CN111918671A - 用于关节炎的持久关节内治疗的多价肽辍合物 - Google Patents
用于关节炎的持久关节内治疗的多价肽辍合物 Download PDFInfo
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Abstract
本公开涉及肽‑聚合物辍合物,及其在治疗关节内疾病或病症中的用途。
Description
相关申请的交叉引用
本申请要求2018年3月9日提交的美国临时申请62/640,749的优先权。出于所有目的将其全文并入本文。
关于序列表的声明
与本申请相关联的序列表以文本格式代替纸质副本提交,其在此通过引用并入说明书中。包含序列表的文本文件名称是052566-504001WO_SL-ST25.txt。文本文件为14,890字节,创建于2019年3月8日,并通过EFS-Web电子提交。
发明背景
有两种给药途径可将药物疗剂递送至关节组织:(1)全身给药(即口服、皮下和静脉内给药),或(2)关节内注射。
全身给药的优点在于可以容易地进行。通常可由患者在家中进行,因此患者的重复给药并不困难。然而,对于强效药物产品,药物的全身性含量过高可能并不理想。因为在患病关节中维持治疗剂量所需的高全身性水平,也可能对身体其他部位造成危险副作用。
关节内给药的优点是可以将有效药物直接递送至患病关节。直接给药到关节中的剂量可以低于全身给药后达到相同治疗效果所需的剂量,因为药物已经局部施用于靶组织。但是,关节内给药需要专业人员来安全地将注射剂注射到关节组织中。因此,关节内注射实质上更麻烦且施用成本更高。
对许多关节给药的另一个挑战是,在关节组织周围产生的流体动力学压力会使蛋白质和小分子迅速从关节液中清除。实际上,关节周围的滑膜组织包括淋巴管,可以很容易地收集从关节间隙渗出的液体和其他物质。因此,给药至关节腔内的药物被迅速从关节清除并进入血流,在血流中它们不再能有效地作用于患病的组织。因此,通过关节内注射递送的药物需要频繁地重新给药以维持疗效。
因此,急需通过改进常规注入关节组织的药物在关节内的停留时间。为了增加药物在关节内空间的停留时间,对现有药物进行修饰可能是有用的。通过减少关节内给药的频率,就有可能降低与慢性给药相关的并发症的总体风险。增加生物活性的持续时间也可以提高药物的治疗效果。
与必须更频繁地使用以达到同等治疗功能的同类药物相比,关节内停留时间更长的药物将是患者的首选。虽然关节内注射是在局部麻醉下进行的,一般认为是不疼痛的,但对患者来说,经常前往临床医生办公室进行注射非常麻烦。注射部位也可能会有短期刺激。因此,患者可能会倾向于需要较少关节内注射的等效疗法。
包含生物活性多肽药物和生物相容性聚合物的辍合物,其关节内半衰期大于未与生物相容性聚合物辍合时生物活性多肽的关节内半衰期。增加药物半衰期的作用在于增加药物超过产生有效治疗反应所需的浓度阈值的时间。
在关节中,增加半衰期的辍合物具有一定优势,包括减轻患者的负担;减少给药的数量和/或频率;增加安全性;感染发生率降低;增加患者的依从性;并提高疗效。此外,这些辍合物还能够利用非辍合形式不能在关节中停留足够时间的多肽来治疗关节的疾病和病症。
发明概述
本发明提供了一种治疗位于关节内的疾病或病症的方法。该方法涉及关节内给药由生物聚合物和多个拷贝的生物活性肽,例如抗体组成的生物辍合物,从而治疗疾病或病症。
在一些实施方式中,本发明提供了一种治疗关节内疾病或病症的方法。该方法包括将有效量的辍合物注射到关节中,所述辍合物包括:分子量为约0.1MDa至约3MDa的生物相容性聚合物;以及多个肽,其中所述肽的分子量为约5kDa至约150kDa;其中每个肽与聚合物共价连接,并且辍合物中肽与聚合物的摩尔比为至少约5:1。
