CN107206075A - 用cd154抗体治疗自身免疫性疾病 - Google Patents
用cd154抗体治疗自身免疫性疾病 Download PDFInfo
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Abstract
本发明涉及用针对CD154的抗体治疗自身免疫性疾病或炎症性疾病或神经退行性疾病的方法。
Description
发明领域
本发明涉及用特异性结合CD154的抗体或抗体片段治疗自身免疫性和炎症性疾病、特别是治疗系统性红斑狼疮。
发明背景
自身免疫性疾病传统上包含影响约5%-8%的一般人群的超过80种慢性疾病。近几十年期间在理解免疫系统方面取得了相当大的进展,从而更好地了解了共刺激分子如CD40及其配体CD154的作用。此外,此类分子也在许多更普通得多的疾病如动脉粥样硬化的发病机制中发挥作用,这可以大大扩展靶向该分子的疗法的适用性。
CD154在活化的T淋巴细胞上表达,并且通过与其受体CD40的相互作用在调节T细胞和其他细胞类型之间的相互作用中起关键作用。已知CD154/CD40对介导同源T细胞辅助B细胞,导致B细胞增殖和分化增加、抗体产生和同种型类别转换。CD154还促进淋巴结中生长中心(germinal center)的形成和B细胞存活。因此,CD154有助于增强自身免疫性疾病,并且作为自身免疫性疾病的治疗靶点,所述自身免疫性疾病例如系统性红斑狼疮(SLE)、类风湿性关节炎、强直性脊柱炎,狼疮肾炎、肺出血-肾炎综合征(Goodpasture’s disease)、舍格伦综合征、多肌炎、皮肌炎、银屑病、颞动脉炎、Churg-Strauss综合征、多发性硬化、吉兰-巴雷综合征、横贯性脊髓炎、重症肌无力、艾迪生病、甲状腺炎、乳糜泻、溃疡性结肠炎、结节病、溶血性贫血、特发性血小板减少性紫癜、白塞病、原发性胆汁性肝硬化和自身免疫性糖尿病,并且已经显示CD154的阻断在几种炎症性和自身免疫性模型系统中是高度有效的。CD154也被认为在动脉粥样硬化和神经退行性疾病的炎症方面发挥作用。
CD154,也称为CD40配体(CD40L),以前称为gp39、TRAP或TBAM,是TNF家族的39kDaII型膜糖蛋白。261个氨基酸的CD154多肽,由215个氨基酸的胞外结构域、24个氨基酸的跨膜区和22个氨基酸的胞质尾组成。与TNF家族的其他成员一样,CD154形成三聚体结构,并促进受体即CD40的三聚体化。CD154/CD40相互作用通过带电残基(即CD154上的碱性链和CD40上的酸性链)稳定。
在一系列自身免疫性疾病的临床试验中评估了Hu5c8(也称为BG-9588或replizumab),一种抗人CD154的人源化单克隆IgG1抗体。来自系统性红斑狼疮(SLE)患者的2期研究的结果令人鼓舞,疾病生物标记的显著降低,包括自身抗体的循环水平以及C3水平的显著增加。然而,尽管有临床效果的有希望的证据,因为治疗后出现(treatment-emergent)的心血管血栓形成事件的发生率增加,hu5c8的进一步开发被停止。Hu5c8以20mg/kg的剂量静脉内施用,每2周给予三次剂量,然后每4周再给予四次剂量(总共七次剂量)(Boumpas et al,Arthritis Rheum.2003Mar;48(3):719-27)。尽管在体外暴露于hu5c8后已经证实血小板活化增加,但是hu5c8诱导人血栓形成的作用机制仍不清楚(Meyer etal.,Blood(ASH Annual Meeting Abstracts)2006 108:摘要1516)。
系统性红斑狼疮(SLE)已被归类为可能涉及许多器官系统的自身免疫性疾病、炎症性多系统风湿病或胶原血管疾病。在欧洲和美国,一些研究中受影响人数估计为每十万人中的24至65例。狼疮的倾向因素包括人种为亚洲人或非洲人和性别为女性。90%的狼疮患者是女性,症状发作通常发生在15至50岁。系统性红斑狼疮似乎不是一种均匀的疾病,而是一组相关综合征,具有广泛变化的表现、身体系统参与程度和临床过程。SLE中常见的临床特征是血液和淋巴病(淋巴结病)、心脏病(例如心肌病、心包积液、心包炎)、眼病(例如干燥性角膜结膜炎)、胃肠病(例如口腔溃疡、胰腺炎、腹膜炎、咽炎)、整体失调(generaldisorder)((例如不适、疲劳、发热、体重下降)、神经系统疾病(例如脑血管意外、认知障碍、偏头痛、头痛、周围神经病变)、肌肉骨骼和结缔组织疾病(例如关节痛、关节炎(非侵蚀性或破坏性)、纤维肌痛、骨折、肌炎、骨坏死、骨质疏松症、骨质减少)、精神疾病(例如情绪障碍、焦虑症、抑郁症、精神病、神经症、由于一般医学状况引起的精神障碍、精神障碍)、肾脏和泌尿系统疾病(如狼疮肾炎、肾病综合征)、呼吸系统、胸部和纵隔疾病(例如胸膜炎、肺炎、肺动脉高压)、皮肤和皮下组织疾病(例如脱发、皮肤红斑狼疮、皮炎、广泛性红斑、网状青斑、脂膜炎、皮疹黄斑丘疹(rash maculo-papular)、系统性红斑狼疮皮疹、荨麻疹)和血管疾病(例如高血压、雷诺现象、毛细血管扩张、血小板减少、血栓性静脉炎、血管炎)。另外,大多数SLE患者呈现异常抗体模式,包括抗核-(ANA)和抗双链DNA(抗dsDNA)抗体的存在。
SLE的临床过程是阵发性的,当潜在失能和器官损伤增加时,会反复发作(flarerecurring)。皮质类固醇是治疗的基础,但与长期使用过程中最常见的大量副作用相关。用于较低水平活性情况的其他药物包括镇痛药、非甾体抗炎药(NSAID)、局部类固醇和抗疟药(如氯喹或羟氯喹),其中常见支持性药物治疗包括用于肾性高血压或雷诺综合征的血管扩张药(钙通道阻滞剂、血管紧张素-转化酶[ACE]抑制药)、用于皮疹或干燥性综合征的局部治疗、输血、用于血细胞减少的静脉注射(iv)球蛋白、抗惊厥药、抗偏头痛药物、用于复发性血栓形成的抗凝血剂和抗抑郁药。当其他治疗无效或限制或预防长期主要器官免受疾病或皮质类固醇使用损害(“类固醇保护”)时,高剂量皮质类固醇(例如0.5至1.0mg/kg/天的口服泼尼松(或等同物)或500mg至1g每日脉冲i.v.甲泼尼龙)与通常用于中度和重度病例的免疫抑制剂(如硫唑嘌呤、环磷酰胺、氨甲蝶呤、霉酚酸酯、来氟米特)用于治疗急性SLE发作。由于有限的功效和/或不良事件情况,目前的治疗手段是不足的。尽管具有良好的安全性的SLE的新型有效治疗方法具有很高的医疗需求,但此类治疗方法的开发已被证明是特别困难的,许多治疗候选物已经失败了(Eisenberg,2009)。
CD40/CD154共刺激途径也涉及神经退行性和神经肌肉疾病的发病机制,并且用干扰该途径的化合物治疗似乎可用于治疗神经退行性和神经肌肉疾病(WO 2010/065819,其内容整体并入本文)。
神经退行性和神经肌肉疾病包括阿尔茨海默病、帕金森病、肌萎缩侧索硬化、重症肌无力、多灶性运动神经病变、原发性侧索硬化、脊髓性肌萎缩、肯尼迪病和脊髓小脑共济失调。
肌萎缩侧索硬化(ALS)(有时称为Lou Gehrig病)是一种进行性致命的神经障碍,其特征在于由脊柱和脑中的运动神经元退化引起的肌肉纤维萎缩。ALS影响约30,000名美国公民,只有约10%的病例被归类为ALS的家族形式。虽然ALS特征在于导致肌肉萎缩的脊髓运动神经元的损失,但该疾病本身也表现为轴突运输、蛋白质聚集、兴奋性毒性、星形细胞增生、线粒体功能障碍、小胶质细胞活化和突触重建中的改变。已经很好地描述了小胶质细胞活化、星形细胞增生和来自外周的浸润性炎症细胞的存在。在ALS患者的脊髓中积累了IgG免疫反应性沉积物,淋巴细胞、树突状细胞、单核细胞和巨噬细胞浸润入ALS的脊髓。尽管对浸润性免疫细胞的作用了解甚少,但最近的工作表明,浸润性T细胞群体是神经保护的,而不是细胞毒性的。虽然ALS具有由小胶质细胞和星形胶质细胞的活化介导的免疫组分,但ALS没有被认为是自身免疫性疾病。与其中已经描述了特异性免疫调节途径(例如共刺激途径)的参与的例如类风湿性关节炎或系统性红斑狼疮的疾病不同,对于ALS,没有描述这种途径的参与。
