋白可以在另一种治疗之前的任何时间点施用,包括约120小时、118小时、116小时、114小时、112小时、110小时、108小时、106小时、104小时、102小时、100小时、98小时、96小时、94小时、92小时、90小时、88小时、86小时、84小时、82小时、80小时、78小时、76小时、74小时、72小时、70小时、68小时、66小时、64小时、62小时、60小时、58小时、56小时、54小时、52小时、50小时、48小时、46小时、44小时、42小时、40小时、38小时、36小时、34小时、32小时、30小时、28小时、26小时、24小时、22小时、20小时、18小时、16小时、14小时、12小时、10小时、8小时、6小时、4小时、3小时、2小时、1小时、55分钟、50分钟、45分钟、40分钟、35分钟、30分钟、25分钟、20分钟、15分钟、10分钟、9分钟、8分钟、7分钟、6分钟、5分钟、4分钟、3分钟、2分钟和1分钟。CD24蛋白可以在CD24蛋白的第二次治疗之前的任何时间点施用,包括约120小时、118小时、116小时、114小时、112小时、110小时、108小时、106小时、104小时、102小时、100小时、98小时、96小时、94小时、92小时、90小时、88小时、86小时、84小时、82小时、80小时、78小时、76小时、74小时、72小时、70小时、68小时、66小时、64小时、62小时、60小时、58小时、56小时、54小时、52小时、50小时、48小时、46小时、44小时、42小时、40小时、38小时、36小时、34小时、32小时、30小时、28小时、26小时、24小时、22小时、20小时、18小时、16小时、14小时、12小时、10小时、8小时、6小时、4小时、3小时、2小时、1小时、55分钟、50分钟、45分钟、40分钟、35分钟、30分钟、25分钟、20分钟、15分钟、10分钟、9分钟、8分钟、7分钟、6分钟、5分钟、4分钟、3分钟、2分钟和1分钟。
CD24蛋白可以在另一种治疗之后的任何时间点施用,包括约1分钟、2分钟、3分钟、4分钟、5分钟、6分钟、7分钟、8分钟、9分钟、10分钟、15分钟、20分钟、25分钟、30分钟、35分钟、40分钟、45分钟、50分钟、55分钟、1小时、2小时、3小时、4小时、6小时、8小时、10小时、12小时、14小时、16小时、18小时、20小时、22小时、24小时、26小时、28小时、30小时、32小时、34小时、36小时、38小时、40小时、42小时、44小时、46小时、48小时、50小时、52小时、54小时、56小时、58小时、60小时、62小时、64小时、66小时、68小时、70小时、72小时、74小时、76小时、78小时、80小时、82小时、84小时、86小时、88小时、90小时、92小时、94小时、96小时、98小时、100小时、102小时、104小时、106小时、108小时、110小时、112小时、114小时、116小时、118小时和120小时。CD24蛋白可以在前一CD24治疗之后的任何时间点施用,包括约120小时、118小时、116小时、114小时、112小时、110小时、108小时、106小时、104小时、102小时、100小时、98小时、96小时、94小时、92小时、90小时、88小时、86小时、84小时、82小时、80小时、78小时、76小时、74小时、72小时、70小时、68小时、66小时、64小时、62小时、60小时、58小时、56小时、54小时、52小时、50小时、48小时、46小时、44小时、42小时、40小时、38小时、36小时、34小时、32小时、30小时、28小时、26小时、24小时、22小时、20小时、18小时、16小时、14小时、12小时、10小时、8小时、6小时、4小时、3小时、2小时、1小时、55分钟、50分钟、45分钟、40分钟、35分钟、30分钟、25分钟、20分钟、15分钟、10分钟、9分钟、8分钟、7分钟、6分钟、5分钟、4分钟、3分钟、2分钟和1分钟。