在一些实施方式中,本发明提供了生物相容性聚合物和多个肽的辍合物;所述生物相容性聚合物的分子量为约0.1MDa至约3MDa;所述肽的分子量为约5kDa至约150kDa;其中每个肽与聚合物共价连接,并且辍合物中肽与聚合物的摩尔比为至少约5:1。
在一个实施方式中,本发明提供了一种辍合物,其包含分子量为约0.1MDa至约2MDa的生物相容性聚合物;以及多个肽,其中所述肽的分子量为约5kDa至约100kDa;其中每个肽与聚合物共价连接,聚合物的分子量为每个肽约5kDa至约50kDa,并且辍合物中肽与聚合物的摩尔比为至少约5∶1。
本发明还提供了一种药物组合物,其包含本发明的辍合物和药学上可接受的赋形剂、稀释剂和/或载体。
本公开还包括一种治疗关节疾病或病症的方法,该方法包括将治疗有效量的本文所述的辍合物或包含所述辍合物的药物组合物注射入关节中。
在一些实施方式中,本发明提供了一种治疗关节疾病或病症的方法,该方法包括将有效量的辍合物注射到关节中,所述辍合物包括:分子量为约0.1MDa至约3MDa的生物相容性聚合物;以及多个肽,其中所述肽的分子量为约5kDa至约150kDa;其中每个肽与聚合物共价连接,并且辍合物中肽与聚合物的摩尔比为至少约5:1。在一些实施方式中,生物相容性聚合物具有约0.1MDa至约2MDa的分子量;以及多个肽,其中所述肽的分子量为约5kDa至约100kDa;其中每个肽与聚合物共价连接,聚合物的分子量为每个肽约5kDa至约50kDa,并且辍合物中肽与聚合物的摩尔比为至少约5∶1。
附图的简要说明
图1显示了用于本公开的方法中生产抗炎生物辍合物的辍合反应的通用示意图。第一步是将反应性交联剂与合适的生物聚合物上的特定官能团共价加成。在该实例中,用于生物聚合物的化学结构是HyA,并且交联剂EMCH通过碳二亚胺化学反应添加至羧酸官能团上。在第二步中,使反应性生物聚合物与抗炎肽反应,该肽包括靶向与化学交联剂共价结合的残基。在这个例子中,肽包含一个残基,该残基以巯基为辍合目标。
图2A显示了用于验证抗炎抗TNFαVHH抗体(SEQ ID NO:7)与各种MW的HyA共价辍合的SDS-PAGE凝胶图。凝胶在还原条件下运行,该条件将逆转非共价相互作用,因此抗炎生物辍合物将保留在分离胶顶部。图2B显示了用于验证抗炎抗TNFα亲和体(SEQ ID NO:6)与HyA和CMC共价辍合的SDS-PAGE凝胶图。图2C显示了用于验证抗炎抗TNFαVHH抗体(SEQ ID NO:7)与CM壳聚糖之间共价辍合的SDS-PAGE凝胶图。图2D显示了用于验证抗炎抗IL-1βscFv(SEQ ID NO:9)抗体与HyA和CMC共价辍合的SDS-PAGE凝胶图。图2E显示了用于验证抗炎抗TNFαVHH(SEQ ID NO:7)抗体与CMC的共价辍合的SDS-PAGE凝胶图。
图3A显示了多价辍合物的特征,以说明基于肽进料比率的各种生物聚合物的抗炎肽价态。在该实施例中,VHH的辍合效率为62±10%,与HyA分子量无关。图3B显示了辍合反应后生物辍合物HyA组分的最终分布。图3C显示了使用尺寸排阻柱分离后抗炎生物辍合物的紫外吸收和静态光散射色谱。图3D显示了通过静态光散射分析所确定的抗炎生物辍合物在如图3D所示色谱峰值上的回转半径(Rg,z)。