本领域需要对自身免疫性、炎症性、神经退行性和神经肌肉疾病进行新的有效治疗。CD40-CD40L(CD154)相互作用途径已被证明与病理生理学自身免疫性、炎症性、神经退行性和神经肌肉疾病有关。需要新的使用以安全有效剂量施用的特异性结合CD154的抗体或抗体片段治疗自身免疫性、炎症性、神经退行性和神经肌肉疾病的方法。
发明概述
以下概述不旨在定义本发明的每个方面,并且在其他部分(例如详述)中描述其他方面。整个文件旨在作为统一的公开内容相关,并且应当理解,设想了本文所描述的特征的所有组合,即使特征的组合没有一起见于本文件的同一句子、段落或部分中。关于用“a”或“an”描述或要求保护的本发明的方面,应当理解,除非上下文明确地要求更为局限的含义,这些术语指“一个或多个”。除非上下文另有明确要求,术语“或”应理解为涵盖替代的项目或所有的项目。如果本发明的方面被描述为“包含”特征,则实施方案也被设想为“由该特征组成”或“基本上由该特征组成”。在使用术语“约”的情况下,本申请也公开了使用所指定的确切值。在涉及点值的情况下,本申请也公开了所采用的这些值,与范围的端点相同。
在患有系统性红斑狼疮(SLE)的血清阳性患者中进行临床I期随机、双盲、安慰剂对照的特异性结合CD154的单价聚乙二醇化Fab'(CDP7657)的安全性和耐受性的研究。特异性结合CD154的单价聚乙二醇化Fab'具有良好的耐受性,并且没有观察到血栓栓塞副作用。
作为研究的结果,现在已经发现了特异性结合CD154的抗体或抗体片段用于治疗自身免疫性和炎症性疾病如SLE或神经退行性或神经肌肉疾病的新的给药方案。
在一个实施方案中,本发明提供了特异性结合CD154的抗体或抗体片段,其用于在哺乳动物受试者中治疗自身免疫性、炎症性、神经退行性或神经肌肉疾病的方法,所述方法包括向需要这种治疗的受试者施用初始加载剂量为约20-60mg/kg的特异性结合CD154的抗体或抗体片段;和在初始加载剂量后约2周以约每隔一周一次的频率向需要这种治疗的受试者施用另外的一个或多个约为初始加载剂量一半的剂量的特异性结合CD154的抗体或抗体片段。
在本发明的另一个实施方案中,特异性结合CD154的抗体或抗体片段被施用于需要的患者至少12周。
在本发明的另一个实施方案中,特异性结合CD154的抗体或抗体片段是中和抗体或抗体片段。根据本发明第一、第二或第三实施方案特异性结合CD154的抗体或抗体片段优选具有通过表面等离子体共振测定的KD≤4.55pM的单价结合CD40的解离常数。
在本发明的另一个实施方案中,特异性结合CD154的抗体或抗体片段含有具有分别包含SEQ ID NO:1、2和3的氨基酸序列的CDR1、CDR2和CDR3的轻链可变区(LCVR)和具有分别包含SEQ ID NO:4、5和6的氨基酸序列的CDR1、CDR2和CDR3的重链可变区(HCVR)。
在本发明的其它实施方案中,特异性结合CD154的抗体或抗体片段含有SEQ IDNO:7所示的VL链序列和SEQ ID NO:8所示的VH链序列,或者特异性结合CD154的抗体或抗体片段具有SEQ ID NO:9所示的轻链序列和SEQ ID NO:10所示的重链序列。
在本发明另外的实施方案中,根据本发明的任何实施方案特异性结合CD154的抗体或抗体片段是具有SEQ ID NO:9所示轻链序列和SEQ ID NO:10所示重链序列的单价Fab',其在经修饰的铰链区中的半胱氨酸处被聚乙二醇化。优选地,根据第十一个实施方案的具有SEQ ID NO:9所示轻链序列和SEQ ID NO:10所示重链序列的单价Fab'具有与经修饰的铰链区中的单个硫醇基团共价连接的马来酰亚胺基团;赖氨酸残基与马来酰亚胺基团共价连接;和分子量约20KDa的甲氧基聚(乙二醇)聚合物连接到赖氨酸残基上的每个胺基上。因此,与单价Fab'共价连接的整个PEG的总分子量约40KDa。
附图简要说明
图1显示了患有SLE的受试者中抗药物抗体的发生率。在患有SLE的受试者的所有剂量下观察到非常弱的抗药物抗体应答(即非常接近分界点(cut point))。最高应答在剂量组60mg/kg中,其中测量的ADA随药物清除而增加。测定分界点为0.0063单位/mL(其中1单位/mL相当于1μg/mL校准物)。发现在SLE患者中发展至非常低水平的总体抗药物抗体不影响特异性结合CD154的单价聚乙二醇化Fab'的药代动力学。
图2显示了在使用CDP7657(研究SL0014)的初始概念验证临床研究中遵循的给药方案,其中建立了使用较大加载剂量然后定期等量维持剂量的原则。
图3显示了研究SL0014的标题结果,其中两个关键功效结果是
·SLEDAI-2K响应者指数(SRI-4)的最小4点改善,以及
·根据基于英国狼疮评估组(BILAG)的复合狼疮评估(BICLA)的应答
与对于接受安慰剂治疗的受试者相比,对于在所述给药方案下接受CDP7657的受试者,两者都表现出一致且显著更高的应答率。
图4显示了在开始治疗的一个月内观察到的CDP7657的实质性临床应答,其继续发展直到3个月时治疗结束,并且此后又持续了3个月。
图5显示了与研究SL0014中使用的给药方案相比,施用单次60mg剂量的CDP7657的受试者的不同等离子体暴露曲线。持续给药的同时,前者产生快速获得并且然后始终维持在100μg/mL以上的指定目标等离子体水平。
图6显示了图5所示的两种给药方案的药代动力学数据,并证实了研究SL0014方案在至少90%的时间内将暴露水平成功维持在100μg/mL以上。
图7显示随机分组到活性药物组和安慰剂治疗组的受试者的基线人口学特征,并且表明实现了良好平衡的随机分组。
图8显示研究SL0014期间观察到的不良事件的发生率和特征,其表明活性药物组和安慰剂治疗组之间几乎没有显著差异。没有发生或暗示血栓栓塞的事件。
发明详述
本发明涉及治疗自身免疫性或炎症性疾病或神经退行性疾病的方法,其中施用特异性结合CD154的抗体或抗体片段是有益的。本发明的各种实施方案涉及用特异性结合CD154的抗体或抗体片段、特别是CDP7657治疗自身免疫性或炎症性疾病或神经退行性疾病。
为了更容易理解本发明,首先定义某些术语。
本文所用的术语“抗体(antibody或antibodies)”是指由四条多肽链(通过二硫键相互连接的两条重(H)链和两条轻(L)链)组成的免疫球蛋白分子。每条重链由重链可变区(本文缩写为HCVR或VH)和重链恒定区组成。重链恒定区由三个结构域CH1、CH2和CH3组成。重链恒定区也可以具有第四恒定结构域CH4。每条轻链由轻链可变区(本文缩写为LCVR或VL)和轻链恒定区组成。轻链恒定区由一个结构域CL组成。VH和VL区可以进一步细分为高变区(称为互补决定区(CDR)),更保守的区域(称为框架区(FR))穿插其间。每个VH和VL由三个CDR和四个FR组成,从氨基末端到羧基末端按以下顺序排列:FR1,CDR1,FR2,CDR2,FR3,CDR3,FR4。这些CDR的确切边界已根据不同的系统被不同地定义。Kabat描述的系统不仅提供了适用于任意抗体可变区的明确的残基编号系统,而且提供了定义三个CDR的精确残基边界。这些CDR可以称为Kabat CDR。Chothia等人发现,尽管在氨基酸序列水平上具有很大的多样性,Kabat CDR中的某些子部分采用几乎相同的肽主链构象(Chothia et al.(1987)Mol.Biol.196:901-917;Chothia et al.