实例1
CD24在小鼠体内的药代动力学
将1mg CD24Fc(CD24Fc)注入未处理的C57BL/6小鼠中,并在不同时间点(5分钟、1小时、4小时、24小时、48小时、7天、14天和21天)采集血液样品,其中每个时间点3只小鼠。血清以1:100稀释,并使用夹心ELISA,使用纯化的抗人CD24(3.3μg/ml)作为捕获抗体,过氧化物酶偶联的山羊抗人IgG Fc(5μg/ml)作为检测抗体来检测CD24Fc的水平。如图3A所示。CD24Fc的衰减曲线显示了蛋白质的典型双相衰减。第一生物分布阶段的半衰期为12.4小时。第二阶段遵循从中央隔室进行一阶消除的模型。第二阶段的半衰期为9.54天,与体内抗体相似。这些数据表明融合蛋白在血流中非常稳定。在另一项皮下注射融合蛋白的研究中,观察到几乎相同的9.52天半衰期(图3B)。更重要的是,尽管CD24Fc大约需要48小时才能达到血液中的峰值水平,但通过AUC测得的血液中融合蛋白的总量在任一种注射途径下都基本上相同。因此,从治疗的角度来看,不同的注射途径不应影响药物的治疗效果。这种观察大大简化了灵长类动物毒性的实验设计和临床试验。
实例2
宿主对组织损伤的反应中的CD24-Siglec 10相互作用
近二十年前,Matzinger提出了通常被称为危险理论的内容。从本质上讲,她认为免疫系统在感知到宿主的危险时就会打开。尽管当时危险的性质还没有很好的定义,但是已经确定坏死与细胞内组分如HMGB1和热休克蛋白的释放有关,这些组分被称为DAMP,用于危险相关的分子模式。发现DAMP促进炎性细胞因子和自身免疫性疾病的产生。在动物模型中,发现HMGB1和HSP90抑制剂可改善RA。DAMP的参与提出了可以探索RA疗法对宿主对DAMP反应的负调节的前景。
使用对乙酰氨基酚诱发的肝坏死并确保炎症,已观察到通过相互作用Siglec G,CD24为宿主对组织损伤的反应提供了强有力的负调节。CD24是GPI锚定分子,在造血细胞和其他组织干细胞中广泛表达。对人类多种自身免疫性疾病的遗传分析,包括多发性硬化症、系统性红斑狼疮、RA和巨细胞关节炎,表明CD24多态性与自身免疫性疾病风险之间存在显著关联。Siglec G是I-凝集素家族的成员,由其识别含有唾液酸的结构的能力来界定。Siglec G识别CD24上含有唾液酸的结构,并通过树突状细胞负调节炎性细胞因子的产生。就其与CD24相互作用的能力而言,人类Siglec 10和小鼠Siglec G在功能上是等效的。然而,尚不清楚小鼠和人类同源物之间是否存在一一对应的关系。尽管机制尚待充分阐明,但SiglecG相关的SHP1可能参与了负调节似乎是合理的。这些数据产生了一个新模型,其中CD24-Siglec G/10相互作用可能在区分病原体相关分子模式(PAMP)与DAMP中起关键作用(图4)。
至少两种重叠机制可以解释CD24的功能。首先,通过与多种DAMP结合,CD24可以捕获炎性刺激,以防止其与TLR或RAGE相互作用。CD24与包括HSP70、90、HMGB1和核仁蛋白在内的多个DAMP分子缔合的观察结果支持了这一观点。其次,也许在与DAMP缔合后,CD24可能会刺激Siglec G的信号传导。这两种机制都可能与具有任一基因的靶向突变的小鼠协同发挥更强的炎症反应。实际上,当用HMGB1、HSP70或HSP90刺激时,从CD24-/-或SiglecG-/-小鼠的骨髓中培养的DC产生更高的炎性细胞因子。相反,未发现它们对LAMP和PolyI:C等PAMP反应的影响。这些数据不仅提供了先天免疫系统区分病原体与组织损伤的机制,而且还表明CD24和Siglec G是与组织损伤相关的疾病的潜在治疗靶标。