图4A显示抗TNFαVHH(SEQ ID NO:7)+HyA(850kDa)生物辍合物的TNFα结合亲和力大于未辍合的抗TNFαVHH抗体的TNFα结合亲和力,如通过生物层干涉法测定的(ForteBioOctet,学生t检验,n=3的测试)。图4B显示了使用竞争性ELISA(n=5)比较抗TNFαVHH(SEQID NO:7)+HyA(850kDa)生物辍合物和未辍合的抗TNFαVHH在溶液中结合TNFα的能力。图4C比较了抗TNFαVHH(SEQ ID NO:7)+HyA(850kDa)生物辍合物和未辍合的抗TNFαVHH,在生物测定中抑制TNFα诱导L929成纤维细胞凋亡的生物活性。图4D显示基于图4C拟合计算的IC50,抗TNFαVHH+HyA生物辍合物的效能比未辍合的VHH抗体高约10倍(学生t检验,n=4)。
图5A显示了在48小时内的各个时间点,将抗TNFαVHH和抗TNFαVHH(SEQ ID NO:7)+HyA(850kDa)生物辍合物装载在由开孔膜组成的腔室内的浓度。膜的平均孔径为直径约20nm或100nm。图5B显示了VHH和生物辍合物的运输半衰期,其通过两个膜孔径中的每一个的指数衰减拟合(R2>0.9000)来确定。与未修饰的VHH抗体相比,多价辍合物在膜上的扩散明显更慢(a-b,a-c,a-c:p<0.005,方差分析,n=4)。
图6A显示抗TNFαVHH抗体(SEQ ID NO:7;n=4)和由抗TNFαVHH(SEQ ID NO:7)与HyA辍合制成的抗炎生物辍合物的关节内半衰期,HyA的分子量为350kDa(n=3))、750kDa(n=3)、850kDa(n=3)和2000kDa(n=4)。使用红外标记处理肽在96小时内的ROI辐射效率的指数衰减拟合来计算关节内半衰期。使用850kDa和2000kDa HyA制备的生物辍合物的半衰期显著长于未辍合的VHH(a-b:p<0.05,a-c:p<0.0001,b-c:p<0.0005,单向方差分析)。图6B显示抗TNFαVHH抗体(n=4)和由与700kDa CMC辍合的抗TNFαVHH(SEQ ID NO:7)制成的抗炎生物辍合物的关节内半衰期(n=3)。这种生物辍合物的半衰期与未辍合的VHH的半衰期没有显著差异(p=0.32,学生t检验)。图6C显示抗TNFαVHH抗体(n=3)和由与850kDa HyA辍合的抗TNFαVHH制成的抗炎生物辍合物(n=3)的关节内半衰期。这种生物辍合物的半衰期明显长于未辍合的VHH(p<0.05,学生t检验)。
图7示出了建立的预测药物何时会低于其治疗阈值的药理学模型。该模型可以标准化药物的初始剂量,以考虑不同治疗方法的生物活性和分子量的差异。典型地,抗炎IgG抗体(150kDa)大约需要每周给药一次,以有效改善炎症性关节疾病。使用我们的方法进行生物辍合后,数据显示效能(图4A-D)和IA半衰期(图5A-B)增加,我们预计,使用生物活性与之前临床研究中使用的IgG相当的VHH抗体(15kDa)制备生物辍合物,当量剂量(mass-equivalent dose)的生物辍合物需要每11-12周重新给药一次,以获得同等的治疗效果。
发明详述
I.概述
本发明提供了高分子量聚合物和多个肽的辍合物,其具有比未辍合的肽更强的效力,以及增加的半衰期,使得辍合物可以治疗关节内疾病和病症等。
II.定义
除非另外特别指出,否则本文中使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同含义。另外,与本文描述的方法或材料相似或等同的任何方法或材料都可以用于本发明的实践中。为了本发明的目的,定义以下术语。
如本文所用,“HyA”是指透明质酸。
“CMC”是指羧甲基纤维素。
“scFV”是指小链可变片段抗体。
如本文所用,“VHH”是指单结构域重链抗体。
“DARPin”是指设计的锚蛋白重复蛋白,其是可以表现出高度特异性和高亲和力的靶蛋白结合的基因工程抗体模拟蛋白。
如本文所用,“关节”是指纤维或软骨接头,其为纤维或软骨区域,其中两个或更多个骨头彼此连接。