(1989)Nature 342:877-883)。这些区域可以称为Chothia CDR,其具有与Kabat CDR重叠的边界。定义与Kabat CDR重叠的CDR的其他边界已经由Padlan(1995)FASEB J.9:133-139and MacCallum(1996)J.Mol.Biol.262(5):732-45进行了描述。仍有其他CDR边界定义可能不会严格遵循本文描述的系统之一,但是仍将与Kabat CDR重叠,尽管根据预测或实验发现,特定残基或残基组或甚至整个CDR可能缩短或延长不显著影响抗原结合。尽管某些实施方案使用Kabat或Chothia定义的CDR,本文使用的方法可以利用根据这些系统中的任何一个定义的CDR。术语免疫球蛋白(immunoglobulin或immunoglobulins)分别与“抗体(antibody或antibodies)”同义使用。本文所用的术语“抗体”包括但不限于通过本领域已知的重组技术产生的重组抗体。“抗体”可以具有任何来源,包括来自哺乳动物物种例如人类、非人灵长类动物(例如人类如来自黑猩猩、狒狒、恒河猴或食蟹猴)、啮齿动物(例如来自小鼠、大鼠、兔或豚鼠)、山羊、牛或马物种;或具有鸟类物种来源如鸡抗体或具有鱼类物种来源如鲨鱼抗体。“抗体”包括任何同种型的抗体,包括人同种型IgA1,IgA2,IgD,IgG1,IgG2a,IgG2b,IgG3,IgG4,IgE和IgM及其经修饰的变体。本文中的抗体针对感兴趣的“抗原”。优选地,抗原是生物学上重要的多肽,并且对患有疾病或障碍的哺乳动物施用抗体可导致该哺乳动物的治疗益处。然而,也考虑了针对非多肽抗原的抗体。当抗原是多肽时,其可以是跨膜分子(例如受体)或配体,例如生长因子或细胞因子。本发明所涵盖的抗体的优选分子靶标包括CD多肽如CD3,CD4,CD8,CD19,CD20,CD22,CD34,CD38,CD40和CD154;FcRn;OX40;HER受体家族成员如EGF受体,HER2,HER3或HER4受体;细胞粘附分子如LFA-1,Mac1,p150,95,VLA-4,ICAM-1,VCAM和av/b3整联蛋白,包括其α或β亚单位(例如抗CD11a,抗CD18或抗CD11b抗体);趋化因子和细胞因子或其受体如IL-1α和β,IL-2,IL-6,IL-6受体,IL-7,IL-12,IL-13,IL-17形式,IL-18,IL-21,IL-23,TNFα和TNFβ;生长因子如VEGF;IgE;血型抗原;flk2/flt3受体;肥胖(OB)受体;mpl受体;CTLA-4;多肽C;等等。
本文所用的术语“抗体片段”是指缺少一个或多个结构域或一个或多个氨基酸的天然存在的抗体。通常,抗体片段含有这种天然存在的抗体的整个抗原结合区或其可变区。抗体片段的实例包括缺少或没有Fc部分的任何抗体。抗体片段的实例还包括Fab,Fab',F(ab’)2,Fv和scFv片段;双抗体;三抗体;四抗体;微抗体;基本上由单个、两个或三个免疫球蛋白结构域组成的抗体,如Domain AntibodiesTM;单链抗体;上述任意的双特异性、三特异性、四特异性或多特异性变体。本文所用的术语“抗体片段”还指骆驼抗体(例如来自骆驼或美洲驼,例如NanobodiesTM)及其衍生物。抗体片段是本领域熟知的(Holliger and Hudson,2005)。已经开发了用于生产抗体片段的各种技术,并且是本领域已知的(Glover andHumphreys,2004)。本文所用的术语“抗体片段”包含人、人源化、灵长类和嵌合抗体片段。
本文所用的术语“BILAG评分”或“BILAG”指数分别指英国狼疮评估组评分和指数(Symmons DP et al.Q J Med.1988Nov;69(259):927-37)。BILAG指数在研究SL0007中用于评估治疗SLE患者的疗效。它是测量SLE疾病活动的综合指数。研究使用2004年版本的BILAG指数。该版本由8个身体系统(一般,黏膜皮肤,神经学,肌肉骨骼,心血管和呼吸,血管炎,肾脏和血液学)的86个问题组成。一些问题是根据患者的病史,一些是检查结果,另一些是实验室检查结果。每个身体系统得分范围从E到A,A是最严重的疾病活动。身体系统评分的解释如下:A(“活性”)=严重活动性疾病(足以需要改变疾病的治疗,例如大于20mg/天的泼尼松、免疫抑制剂、细胞毒素);B(“当心”)=中度活动性疾病(仅需症状疗法,例如,小于或等于20mg/天的泼尼松或抗疟药;C(“满意”)=轻度稳定疾病(治疗无变化迹象);D=以前活动的疾病-但目前没有;E=以前没有活动的疾病。当BILAG字母器官身体系统评分被转换为数值并相加时(使用以下规则,其中每个BILAG A=9,每个BILAG B=3,每个BILAG C=1,并且每个BILAG D或E的值为0),这被称为BILAG总分。
本文所用的术语“CDP7657”是指特异性结合CD154的单价PEG化Fab',其公开于WO2008/118356(其全部内容并入本文)。CDP7657含有具有分别具有SEQ ID NO:1、2和3的氨基酸序列的CDR1、CDR2和CDR3的轻链可变区(LCVR),以及具有分别具有SEQ ID NO:4、5和6的氨基酸序列CDR1、CDR2和CDR3的重链可变区(HCVR)。CDP7657具有SEQ ID NO:7所示的VL链序列和SEQ ID NO:8所示的VH链序列。CDP7657具有SEQ ID NO:9所示的轻链序列和SEQ IDNO:10所示的重链序列。如在WO 2008/118356中所述,CDP7657在经修饰的铰链区中的半胱氨酸处被聚乙二醇化。
本文所用的术语“组合治疗”是指施用两种或更多种治疗物质,例如特异性结合CD154的抗体或抗体片段和皮质醇。皮质醇可以与施用特异性结合CD154的抗体或抗体片段伴随、之前或之后施用。
本文所用的术语“每隔一周”,其涉及用根据本发明的特异性结合CD154的抗体或抗体片段或包含其的组合物的施用或给药的治疗,是指每9-19天、更优选每11-17天、甚至更优选每13-15天、以及最优选每14天施用根据本发明的特异性结合CD154的抗体或抗体片段或所述组合物。
本文所用的术语“KD”旨在表示特定抗体-抗原相互作用的解离常数。解离常数可以指单价结合或二价结合。优选地,解离常数通过表面等离子体共振来测定。
本文所用的术语“中和抗体”(或“中和CD154活性的抗体”)意指其与CD154的结合导致抑制CD154的生物学活性的抗体。可以通过测量CD154生物学活性的一个或多个指标来评估CD154的生物学活性的这种抑制。CD154生物学活性的这些指标可以通过本领域已知的几种标准体外或体内测定中的一种或多种进行评估。例如,体外测定可以测量抗体抑制纯化的CD40蛋白与表达CD40L的细胞或细胞系的结合的能力或T细胞依赖性B细胞活化的测定,涉及表达CD40L的T细胞或T细胞系与B细胞或B细胞系的共培养,并监测在后者细胞上细胞间粘附分子1(ICAM-1)的表达。体内测定可以包括研究在合适的物种例如非人灵长类动物(如果抗体识别该物种)中或在小鼠(如果抗体识别该物种)中的抗原如破伤风类毒素或钥孔血蓝蛋白的免疫应答。如果抗体确实识别小鼠CD40L,则可以在SLE的小鼠模型如NZB/W或MRL/lpr小鼠中进行评估。
本文所用的术语“聚乙二醇化”、“聚乙二醇”或“PEG”是指聚亚烷基二醇化合物或其衍生物的连接,例如通过共价键合,在具有或不具有偶联剂的情况下,或用偶联或活化部分进行衍生化(例如用硫醇,三氟甲磺酸酯,三氟乙基磺酸酯(tresylate),氮丙啶(azirdine),环氧乙烷或优选用马来酰亚胺部分例如PEG-马来酰亚胺)。其它合适的聚亚烷基二醇化合物包括但不限于马来酰亚胺基单甲氧基PEG,活化的PEG聚丙二醇,还包括以下类型的带电或中性聚合物:葡聚糖,多聚乙酰神经氨酸,或其它基于碳水化合物的聚合物,氨基酸聚合物,和生物素和其他亲和试剂衍生物。