实例3
CD24Fc与髓磷脂相关糖蛋白(MAG)的体外结合
髓磷脂相关糖蛋白(MAG),也称为Siglec-4,是Siglec家族的成员,该家族识别含有唾液酸的结构,并在神经元轴突上表达,并充当轴突生长和神经元再生的负调节剂。MAG蛋白在小鼠和人类之间保守,从而允许在小鼠模型中测试CD24Fc。为了确认CD24Fc与MAG的结合,使用了重组MAG-Fc融合蛋白,其包含通过多肽接头与人IgG1的羧基端Fc区融合的大鼠MAG的细胞外结构域(Sigma产品号M 5063)。人MAG(Genbank登录号NP_002352)和大鼠MAG(Genbank登录号NP_058886)的细胞外结构域具有96%的同一性。
通过Biacore表面等离子体共振(SPR)分析检测到CD24Fc与MAG的相互作用。简而言之,将CD24Fc和人IgG Fc对照都进行了生物素化处理,并固定在预先用抗生蛋白链菌素固定的传感器芯片上。在准备好传感器芯片表面后,将不同浓度(1、6和24μM)的10μl MAG-Fc依次注入流道中。每次注射后,通过用HBS作为洗脱液洗涤而解离10分钟。MAG-Fc与固定在传感器表面的CD24Fc或人IgG Fc的结合产生了与结合质量成比例的响应。响应以共振单位(RU)的形式测量,反映了注入不同浓度的MAG-Fc后记录的信号变化。
响应单位随时间变化的实时图谱表明,与人IgG Fc相比,CD24Fc对MAG-Fc具有更高的结合力。特异性结合以剂量依赖性方式呈现(图5)。因此,CD24Fc可能在轴突生长和神经元再生过程中阻断MAG的功能。
实例4
CD24Fc在临床前模型中的治疗功效
治疗具有持续性EAE临床体征的动物。
用100μL总体积的CFA(每毫升400μg结核分枝杆菌)中的200μg MOG(大鼠来源的肽35-55(MEVGWYRSPFSRVVHLYRNGK)对8-12周龄的C57BL/6小鼠进行皮下免疫。免疫后,每只小鼠立即在尾静脉中接受200ng百日咳毒素(List Biological,Campbell,California,USA)的200μL PBS溶液,于48小时后再次接受。每隔一天观察一次小鼠,以0-5的等级评分,中间评分为0.5级:0,无临床体征;1,失去尾音;2,步态摆动;3,后肢瘫痪;4,后肢和前肢瘫痪;5,死亡。免疫后第14-21天,将临床评分为2.5-3.5的小鼠随机分为两组,并用对照IgG1 Fc或CD24Fc处理。每隔一天腹膜内(i.p.)注射五次,每次200g/小鼠。如图6所示,CD24Fc具有显著且剂量依赖性的治疗作用。
用致敏的自身反应性T细胞处理动物。
为了测试CD24Fc是否可以防止自身反应性T细胞的破坏,我们在免疫后第7天处理了免疫小鼠。此时,可在淋巴结中发现MOG反应性T细胞,但未观察到临床症状。免疫后第7天,将免疫小鼠分为2组,每组9只小鼠,通过每隔一天腹膜内注射对照免疫球蛋白(Ig)或CD24Fc融合蛋白(200μg/注射/小鼠),共注射5次(第7、9、11、13和15天)来处理。每天检查小鼠以对如上所述的临床症状评分。
如图7所示,在施用对照IgG或CD24Fc后2天,与对照组相比,用CD24Fc处理的组显示出临床症状发展的延迟。当考虑到两组的所有数据时,两项统计分析显示出非常显著的差异(P=0.0019,Fisher的PLSD检验)。这些结果表明,用CD24Fc融合蛋白处理可以延缓和减轻EAE的临床症状。