如本文所用,治疗有效量是指对其产生治疗效果的剂量。确切的剂量将取决于治疗的目的,并且将由本领域技术人员使用已知技术确定(参见,例如,Lieberman,《药物剂型》(1992年,第13卷);Lloyd,《药物合成的艺术、科学和技术》(1999年);Pickar,《剂量计算》(1999年);和《雷明顿:药学的科学与实践》,第20版,2003年,Gennaro编辑,Lippincott,Williams&Wilkins著)。在致敏细胞中,治疗有效剂量通常可以低于对未敏化细胞的常规治疗有效剂量。
如本文所用,“生物相容性聚合物”是指与关节的注射部位相容的聚合物。代表性的生物相容性聚合物包括但不限于,多糖、糖胺聚糖和透明质酸。
如本文所用,“聚合物分子量”是指聚合物的分子量。
“肽”、“多肽”和“蛋白质”在本文可互换使用,是指任何长度的天然存在的和合成的氨基酸,以及以类似于天然存在的方式起作用的氨基酸类似物和氨基酸模拟物氨基酸。术语“多肽”包括融合蛋白,包括但不限于具有异源氨基酸序列的融合蛋白、具有异源和同源前导序列、具有或不具有N端甲硫氨酸残基的融合蛋白;免疫标记蛋白等等。术语“多肽”包括翻译后修饰的多肽。
如本文所用,“调节”是指化合物增加或降低相关活性的功能或活性(例如,免疫细胞功能)的能力。
“免疫细胞功能”包括,例如免疫应答的调节。调节可以是免疫抑制或免疫刺激的。免疫应答的例子可以包括,但不限于体液免疫应答、细胞介导的免疫应答或炎性应答。
如本文所用,“抑制作用”、“抑制”和“抑制剂”是指阻止特定作用或功能的化合物或阻止特定作用或功能的方法。
如本文所用,“抗体”是指由免疫球蛋白基因或其片段编码的多肽,其特异性结合并识别抗原。公认的免疫球蛋白基因包括κ、λ、α、γ、δ、ε和μ恒定区基因,以及无数个免疫球蛋白可变区基因。轻链分为κ或λ。重链被分类为γ、μ、α、δ或ε,这又分别定义了免疫球蛋白类别,IgG、IgM、IgA、IgD和IgE。抗体代表多种受体,包括激素受体、药物靶标(例如外周苯二氮卓受体)和载体蛋白。代表性抗体包括,但不限于单克隆IgG抗体、IgG抗体片段、单链scFv抗体、单域重链VHH抗体或工程化的类抗体支架,例如安耐汀(adnectin)、亲和体、安替开林(anticalin)、DARPins和工程化的Kunitz型抑制剂。其他例子还包括免疫调节细胞因子的受体诱饵,例如肿瘤坏死因子-α和IL-1β,IL-6或干扰素-γ。
如本文所用,“硫键”是指具有硫共价键的任何部分。
如本文所用,“接头”是指直接或间接将多肽与聚合物共价连接的化学部分。可用于本发明的接头可以为约100Da至500Da。本发明的接头的类型包括但不限于酰亚胺、酰胺、胺、酯、氨基甲酸酯、脲、硫醚、硫代氨基甲酸酯、硫代碳酸酯和硫脲。本领域技术人员将理解,其他类型的接头可用于本发明。
如本文所用,“扩散半衰期”是指在给定体积或空间内辍合物的初始浓度降低一半所花费的时间,其中浓度的降低是浓度梯度的函数。
如本文所用,“关节内半衰期”是指在特定关节内辍合物的初始浓度降低一半所花费的时间,其中通过对流从关节中转运出来。对流输运是通过扩散和对流进行输运的组合,其中对流输运是物质通过牵连运动(bulk motion)进行的输运。
如本文所用,“药物组合物”是指包含指定量的指定成分的产品,以及直接或间接地由指定量的指定成分的组合产生的任何产品。该药物组合物通常对于生物用途是安全的。
如本文所用,“药学上可接受的运载体”和“药学上可接受的赋形剂”是指有助于将活性剂给予受试者吸收的物质。可用于本发明的药物运载体和/或赋形剂包括但不限于粘合剂、填充剂、崩解剂、润滑剂、包衣、甜味剂、调味剂和色素。本领域技术人员将认识到其他药物运载体和/或赋形剂可用于本发明。