术语“SLEDAI评分”或“SLEDAI”指数分别指系统性红斑狼疮病活动评分/指数(Hawker et al.,J Rheumatol.1993)。
“SRI评分”或“SRI”指数是指系统性红斑狼疮应答指数评分/指数(Furie RA etal.,Arthritis Rheum.2009)
本文所用的术语“表面等离子体共振”是指允许通过检测生物传感器基质内的蛋白质浓度变化来分析实时生物特异性相互作用的光学现象,例如使用BIAcore系统(Pharmacia Biosensor AB,Uppsala,Sweden and Piscataway,NJ)。有关进一步描述,请参见实施例1和U.,et al.(1993)Ann.Biol.Clin.51:19-26;U.,et al.(1991)Biotechniques 11:620-627;Johnsson,B.,et al.(1995)J.Mol.Recognit.8:125-131;以及Johnnson,B.,et al.(1991)Anal.Biochem.198:268-277。
在第一个实施方案中,本发明提供特异性结合CD154的抗体或抗体片段,其用于在哺乳动物受试者中治疗自身免疫性、炎症性、神经退行性或神经肌肉疾病的方法,所述方法包括:
(a)向需要这种治疗的受试者施用初始加载剂量为约20-60mg/kg的特异性结合CD154的抗体或抗体片段;和
(b)在初始加载剂量后约2周以约每隔一周一次的频率向需要这种治疗的受试者施用另外的一个或多个约为初始加载剂量一半的剂量的特异性结合CD154的抗体或抗体片段。初始加载剂量可以是大约20mg/kg,25mg/kg,30mg/kg,35mg/kg,40mg/kg,45mg/kg,50mg/kg,55mg/kg或60mg/kg。另外的剂量可以是大约10mg/kg,12.5mg/kg,15mg/kg,17.5mg/kg,20mg/kg,22.5mg/kg,25mg/kg,27.5mg/kg或30mg/kg。
在本发明的第二个实施方案中,将根据本发明第一个实施方案的特异性结合CD154的抗体或抗体片段被施用于需要的患者至少12周。
在本发明的第三实施方案中,根据本发明的第一个或第二个实施方案的特异性结合CD154的抗体或抗体片段是中和抗体或抗体片段。
在本发明的第四个实施方案中,根据本发明的第一个、第二个或第三个实施方案的特异性结合CD154的抗体或抗体片段具有通过表面等离子体共振测定的KD≤4.55pM的单价结合CD40的解离常数。
在本发明的第五个实施方案中,根据本发明第一个、第二个、第三个或第四个实施方案的特异性结合CD154的抗体或抗体片段含有具有分别包含SEQ ID NO:1、2和3的氨基酸序列的CDR1、CDR2和CDR3的轻链可变区(LCVR)和具有分别包含SEQ ID NO:4、5和6的氨基酸序列的CDR1、CDR2和CDR3的重链可变区(HCVR)。
在本发明的第六个实施方案中,根据本发明第一个、第二个、第三个、第四个或第五个实施方案的特异性结合CD154的抗体或抗体片段含有可变轻(VL)链的框架区,优选所述框架区来自Vκ1人种系家族,更优选来自Vκ1 2-1-(1)O12V-区,并且最优选来自SEQ IDNO:7所示的VL链框架序列。可变重链(VH)链的框架区优选来自VH4链人种系家族,更优选来自VH4 1-1 4-59序列,并且最优选来自SEQ ID NO:8所示的VH框架序列。
在本发明的第七个实施方案中,根据本发明的第一个、第二个、第三个、第四个、第五个或第六个实施方案的特异性结合CD154的抗体或抗体片段表现出单价结合CD40,并且优选仅具有一个特异性结合CD154的结合位点。优选地,特异性结合CD154的抗体或抗体片段是VH结构域或结构域抗体(dAb),Fab,Fab',Fv,Fab-Fv,Fab-dsFv,Fab-Fv-Fv,Fd,HL,dsHL,LH,dsLH,单链抗体(例如scFv,scFab和scFabΔC)或其它单价片段或抗体衍生物,或表现出特异性和单价结合CD154的双特异性或多特异性抗体,例如DVD-Ig,TriomabTM,F(ab)2,F(ab')2,F(ab')3,(Fab-Fv)2-Fc或三抗体。
在本发明的第八个实施方案中,根据本发明的第一个、第二个、第三个、第四个、第五个、第六个或第七个实施方案的特异性结合CD154的抗体或抗体片段是包含特异性结合CD154的任何抗体或抗体片段的缀合物,其共价或非共价,或直接或间接地缀合至功能部分,例如载体蛋白,毒素或其他效应分子,或例如PEG。特异性结合CD154的抗体或抗体片段可以是(例如在一个或多个半胱氨酸或赖氨酸残基处)PEG化的。在某些实施方案中,特异性结合CD154的抗体片段是通过马来酰亚胺接头PEG化的Fab或Fab'片段。在本发明另外的实施方案中,特异性结合CD154的抗体片段缀合至功能部分,其为阻断部分,可检测部分(例如,荧光部分,放射性同位素部分,不透射线部分等,包括诊断部分),和/或治疗部分(例如,细胞毒性剂,抗炎剂,免疫调节剂,抗感染剂,抗癌剂,抗神经退行性剂,放射性核素等)。
在本发明的第九个实施方案中,根据本发明的第一个、第二个、第三个、第四个、第五个、第六个、第七个或第八个实施方案的特异性结合CD154的抗体或抗体片段,抗体含有SEQ ID NO:7所示的VL链序列和SEQ ID NO:8所示的VH链序列。
在本发明的第十个实施方案中,根据本发明的第一个、第二个、第三个、第四个、第五个、第六个、第七个、第八个或第九个实施方案的特异性结合CD154的抗体或抗体片段,抗体具有SEQ ID NO:9所示的轻链序列和SEQ ID NO:10所示的重链序列。
在本发明的第十一个实施方案中,根据第一个、第二个、第三个、第四个、第五个、第六个、第七个、第八个、第九个或第十个实施方案的特异性结合CD154的抗体或抗体片段,其用于在哺乳动物受试者中治疗自身免疫性、炎症性、神经退行性或神经肌肉疾病的方法,抗体片段是具有SEQ ID NO:9所示轻链序列和SEQ ID NO:10所示重链序列的单价Fab'。
在本发明的第十二个实施方案中,根据本发明第十一个实施方案的具有SEQ IDNO:9所示轻链序列和SEQ ID NO:10所示重链序列的单价Fab'在经修饰的铰链区中的半胱氨酸处是PEG化的。优选地,根据第十一个实施方案的具有SEQ ID NO:9所示轻链序列和SEQID NO:10所示重链序列的单价Fab'具有与经修饰的铰链区中的单个硫醇基团共价连接的马来酰亚胺基团;赖氨酸残基与马来酰亚胺基团共价连接;和分子量约20KDa的甲氧基聚(乙二醇)聚合物连接到赖氨酸残基上的每个胺基上。因此,与单价Fab'共价连接的整个PEG的总分子量约40KDa。
在另外的实施方案中,根据本发明的任何实施方案的特异性结合CD154的抗体或抗体片段,其用于在哺乳动物受试者中治疗自身免疫性、炎症性、神经退行性或神经肌肉疾病的方法,其是如WO 2008/118356和WO 2006/030220(两者的内容全部并入本文)中描述的抗体、抗体片段或衍生物。
本发明的第十三个实施方案是根据第一个、第二个、第三个、第四个、第五个、第六个、第七个、第八个、第九个、第十个、第十一个或第十二个实施方案的特异性结合CD154的抗体或抗体片段,其用于在哺乳动物受试者中治疗自身免疫性、炎症性、神经退行性或神经肌肉疾病的方法,其用于治疗自身免疫性、炎症性、神经退行性或神经肌肉疾病,其中自身免疫性、炎症性、神经退行性或神经肌肉疾病是系统性红斑狼疮(SLE),狼疮肾炎,类风湿关节炎,血清阴性脊柱关节病,银屑病,银屑病关节炎,硬皮病,舍格伦综合征,多发性硬化,I型糖尿病,自身免疫性葡萄膜炎和肾病综合征或血管炎。