为了确定最小有效剂量,我们向MOG免疫小鼠体内注射了100、50和25μg/注射的CD24Fc。我们使用在1个月时段内累积疾病评分降低50%作为端点。如图8所示,观察到剂量依赖性抑制。剂量响应曲线与对数曲线非常吻合,表明每次注射80μg使累积疾病评分降低50%。
SJL模型中复发性缓解型EAE的处理。
C57BL/6小鼠中的EAE具有急性临床病程,不同于绝大多数MS患者所表现出的慢性病程。大部分MS患者都有复发性缓解型临床病程,在EAE的SJL模型中最好地模仿该病程。因此,我们在SJL模型中测试了治疗潜力。处理方案与上述实验相同。简而言之,在免疫后第7天,将免疫的小鼠分成2组,每组14或15只小鼠,通过每隔一天腹膜内注射媒剂对照或本发明的CD24Fc融合蛋白(200μg/注射/小鼠)治疗,总共注射5次(第7、9、11、13和15天)来处理。如图9所示,用CD24Fc处理SJL小鼠使得临床评分显著降低(P=0.0039,Fisher的PLSD检验)。
实例5
正在进行的实验性自身免疫性脑脊髓炎小鼠体内CD24Fc在中枢神经系统中的生物分布。
中枢神经系统(CNS)是多发性硬化症免疫疗法的目标器官。这项研究的目的是研究CD24Fc在未处理小鼠和正在进行的实验性自身免疫性脑脊髓炎(EAE)小鼠的CNS中的生物分布。
图10的结果显示了在施用CD24Fc后24小时,未处理小鼠具有非常低但是可检测的CD24Fc水平(23ng/ml)。然而,在正在进行的EAE小鼠中,CD24Fc水平为约18μg/ml,比未处理小鼠的CNS高780倍以上。增长非常显著(P<0.001,非参数Mann-Whitney T检验)。根据体外抑制分析,CNS中CD24Fc的水平完全在有效范围内。因此,CD24Fc可能会进入CNS并在多发性硬化症(MS)患者的CNS中局部提供治疗效果。
实例6
CD24在治疗脱髓鞘疾病和神经保护中的用途
该实例证实CD24蛋白可用于治疗脱髓鞘疾病和神经免疫疾病,提供神经保护,并维持少突胶质细胞。长期暴露于铜宗是诱发啮齿动物少突胶质细胞损失的经典模型(5)。几组报道了炎症在少突胶质细胞损失中的关键作用。然而,尚未明确描述少突胶质细胞损失的起始信号的性质。Janeway提出,先天免疫主要是通过识别称为病原体相关分子模式或PAMP的微生物产物的模式来引发的(6,7)。随后,Matzinger提出了危险信号,该信号后来被其他人称为DAMP,是引发先天免疫反应的关键(8)。发明人的研究表明,由PAMP和DAMP诱发的炎症可以通过CD24-Siglec G相互作用来区分,因为任一基因的靶向突变选择性增强了宿主对DAMP的反应而不会影响对PAMP的反应(9,10)。在此,在发明人洞悉CD24的潜在新用途之后,通过评估Cd24或Siglecg基因的靶向突变对慢性铜宗处理后少突胶质细胞存活的影响,探索了先天性免疫反应对DAMP的潜在贡献。
年龄和性别匹配的WT、Cd24-/-和Siglecg-/-小鼠(9,10)用CPZ处理4周,并在处理后4周将小鼠安乐死。为了监测少突胶质细胞的恢复,首先将小鼠处理5周,用正常食物使其恢复10天,然后将其安乐死进行分析。切开前囟-1区域(图11A),并使用抗Oligo-2抗体通过免疫荧光染色分析少突胶质细胞的数量,该抗体特异性结合少突胶质细胞谱系中的所有细胞。代表性图像在图11B中示出,而概要数据在图11C中示出。如图11B所示,在CPZ处理之前,所有三个品系的小鼠具有相当数量的少突胶质细胞。这些数据表明,Cd24和Siglec G不参与该区域少突胶质细胞的发育。然而,CPZ处理后4周,Cd24或Siglecg基因的靶向突变导致少突胶质细胞的消耗更为严重。此外,虽然在WT小鼠的10天恢复期后少突胶质细胞数量完全恢复,但是在Cd24-/-和Siglecg-/-脑中仅观察到部分恢复(图11C)。这些数据表明,CD24-Siglec G轴可保护少突胶质细胞免受CPZ毒性。