肽-聚合物辍合物
本发明提供了高分子量聚合物和多个肽的辍合物,其具有比相似浓度的未辍合肽更大的效力。在一些实施方式中,本发明提供了生物相容性聚合物和多个肽的辍合物;所述生物相容性聚合物的分子量为约0.1MDa至约3MDa;所述肽的分子量为约5kDa至约150kDa;其中每个肽与聚合物共价连接,并且辍合物中肽与聚合物的摩尔比为至少约5:1。
在一些实施方式中,生物相容性聚合物具有约0.1MDa至约2MDa的分子量;以及多个肽,其中所述肽的分子量为约5kDa至约100kDa;其中每个肽与聚合物共价连接,聚合物的分子量为每个肽约5kDa至约50kDa,并且辍合物中肽与聚合物的摩尔比为至少约5∶1。
III.生物相容性聚合物
可用于本发明的辍合物的聚合物包括任何合适的生物相容性聚合物。生物相容性聚合物是通常不触发免疫反应的亲水性聚合物。合适的生物相容性聚合物包括,但不限于多糖、糖胺聚糖、透明质酸及其衍生物、纤维素、羧甲基纤维素及其衍生物、肝素及其衍生物、皮肤素、淀粉和改性淀粉、软骨素、壳聚糖、羧甲基壳聚糖等。生物相容性聚合物还可包括聚氯乙烯、聚四氟乙烯、聚醚砜、聚乙烯、聚醚醚酮、聚砜、聚丙烯、聚(乙二醇)、聚(丙二醇)、聚氨酯、乙烯乙酸乙烯酯共聚物、胶原蛋白、聚异丁烯、乙烯乙烯醇共聚物、聚乙烯聚碳酸酯、聚己内酯、聚丙交酯、聚乙交酯、卡波姆、聚酯、聚醚、聚酸酐、聚丙烯酸酯、聚乙酸乙烯酯、聚乙烯吡咯烷酮、多糖(例如透明质酸、羟烷基纤维素、羧烷基纤维素或其衍生物)、聚醚、其衍生物及其组合。可以通过诸如硫酸化、磺化、氘化等方法进一步修饰生物相容性聚合物。
用作生物相容性聚合物的多糖包括但不限于纤维素、羧甲基纤维素、甲基纤维素、羟丙基纤维素、壳聚糖、糖胺聚糖、硫酸软骨素、透明质酸(透明质酸)、肝素、硫酸乙酰肝素等。在一些实施方式中,生物相容性聚合物可以是多糖。在一些实施方式中,生物相容性聚合物可以是糖胺聚糖。在一些实施方式中,生物相容性聚合物可以是透明质酸。
本发明的生物相容性聚合物可以具有任何合适的分子量。例如,合适的生物相容性聚合物可以具有约0.1MDa至约3MDa,或约100kDa至约3,000kDa的分子量。聚合物分子量通常可以表示为数均分子量(Mn)或重均分子量(Mw)。数均分子量是各个大分子的分子量的数学平均值。重均分子量受较大分子的影响,因此其数量大于数均分子量。Mw/Mn之比是聚合物的多分散性,代表聚合物样品中分子量的宽度。除非另有说明,否则本发明中述及分子量是指重均分子量(Mw)。
可用于生物相容性聚合物的分子量包括但不限于,约0.1MDa至约3MDa、约0.1MDa至约2MDa、约0.2MDa至约1.5MDa、约0.8MDa至约3MDa、约1MDa至约3MDa、约1.5MDa至约3MDa、或约1MDa至约2MDa。在一些实施方式中,生物相容性聚合物具有约0.1MDa至约3MDa的分子量。在一些实施方式中,生物相容性聚合物具有约0.1MDa至约2MDa的分子量。在一些实施方式中,生物相容性聚合物具有约0.2MDa至约1.5MDa的分子量。在一些实施方式中,生物相容性聚合物的分子量为约0.8MDa至约3MDa。生物相容性聚合物的分子量可以为约0.1MDa,或0.2、0.25、0.3、0.35、0.4、0.45、0.5、0.55、0.6、0.65、0.7、0.75、0.8、0.85、0.9、0.95、1、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9或约3MDa。在一些实施方式中,生物相容性聚合物具有至少约0.85MDa的分子量。在一些实施方式中,生物相容性聚合物具有约0.9MDa的分子量。在一些实施方式中,生物相容性聚合物具有至少约1MDa的分子量。在一些实施方式中,生物相容性聚合物具有约2MDa的分子量。