在另一个实施方案中,根据本发明任何实施方案的特异性结合CD154的抗体片段或抗体片段用于治疗系统性红斑狼疮(SLE)的方法,其中用特异性结合CD154的抗体或抗体片段治疗的受试者实现从选自SLEDAI、BILAG和医师整体评估(Global Physicianassessment)的一种或多种指数的基线的改善。因此,在一个实施方案中,本发明涉及使用本文所述的方法治疗患有SLE的受试者的方法,其中受试者实现这些指数之一的改善。
在另一个实施方案中,根据本发明的任何实施方案的特异性结合CD154的抗体片段或抗体片段用于治疗系统性红斑狼疮(SLE)的方法,其中用特异性结合CD154的抗体或抗体片段治疗的受试者实现SLEDAI应答指数4(SRI-4)。因此,在一个实施方案中,本发明涉及使用本文所述的方法治疗患有SLE的受试者的方法,其中受试者实现SLEDAI应答指数4。
在另一个实施方案中,根据本发明的任何实施方案的特异性结合CD154的抗体片段或抗体片段用于治疗系统性红斑狼疮(SLE)的方法,其中用特异性结合CD154的抗体或抗体片段治疗的受试者实现从SRI-50指数的基线的50%的改善。因此,在一个实施方案中,本发明涉及使用本文所述的方法治疗患有SLE的受试者的方法,其中受试者实现从SRI-50指数的基线的50%的改善。
在另一个实施方案中,根据本发明的任何实施方案的特异性结合CD154的抗体片段或抗体片段用于治疗系统性红斑狼疮(SLE)的方法,其中用特异性结合CD154的抗体或抗体片段治疗的受试者实现从补体C3和C4浓度的基线增加20%、30%、40%、50%、75%或90%或实现补体C3和C4浓度的正常化,或者实现血清中抗双链DNA滴度降低20%、30%、40%、50%、75%或90%。因此,在一个实施方案中,本发明涉及使用本文所述的方法治疗患有SLE的受试者的方法,其中所述受试者实现从补体C3和C4浓度的基线增加20%、30%、40%、50%、75%或90%或实现补体C3和C4浓度的正常化,或者实现血清中抗双链DNA滴度降低20%、30%、40%、50%、75%或90%。
在另一个实施方案中,根据本发明的任何实施方案的特异性结合CD154的抗体片段或抗体片段用于治疗系统性红斑狼疮(SLE)的方法,其中用特异性结合CD154的抗体或抗体片段治疗的受试者的抗双链DNA抗体从血清阳性逆转为血清阴性。因此,在一个实施方案中,本发明涉及使用本文所述的方法治疗患有SLE的受试者的方法,其中所述受试者的抗双链DNA抗体从血清阳性逆转为血清阴性。
在另一个实施方案中,根据本发明的任何实施方案的特异性结合CD154的抗体或抗体片段通过位于本发明的抗体或抗体片段中的至少一个半胱氨酸残基的硫醇基与PEG共价连接。与抗体或抗体片段连接的每个PEG分子可以共价连接到位于抗体或抗体片段中的半胱氨酸残基的硫原子。共价连接通常是二硫键,或者特别是硫-碳键。当硫醇基团用作连接点时,可以使用适当活化的官能部分,例如硫醇选择性衍生物如马来酰亚胺和半胱氨酸衍生物。活化的PEG可以用作如上所述的PEG修饰的抗体片段的制备中的起始原料。活化的PEG可以是含有硫醇反应性基团的任何PEG,例如卤代羧酸或酯,例如碘乙酰胺,酰亚胺,例如马来酰亚胺,乙烯基砜或二硫化物。在另一个实施方案中,抗体片段缀合物可以包含两个具有两个马来酰亚胺分子的PEG分子。起始原料可以商业获得(例如,可获得自Nektar,以前称为Shearwater Polymers Inc.,Huntsville,AL,USA),或者可以使用常规化学方法从市售原料制备。特定的PEG分子包括分子量为20KDa的甲氧基-PEG-胺(可获得自Nektar,以前称为Shearwater;Rapp Polymere;和SunBio)和M-PEG-SPA(可获得自Nektar,以前称为Shearwater)。
在另一个实施方案中,特异性结合CD154的抗体或抗体片段是经PEG化的修饰的Fab'片段,即具有共价连接到其上的PEG(聚(乙二醇)),例如根据EP0948544中公开的方法(还可参见“Poly(ethyleneglycol)Chemistry,Biotechnical and BiomedicalApplications”,1992,J.Milton Harris(ed),Plenum Press,New York,“Poly(ethyleneglycol)Chemistry and Biological Applications”,1997,J.Milton Harrisand S.Zalipsky(eds),American Chemical Society,Washington DC以及“Bioconjugation Protein Coupling Techniques for the Biomedical Sciences”,1998,M.Aslam and A.Dent,Grove Publishers,New York;Chapman,A.2002,AdvancedDrug Delivery Reviews 2002,54:531-545)。在一个实例中,PEG连接到铰链区中的半胱氨酸。在另一个实例中,PEG修饰的Fab'片段具有共价连接到经修饰的铰链区中的单个硫醇基团的马来酰亚胺基团。赖氨酸残基可以共价连接到马来酰亚胺基团上,赖氨酸残基上的每个胺基可以连接分子量约为20KDa的甲氧基聚(乙二醇)聚合物。因此,连接到Fab'片段的PEG的总分子量可以是约40KDa。
在另一个实施方案中,根据本发明任何实施方案的特异性结合CD154的抗体或抗体片段,使用WO 98/25971(其内容全文并入本文)和WO 04/72116(其内容全部并入本文)中所述的方法连接PEG官能部分,由此将赖氨酰-马来酰亚胺基团连接到重链C末端的半胱氨酸残基,并且赖氨酰残基的每个氨基共价连接至分子量为约20KDa的甲氧基聚(乙二醇)残基。因此,连接到抗体的PEG的总分子量为约40KDa。
本发明的另一个实施方案是根据本发明的任何实施方案的特异性结合CD154的抗体或抗体片段,其用于在哺乳动物受试者中治疗自身免疫性、炎症性、神经退行性或神经肌肉疾病的方法,其中所述方法包括用于静脉内、皮下或肌肉内向有需要的个体施用抗体或抗体片段。皮下给药是有利的,因为患者可以自我施用治疗物质,例如特异性结合CD154的抗体或抗体片段,其对患者和保健提供者二者都是方便的。
在某些实施方案中,特异性结合CD154的抗体或抗体片段包含重链恒定区,例如IgG1,IgG2,IgG3,IgG4,IgA,IgE,IgM或IgD恒定区。优选地,将重链恒定区进行工程改造,使其不被糖基化。此外,抗体可以包含轻链恒定区,κ轻链恒定区或λ轻链恒定区。优选地,抗体包含κ轻链恒定区。
本发明的特异性结合CD154的抗体或抗体片段可以被并入药物组合物中,所述药物组合物适于每隔一周静脉内、皮下或肌内施用于受试者。通常,药物组合物包含本发明的特异性结合CD154的抗体或抗体片段和/或药学上可接受的载体和/或其它活性成分如氨甲蝶呤或皮质醇。
本发明的另一个实施方案是包含根据本发明的任何实施方案的特异性结合CD154的抗体或抗体片段和药学上可接受的载体的药物组合物,其中组合物被制备用于需要其的个体的静脉内、皮下或肌内给药。在另一个实施方案中,组合物是具有使用说明书的试剂盒的一部分,包括说明书和任选的用于对有需要的个体进行静脉内、皮下或肌肉内给药的装置。