为了确定是否可以全身施用Siglec G激动剂CD24Fc(9,10)(在美国专利公开号20130231464中描述,其内容通过引用并入本文)以保护少突胶质细胞,首先确定是否可以通过全身施用将CD24Fc递送至CNS。将10mg CD24Fc腹膜内注射到8周龄的小鼠中。在第1、7、14、21和28天收集血清和CSF,并通过夹心ELISA测量CD24Fc的量。如图11D所示,在整个4周的观察期中可以在CSF中发现CD24Fc,其水平与血浆中观察到的水平基本平行。CSF CD24Fc水平约为血浆水平的0.2-0.3%。在抑制巨噬细胞产生炎性细胞因子的分析中,4周发现的水平高于CD24Fc的IC50。
根据Oligo2+少突胶质细胞的原位分析,在CPZ处理后2周和4周分析了CD24Fc的保护作用。分析了胼胝体前囟-1位置的少突胶质细胞数量(图11E),因为该区域在CPZ处理期间遭受了更多的病理损伤。观察到,在CPZ处理后的2周和4周,CD24Fc处理显著增加了少突胶质细胞的数量(图11F)。
由于少突胶质细胞的损失通常与髓鞘再生减少有关,因此进一步研究Siglecg基因任一CD24的靶向突变是否会导致脱髓鞘加速。出人意料的是,在任一小鼠品系中均未观察到更严重的脱髓鞘。这些数据表明,少突胶质细胞存活的改善可能不足以诱导髓鞘再生。
综上所述,本文所述的数据证明CD24-Siglec G轴保护少突胶质细胞免受CPZ杀伤,并因此暗示宿主对DAMP的反应是CPZ模型中少突胶质细胞损失不为人知的罪魁祸首。对少突胶质细胞损失的发病机制的新见解提出了一种促进体内少突胶质细胞存活的新方法。与该观点一致,已经表明全身施用与DAMP结合的CD24Fc(9,10)并作为Siglec G的激动剂(9,10)足以保护少突胶质细胞免于被CPZ杀伤。由于少突胶质细胞的损失已经牵涉到多种神经退行性疾病(1-4),因此数据表明可以探索细胞损伤中的宿主反应,以进行这些难治性神经疾病的治疗开发。最后,应注意,CD24也被称为共刺激分子,用于激活T细胞(11),包括自身反应性T细胞(12)和肝内CD4 T细胞(13)。相应地,CD24Fc也显示出抑制自身免疫性疾病(14)。由于CD24Fc表型复制了自身免疫性疾病中Cd24基因的遗传缺陷(12,14),因此它可能通过不同的机制作为拮抗剂起作用。
实例7
CD24在人体中的药代动力学
该实例显示了CD24蛋白在人体内的药代动力学分析。这源自于I期、随机、双盲、安慰剂对照、单次上升剂量研究,以评估健康男性和女性成年受试者中CD24Fc的安全性、耐受性和PK。这项研究共纳入了5组,每组8名受试者,总共40名受试者。每组的8名受试者中有6名接受研究药物,2名受试者接受了安慰剂(0.9%氯化钠,生理盐水)。第一组的剂量为10mg。随后各组接受30mg、60mg、120mg和240mg的CD24Fc或相匹配的安慰剂,并至少间隔3周给药,以便回顾先前每一组的安全性和耐受性数据。仅在证明足够的安全性和耐受性后,才允许对新的受试者组施用下一较高的剂量。
在每一组中,最初的2名受试者在第1天为1名研究药物接受者和1名安慰剂接受者。在第7天后对第3至5名受试者和第6至8名受试者进行给药(各亚组之间最少间隔24小时)。在同一亚组中,每名受试者至少间隔1小时给药。如有必要,将延迟其余受试者的给药,直至对在该组中涉及第一或第二亚组的给药后期间可能出现的任何重大安全性问题进行审查。后续组在前一组后至少3周给药。