本文所用的“药学上可接受的载体”包括任何和所有溶剂,分散介质,包衣,抗细菌和抗真菌剂,等渗和吸收延迟剂等,其在生理学上相容并且适于用于本文所述方法施用于受试者。药学上可接受的载体的实例包括水,盐水,磷酸盐缓冲盐水,葡萄糖(dextrose),甘油,乙醇等中的一种或多种,以及它们的组合。在许多情况下,优选在组合物中包括等渗剂,例如糖,多元醇如甘露糖醇,山梨糖醇或氯化钠。药学上可接受的载体还可以包含少量辅助物质,例如润湿剂或乳化剂,防腐剂或缓冲剂,其增强抗体或抗体部分的保质期或有效性。本发明的组合物可以是各种形式。这些包括例如液体溶液(例如可注射和可输注(infusible)溶液),分散体或悬浮液,粉末和脂质体。
优选的形式取决于预期的给药方式和治疗应用。典型的优选组合物是可注射或可输注溶液的形式,例如与用于其他抗体对人的被动免疫的组合物类似的组合物。
治疗组合物通常在制造和储存条件下必须是无菌和稳定的。组合物可以配制成适于高药物浓度的溶液,微乳液,分散体,脂质体或其它有序结构。无菌可注射溶液可以通过将所需量的活性化合物(即,抗体或抗体部分)并入适当的溶剂中,根据需要与上述列举的成分或组合组合,然后过滤灭菌来制备。通常,通过将活性化合物并入含有碱性分散介质的无菌载体和来自上面列举的所需的其它成分来制备分散体。在用于制备无菌可注射溶液的无菌粉末的情况下,优选的制备方法是真空干燥和冷冻干燥,其从先前无菌过滤的溶液中产生活性成分加上任何另外的所需成分的粉末。例如通过使用诸如卵磷脂的包衣,可以通过在分散体的情况下维持所需的粒径和使用表面活性剂来维持溶液的适当的流动性。可以通过在组合物中包含延迟吸收的试剂例如单硬脂酸盐和明胶来实现可注射组合物的延长吸收。在某些实施方案中,活性化合物可以用保护化合物免于快速释放的载体(例如控制释放制剂)制备。可以使用可生物降解的生物相容性聚合物,例如乙烯乙酸乙烯酯,聚乙二醇(PEG),聚酐,聚乙醇酸,胶原,聚原酸酯和聚乳酸。用于制备这些制剂的许多方法是专利的或者本领域技术人员通常已知的。参见例如Sustained and Controlled Release DrugDelivery Systems,J.R.Robinson,ed.,Marcel Dekker,Inc.,New York,1978。
在另一个实施方案中,将额外的活性成分并入包含根据本发明的特异性结合CD154的抗体或抗体片段的药物组合物中。在某些实施方案中,特异性结合CD154的抗体或抗体片段与一种或多种额外的治疗剂共同配制和/或共同施用。例如,特异性结合CD154的抗体或抗体片段可以与皮质类固醇、非甾体抗炎药(NSAID)、或靶向已知参与治疗免疫介导的疾病的许多促炎细胞因子(如TNF,IL-1,IL-6,CTLA-4,IFN)或靶向B细胞活性的那些(例如CD19,CD20(如利妥昔单抗(rituximab)),CD22(例如,epratuzumab),BAFF(例如belimumab)和BLyS/APRIL(例如,atacicept))的治疗共同配制和/或共同施用,这些治疗本身可以用或可以不用聚乙二醇(PEG)部分进行配制。
在另外的实施方案中,根据本发明的特异性结合CD154的抗体或抗体片段或包含其的组合物可以根据本发明的实施方案与一种或多种前述治疗剂组合使用。这种组合治疗可有利地利用较低剂量的施用的治疗剂,从而避免与各种单一治疗相关的可能的毒性或并发症。
根据本发明的方法或用途可以用特异性结合CD154的抗体或抗体片段治疗的自身免疫性疾病或“炎症性疾病”包括但不限于系统性红斑狼疮(SLE),类风湿性关节炎,强直性脊柱炎,狼疮肾炎,舍格伦综合征,多肌炎,皮肌炎,颞动脉炎,ANCA相关性血管炎,Churg-Strauss综合征,抗磷脂综合征,膜性肾小球肾病,肺出血-肾炎综合征,免疫球蛋白A肾病,过敏性紫癜,慢性移植排斥反应,特应性皮炎,寻常型天疱疮(pemiphigus vulgaris),银屑病,哮喘,过敏,系统性硬化症,多发性硬化,吉兰-巴雷综合征,横贯性脊髓炎,慢性免疫多发性神经病,重症肌无力,艾迪生病,甲状腺炎,自身免疫性胃炎,恶性贫血,乳糜泻,溃疡性结肠炎,结节病,溶血性贫血,特发性血小板减少性紫癜,白塞病,原发性胆汁性肝硬化,自身免疫性糖尿病,莱姆神经疏螺旋体病,间质性肺病。
除了以上病症-自身免疫性或交叉反应性免疫介导的炎症建立为主要病理过程-炎症也被视为许多疾病中的贡献过程的组合之一,
其中包括根据本发明的方法或用途可以用特异性结合CD154的抗体或抗体片段治疗的神经退行性疾病是以进行性神经系统功能障碍为特征的遗传性或散发性病症。这些疾病通常与神经系统的受影响的中枢或外周结构的萎缩相关。例如,神经退行性疾病包括但不限于阿尔茨海默病,帕金森病,弗里德赖希共济失调,亨廷顿病,肌萎缩侧索硬化,重症肌无力,多灶性运动神经病变,原发性侧索硬化,脊髓性肌萎缩,肯尼迪氏病和脊髓小脑共济失调。
类似地,诸如动脉粥样硬化,心力衰竭,骨关节炎,非酒精性脂肪性肝炎,肠易激综合征,克罗恩病,糖尿病并发症(肾病,神经病,动脉病变,视网膜病变),哮喘,囊性纤维化,慢性阻塞性气道疾病,癫痫,青光眼,年龄相关性黄斑变性,精神障碍(焦虑,抑郁,精神病),慢性疲劳综合征,末端病(enthesiopathy)/肌腱病(tendinopathy),早产/产前感染,肥胖/代谢综合征,皮肤病学(寻常痤疮,玫瑰痤疮,日光角化病),异常伤口愈合(瘢痕疙瘩瘢痕形成(keloid scarring)),泌尿生殖系统疾病(前列腺症候群/前列腺炎,膀胱过度活动综合征)和癌症发展的病症都适用于用特异性结合CD154的抗体或抗体片段根据本发明的方法或用途的治疗。
可以通过在宿主细胞中重组表达免疫球蛋白轻链和重链基因来制备根据本发明特异性结合CD154的抗体或抗体片段。为了重组表达抗体,用携带编码抗体的免疫球蛋白轻链和重链的DNA片段的一个或多个重组表达载体转染宿主细胞,使得轻链和重链在宿主细胞中表达,并且优选分泌到培养宿主细胞的培养基,从该培养基中可以回收抗体。使用标准重组DNA方法获得抗体重链和轻链基因,将这些基因并入重组表达载体中,并将载体导入宿主细胞,例如在Sambrook,Fritsch and Maniatis(eds),Molecular Cloning;ALaboratory Manual,Second Edition,Cold Spring Harbor,N.Y.,(1989),Ausubel,F.M.et al.(eds.)Current Protocols in Molecular Biology,Greene PublishingAssociates,(1989)和美国专利号4,816,397中所描述的那些。
为了表达根据本发明的特异性结合CD154的抗体或抗体片段,将通过本领域已知的重组DNA技术获得的编码轻链和重链的DNA插入到表达载体中,使得基因可操作地连接到转录和翻译控制序列。在该语境中,术语“可操作地连接”旨在表示将抗体基因连接到载体中,使得载体内的转录和翻译控制序列用于调节根据本发明的特异性结合CD154的抗体或抗体片段的重链和轻链的基因的转录和翻译的预期功能。选择表达载体和表达控制序列与所用表达宿主细胞相容。轻链基因和重链基因可以插入到分开的载体中,或者更典型地,将两个基因插入到同一表达载体中。通过标准方法将抗体基因插入表达载体(例如,在基因片段和载体上连接互补限制性位点,或者如果不存在限制性位点,则连接平端连接)。重组表达载体可以编码促进抗体链从宿主细胞分泌的信号肽。抗体链基因可以克隆到载体中,使得信号肽与抗体链基因的氨基末端同框连接。信号肽可以是免疫球蛋白信号肽或异源信号肽(即来自非免疫球蛋白的信号肽)。