筛选期:
筛选访问(访问1)发生在有效治疗期开始之前的21天之内。提供知情同意书后,受试者进行资格筛查程序。
治疗期:
受试者在第-1天(访问2)进入临床药理学部门(CPU),随机治疗期在最少10小时禁食过夜后的第1天开始。将受试者随机分配为单剂量CD24Fc或安慰剂治疗。受试者一直被限制到第4天早上。
跟踪:
所有受试者在第7天、第14天、第21天、第28天和第42天(±1天)返回CPU,进行跟踪访问(访问3、访问4、访问5、访问6和访问7)。访问7是所有受试者的最后一次访问。
治疗持续时间:每名受试者的总研究持续时间长达63天。在第1天进行单剂量施用。
受试者数量:
计划:40名受试者
筛选:224名受试者
随机:40名受试者
完成:39名受试者
中断:1名受试者
诊断和纳入的主要标准:该研究的人群为年龄在18至55岁(含)之间的健康男性和女性,体重指数在18kg/m2至30kg/m2(含)之间。
研究产品和比较物信息:
CD24Fc:通过静脉内输注施用10mg、30mg、60mg、120mg或240mg的单剂量;批号:09MM-036。CD24Fc是完全人源化的融合蛋白,由人CD24的成熟序列和人免疫球蛋白G1的片段可结晶区(IgG1Fc)组成。CD24Fc以无菌、透明、无色、不含防腐剂的水溶液形式提供,用于静脉内注射。CD24Fc配制成单剂量注射溶液,浓度为10mg/mL,pH值为7.2。每个CD24Fc小瓶在16mL±0.2mL CD24Fc中含有160mg CD24Fc、5.3mg氯化钠、32.6mg磷酸氢二钠七水合物和140mg磷酸二氢钠一水合物。CD24Fc装在透明的硼硅玻璃小瓶中,带有氯丁基橡胶塞和铝翻转密封件。
通过静脉内输注匹配的安慰剂(0.9%氯化钠,生理盐水);批号:P296855、P311852、P300715、P315952。
意向治疗(ITT)人群由接受至少1剂研究药物的所有受试者组成。ITT人群是受试者信息和安全性评估的主要分析人群。
通过治疗和访问总结了临床实验室评估(化学、血液学和尿液分析)。还总结了从基线的变化。通过治疗和时间点总结生命体征(血压、心率、呼吸频率和体温)。还总结了从基线的变化。列出所有身体检查数据。总结了心电图参数和从基线的变化。列出了总体解释。
血浆CD24Fc浓度
如图12所示,CD24Fc的平均血浆浓度与所施用的CD24Fc的剂量成比例地增加。对于除120mg以外的所有剂量组,在给药后1小时达到CD24Fc的最大平均血浆浓度。给药后2小时达到120mg组的CD24Fc的最大平均血浆浓度。到第42天(984小时),所有组的CD24Fc的平均血浆浓度已降至最大平均血浆浓度的2%至4%之间。
表1总结了通过对PK可评估人群进行治疗的血浆CD24Fc PK参数。
表1通过治疗的血浆CD24Fc药代动力学参数汇总-PK可评估人群
血浆CD24Fc剂量比例分析
图13示出了针对PK可评估人群的CD24Fc Cmax与剂量的剂量比例图。图14示出了针对PK可评估人群的CD24Fc AUC0-42d与剂量的剂量比例图。图15示出了针对PK可评估人群的CD24Fc AUC0-inf与剂量的剂量比例图。表2显示了剂量比例的功效分析。
表2剂量比例的功效分析:血浆CD24Fc药代动力学参数-PK可评估人群
Cmax斜率估计值为1.172,90%CI为1.105至1.240。AUC0-42d斜率估计值为1.088,90%CI为1.027至1.148。AUC0-inf斜率估计值为1.087,90%CI为1.026至1.1。
药代动力学结论
血浆CD24Fc的Cmax和AUC与在小鼠、猴和人中施用的剂量成比例地增加。血浆CD24Fc在1.01和1.34小时之间达到Tmax。血浆CD24Fc的t1/2在280.83至327.10小时之间。
参考文献
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国家儿童医疗中心
Liu, Yang
Zheng, Pan
Li, Ning
Devenport, Martin
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Claims (18)
1.一种CD24蛋白,其用于治疗受试者的脱髓鞘病症。
2.根据权利要求1所述使用的CD24蛋白,其中所述脱髓鞘病症选自由以下组成的组:阿尔茨海默氏病、帕金森氏病、多发性硬化症、急性播散性脑脊髓炎、视神经脊髓炎谱系病症、视神经炎、横贯性脊髓炎和急性弛缓性脊髓炎。
3.根据权利要求1所述使用的CD24蛋白,其中所述CD24蛋白维持少突胶质细胞。
4.根据权利要求1所述使用的CD24蛋白,其中向所述受试者施用促进少突胶质细胞转化的另一种药剂。
5.根据权利要求1所述使用的CD24蛋白,其中向所述受试者施用促进少突胶质细胞产生髓磷脂的另一种药剂。
6.根据权利要求1所述使用的CD24蛋白,其中所述CD24蛋白包含成熟的人CD24或其变体。
7.根据权利要求6所述使用的CD24蛋白,其中所述成熟的人CD24包含SEQ ID NO:1或2所示的氨基酸序列。
8.根据权利要求6所述使用的CD24蛋白,其中所述CD24蛋白还包含蛋白质标签,其中所述蛋白质标签在所述CD24蛋白的N端或C端融合。
9.根据权利要求8所述使用的CD24蛋白,其中所述蛋白质标签包含哺乳动物免疫球蛋白(Ig)蛋白的一部分。
10.根据权利要求9所述使用的CD24蛋白,其中所述Ig部分是人Ig蛋白的Fc区。
11.根据权利要求10所述使用的CD24蛋白,其中所述Fc区包含所述人Ig蛋白的铰链区以及CH2和CH3结构域,并且其中所述Ig选自由IgG1、IgG2、IgG3、IgG4和IgA组成的组。
12.根据权利要求10所述使用的CD24蛋白,其中所述Fc区包含IgM的铰链区以及CH2、CH3和CH4结构域。
13.根据权利要求11所述使用的CD24蛋白,其中所述CD24蛋白包含SEQ ID NO:6、11或12所示的氨基酸序列。
14.根据权利要求1所述使用的CD24蛋白,其中所述CD24蛋白是可溶的。
15.根据权利要求1所述使用的CD24蛋白,其中所述CD24蛋白被糖基化。
16.根据权利要求1所述使用的CD24蛋白,其中所述CD24蛋白是使用真核蛋白质表达系统产生的。
17.根据权利要求16所述使用的CD24蛋白,其中所述表达系统包含中国仓鼠卵巢细胞系中所含的载体或复制缺陷型逆转录病毒载体。
18.根据权利要求17所述使用的CD24蛋白,其中所述复制缺陷型逆转录病毒载体被稳定地整合到真核细胞的基因组中。
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EP3624838B1 (en) | 2023-01-25 |
US20200181235A1 (en) | 2020-06-11 |
WO2018213266A1 (en) | 2018-11-22 |
EP3624838A1 (en) | 2020-03-25 |
US20220098278A1 (en) | 2022-03-31 |
EP3624838A4 (en) | 2021-02-24 |
TW201900671A (zh) | 2019-01-01 |
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