除了根据本发明的特异性结合CD154的抗体或抗体片段的抗体链基因之外,本发明的重组表达载体携带控制宿主细胞中抗体链基因表达的调控序列。术语“调控序列”旨在包括控制抗体链基因的转录或翻译的启动子、增强子和其他表达控制元件(例如多聚腺苷酸化信号)。这些调节序列描述于例如Goeddel;Gene Expression Technology:Methods inEnzymology 185,Academic Press,San Diego,Calif.(1990)中。本领域技术人员将理解,包括调控序列的选择的表达载体的设计可以取决于诸如待转化的宿主细胞的选择、所需蛋白质的表达水平等因素。哺乳动物宿主细胞表达的优选调控序列包括在哺乳动物细胞中引导高水平蛋白质表达的病毒元件,例如源自巨细胞病毒(CMV)(如CMV启动子/增强子)、猿猴病毒40(SV40)(例如SV40启动子/增强子)、腺病毒(例如,腺病毒主要晚期启动子(AdMLP))和多瘤病毒的启动子和/或增强子。
除了抗体链基因和调控序列之外,重组表达载体可以携带额外的序列,例如调节载体在宿主细胞中的复制(例如复制起点)和可选择标记基因的序列。可选择标记基因有助于选择已经引入载体的宿主细胞(参见例如美国专利号5,179,017)。
为了表达轻链和重链,通过标准技术将编码重链和轻链的表达载体转染到宿主细胞中。术语“转染”的各种形式旨在涵盖通常用于将外源DNA引入原核或真核宿主细胞的各种技术,例如电穿孔,磷酸钙沉淀,DEAE-葡聚糖转染等。尽管理论上可以在原核或真核宿主细胞中表达本发明的抗体,但是真核细胞中、最优选哺乳动物宿主细胞中的抗体的表达是最优选的,因为这样的真核细胞、特别是哺乳动物细胞是更可能比原核细胞组装和分泌正确折叠和免疫活性的抗体。
用于表达用于根据本发明方法的根据本发明的特异性结合CD154的抗体或抗体片段的优选哺乳动物宿主细胞包括中国仓鼠卵巢(CHO细胞),NSO骨髓瘤细胞,COS细胞和SP2细胞。当将编码抗体基因的重组表达载体导入哺乳动物宿主细胞时,通过将宿主细胞培养足以允许抗体在宿主细胞中表达的时间段,或更优选将抗体分泌至其中培养宿主细胞的培养基,来生产抗体。可以使用标准蛋白质纯化方法从培养基中回收抗体。
在用于重组表达根据本发明的特异性结合CD154的抗体或抗体片段的优选系统中,通过磷酸钙介导的转染将编码抗体重链和抗体轻链的重组表达载体导入dhfr-CHO细胞。在重组表达载体内,抗体重链和轻链基因各自可操作地连接到CMV增强子/AdMLP启动子调控元件以驱动基因的高水平转录。重组表达载体还携带DHFR基因,其允许使用氨甲蝶呤选择/扩增来选择被载体转染的CHO细胞。选择的转化体宿主细胞是允许表达抗体重链和轻链的培养物,并从培养基中回收完整的抗体。使用标准分子生物学技术制备重组表达载体,转染宿主细胞,选择转化体,培养宿主细胞并从培养基中回收抗体。
适用于给予人受试者的根据本发明实施方案的方法的优选组合物包含根据本发明的特异性结合CD154的抗体或抗体片段和药学上可接受的载体、赋形剂或稳定剂。本文所用的“药学上可接受的载体”包括任何和所有溶剂,分散介质,包衣,抗细菌和抗真菌剂,等渗和吸收延迟剂等,其在生理学上相容并且适于用于本文所述方法施用于受试者。可接受的载体、赋形剂或稳定剂在所使用的剂量和浓度对接受者无毒,并且包括缓冲液如磷酸盐,柠檬酸盐和其它有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(例如十八烷基二甲基苄基氯化铵;氯化己烷双胺(hexamethonium chloride);苯扎氯铵,苄索氯铵;苯酚,丁基或苄醇;对羟基苯甲酸烷基酯如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;邻苯二酚;间苯二酚;环己醇;3-戊醇;间甲酚);低分子量(不超过约10个氨基酸残基)肽;蛋白质,如血清白蛋白,明胶或免疫球蛋白;亲水性聚合物如聚乙烯吡咯烷酮;氨基酸,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;螯合剂如EDTA;糖如蔗糖,甘露糖醇,海藻糖或山梨糖醇;形成盐的反荷离子如钠;金属络合物(例如Zn-蛋白质复合物);和/或非离子表面活性剂如TWEEN,PLURONICS或聚乙二醇。
治疗组合物通常在制造和储存条件下必须是无菌和稳定的。组合物可以配制成溶液或冷冻干燥形式。
在本说明书的语境中包含(comprising)意指包括(including)。
技术上合适的情况下,本发明的实施方案可以组合。
现在将参考以下实施例来描述本发明,这些实施例仅仅是说明性的,不以任何方式被解释为限制本发明的范围。
实施例
实施例1
测定结合亲和力。
使用BIAcore 3000仪器进行生物分子相互作用分析(BIA)。特异性针对人IgG、F(ab’)2片段的Affinipure山羊F(ab’)2片段经由胺偶联化学固定在CM5传感器芯片上,达到约4000个响应单位(RU)的捕获水平。使用HBS-EP缓冲液(10mM HEPES pH 7.4,0.15M NaCl,3mM EDTA,0.005%(v/v))Surfactant P20)作为运行缓冲液,流速为10μL/分钟(min)。使用10μg/mL的试验CD154抗体或Fab的10μL注射液用于通过固定的抗人IgG-F(ab’)2捕获。将人CD154以3μL/min的流速对不同浓度(1nM或更低)的捕获的CD154抗体或Fab进行滴定。通过40mM HCl的2×10μL注射液接着流速为10μL/min的5mM NaOH的5μL注射液来再生表面。
实施例2
研究SL0013:两个部分的临床研究,其中在第一部分中,在5组(每组3名健康男性志愿者)中以0.004mg/kg、0.02mg/kg、0.1mg/kg、0.5mg/kg和1.7mg/kg的剂量又接着在2个3名健康男性志愿者和3名健康女性志愿者的组中以5mg/kg的剂量评估上升单次静脉内剂量的CDP7657的安全性、耐受性和药代动力学曲线。建立了可接受的曲线之后,第二部分的研究在4个3名患者志愿者(已经确诊为系统性红斑狼疮;SLE)的组中以5mg/kg、15mg/kg、30mg/kg和60mg/kg的剂量评估了单次静脉注射剂量。除了进一步评估安全性、耐受性和药代动力学之外,还使用各种疾病标记探讨了药效学作用。
在进行本研究中,建立了抗CD154抗体/抗体片段及其PEG组分的基本特征。
实施例3
研究SL0014:临床研究,其中确诊为SLE的患者以双盲方式随机分配,以在10周的时间段接受六次静脉内剂量的CDP7657(n=16)或匹配的安慰剂(n=8)。所测试的给药方案(在接受活性药物的方案中)包含30mg/kg的单次加载剂量,随后为每2周15mg/kg的维持剂量,总共6次剂量的CDP7657。除了评估CDP7657vs.安慰剂的安全性、耐受性和药代动力学曲线之外,本研究还探讨了免疫原性(抗CD154和PEG组分)、治疗过程中以及治疗后18周对各种疾病标记的影响和临床疾病参数的影响。以这种方式建立了给药方案提供疾病改善作用的安全性、耐受性和能力。
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Claims (17)
1.特异性结合CD154的抗体或抗体片段,其用于在哺乳动物受试者中治疗自身免疫性、炎症性、神经退行性或神经肌肉疾病的方法,所述方法包括:
a)向需要这种治疗的受试者施用初始加载剂量为约20-60mg/kg的特异性结合CD154的抗体或抗体片段;和
b)在初始加载剂量后约2周以约每隔一周一次的频率向需要这种治疗的受试者施用另外的一个或多个约为初始加载剂量一半的剂量的特异性结合CD154的抗体或抗体片段。
2.根据权利要求1所述的特异性结合CD154的抗体或抗体片段,其用于在哺乳动物受试者中治疗自身免疫性、炎症性、神经退行性或神经肌肉疾病的方法,其中初始加载剂量为约30mg/kg,而另外的剂量为约15mg/kg。
3.根据权利要求1或2所述的特异性结合CD154的抗体或抗体片段,其用于在哺乳动物受试者中治疗自身免疫性、炎症性、神经退行性或神经肌肉疾病的方法,其中特异性结合CD154的抗体或抗体片段被施用于需要的患者至少12周。
4.根据权利要求1、2或3所述的特异性结合CD154的抗体或抗体片段,其为中和抗体或抗体片段。
5.根据权利要求1-4任一项所述的特异性结合CD154的抗体或抗体片段,其具有通过表面等离子体共振测定的KD≤4.55pM的单价结合CD40的解离常数。
6.根据权利要求1-5任一项所述的特异性结合CD154的抗体或抗体片段,其含有具有分别包含SEQ ID NO:1、2和3的氨基酸序列的CDR1、CDR2和CDR3的轻链可变区(LCVR)和具有分别包含SEQ ID NO:4、5和6的氨基酸序列的CDR1、CDR2和CDR3的重链可变区(HCVR)。
7.根据权利要求1-6任一项所述的特异性结合CD154的抗体或抗体片段,其表现出单价结合CD40,并且优选仅具有一个特异性结合CD154的结合位点。
8.根据权利要求6或7所述的特异性结合CD154的抗体或抗体片段,其含有SEQ ID NO:7所示的VL链序列和SEQ ID NO:8所示的VH链序列。
9.根据权利要求8所述的特异性结合CD154的抗体或抗体片段,其具有SEQ ID NO:9所示的轻链序列和SEQ ID NO:10所示的重链序列。
10.根据权利要求9所述的特异性结合CD154的抗体或抗体片段,其是具有SEQ ID NO:9所示轻链序列和SEQ ID NO:10所示重链序列的单价Fab'。
11.根据权利要求10所述的特异性结合CD154的抗体片段,其具有
a)与经修饰的铰链区中的单个硫醇基团共价连接的马来酰亚胺基团;赖氨酸残基与马来酰亚胺基团共价连接;和
b)分子量约20KDa的甲氧基聚(乙二醇)聚合物连接到赖氨酸残基上的每个胺基上。
12.根据前述任一项权利要求所述的特异性结合CD154的抗体或抗体片段,其用于在哺乳动物受试者中治疗自身免疫性、炎症性、神经退行性或神经肌肉疾病的方法,其中所述疾病是系统性红斑狼疮(SLE)、狼疮肾炎、类风湿性关节炎、血清阴性脊柱关节病、银屑病、银屑病关节炎、硬皮病、舍格伦综合征、多发性硬化、I型糖尿病、自身免疫性葡萄膜炎和肾病综合征或血管炎。
13.根据前述任一项权利要求所述的特异性结合CD154的抗体或抗体片段,其用于治疗系统性红斑狼疮(SLE)的方法,其中所治疗受试者实现从选自SLEDAI、BILAG和医师整体评估(Global Physician assessment)的一种或多种指数的基线的改善。
14.根据前述任一项权利要求所述的特异性结合CD154的抗体或抗体片段,其用于治疗系统性红斑狼疮(SLE)的方法,其中所治疗的受试者实现SLEDAI应答指数4(SLEDAIResponder Index 4,SRI-4)。
15.根据前述任一项权利要求所述的特异性结合CD154的抗体或抗体片段,其用于治疗系统性红斑狼疮(SLE)的方法,其中所治疗的受试者实现从SRI-50指数的基线的50%的改善。
16.根据前述任一项权利要求所述的特异性结合CD154的抗体或抗体片段,其用于治疗系统性红斑狼疮(SLE)的方法,其中所治疗的受试者实现从补体C3和C4浓度的基线增加20%、30%、40%、50%、75%或90%或实现补体C3和C4浓度的正常化,或者实现血清中抗双链DNA滴度降低20%、30%、40%、50%、75%或90%。
17.根据前述任一项权利要求所述的特异性结合CD154的抗体或抗体片段,其用于治疗系统性红斑狼疮(SLE)的方法,其中所述受试者的抗双链DNA抗体从血清阳性逆转为血清阴性。
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CA3002789A1 (en) | 2015-09-04 | 2017-03-09 | Primatope Therapeutics Inc. | Humanized anti-cd40 antibodies and uses thereof |
WO2017148904A1 (en) * | 2016-02-29 | 2017-09-08 | Franz Grus | Predictive markers useful in the treatment of wet age-related macular degeneration |
AU2019347730A1 (en) * | 2018-09-24 | 2021-03-25 | Janssen Biotech, Inc. | Method of providing safe administration of an anti-CD154 antibody |
AU2022402319A1 (en) * | 2021-12-01 | 2024-05-02 | Biogen Ma Inc | Formulations comprising fab-peg |
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US20210324095A1 (en) | 2021-10-21 |
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EP3744735A1 (en) | 2020-12-02 |
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AU2015379642A1 (en) | 2017-07-27 |
DK3250600T3 (da) | 2020-06-08 |
RU2695443C2 (ru) | 2019-07-23 |
NZ733454A (en) | 2023-12-22 |
KR102543877B1 (ko) | 2023-06-14 |
US11884737B2 (en) | 2024-01-30 |
RU2017130464A3 (zh) | 2019-02-28 |
AU2015379642B2 (en) | 2021-11-04 |
EP3250600A1 (en) | 2017-12-06 |
HRP20201013T1 (hr) | 2020-10-16 |
EP3250600B1 (en) | 2020-05-06 |
CY1123116T1 (el) | 2021-10-29 |
LT3250600T (lt) | 2020-07-27 |
PL3250600T3 (pl) | 2020-09-21 |
PT3250600T (pt) | 2020-06-17 |
HUE050024T2 (hu) | 2020-11-30 |
CA2975336A1 (en) | 2016-08-04 |
WO2016119909A1 (en) | 2016-08-04 |
RS60575B1 (sr) | 2020-08-31 |
RU2017130464A (ru) | 2019-02-28 |
KR20170106476A (ko) | 2017-09-20 |
CA2975336C (en) | 2022-10-18 |
ES2802982T3 (es) | 2021-01-22 |
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