生物相容性聚合物的分子量可以为每个肽约5kDa至约600kDa,或约5kDa至500kDa、约5kDa至约400kDa、约5kDa至约300kDa、约5kDa至约200kDa、约5kDa至约100kDa、约5kDa至约50kDa、约5kDa至约40kDa、约5kDa至约30kDa、约5kDa至约20kDa,或每个肽约5kDa至约10kDa。生物相容性聚合物的分子量可为每个肽约5kDa,或6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22,23、24、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或约100kDa。
肽类
适用于本发明的肽是具有至少约2kDa的分子量并显示三级结构的肽。代表性的肽包括但不限于多肽、一种或多种适体,基于人A结构域支架的avimer支架、双抗体、骆驼科动物、鲨鱼IgNAR抗体,具有修饰的特异性的III型纤连蛋白支架、抗体、抗体片段、蛋白质、肽、多肽。
在一个特别有用的实施方式中,该肽是治疗性蛋白。在整个申请中公开了许多治疗性蛋白,例如但不限于,促红细胞生成素、粒细胞集落刺激因子(G-CSF)、GM-CSF、干扰素α、干扰素β、人生长激素和伊米苷酶。
在一个实施方式中,该肽可以选自特别鉴定的蛋白质或肽试剂,包括但不限于:Aβ、海藻糖苷酶、阿耳法西普(alefacept)、碱性磷酸酶、天冬酰胺酶、阿莫索韦(DAPD)、抗排卵素(antide)、培卡敏(becaplermin)、肉毒杆菌毒素(包括A型和B型)以及具有肉毒杆菌毒素活性的低分子量化合物、降钙素、氰基维林(cyanovirin)、地尼白介素(denileukindiftitox)、促红细胞生成素(EPO)、EPO激动剂、链道酶α(dornaseα)、促红细胞生成刺激蛋白(NESP)、凝血因子如因子V、因子VII、因子VIIa、因子VIII、因子IX、因子X、因子XII、因子XIII,血管性血友病(von Willebrand)因子;西利酶(ceredase)、伊米苷酶(cerezyme)、α-葡萄糖苷酶、N-乙酰半乳糖胺-6-硫酸盐硫酸酯酶、胶原蛋白、环孢菌素、α防御素、β防御素、去氨加压素、艾塞那肽-4(exendin-4)、细胞因子、细胞因子受体、粒细胞集落刺激因子(G-CSF)、血小板生成素(TPO)、α-1蛋白酶抑制剂、依降钙素(elcatonin)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、纤维蛋白原、非格司亭(filgrastim)、生长激素人类生长激素(hGH)、生长激素、生长激素释放激素(GHRH)、GRO-β,GRO-β抗体、骨形态发生蛋白如骨形态发生蛋白-2、骨形态发生蛋白-6、甲状旁腺激素、甲状旁腺激素相关肽、OP-1;酸性成纤维细胞生长因子、碱性成纤维细胞生长因子、成纤维细胞生长因子21、CD-40配体、肝素、人血清白蛋白、低分子量肝素(LMWH)、干扰素α、干扰素β、干扰素γ、干扰素ω、干扰素τ、复合干扰素、人类赖氨酰氧化酶样2(LOXL2);白介素和白介素受体如白介素-1受体、白介素-2、白介素-2融合蛋白、白介素-1受体拮抗剂、白介素-3、白介素-4、白介素-4受体、白介素-6、白介素8、白介素-12、白介素-17、白介素-21、白介素-23、p40、白介素-13受体、白介素-17受体;乳铁蛋白和乳铁蛋白片段、促黄体生成激素释放激素(LHRH)、胰岛素、胰岛素原、胰岛素类似物、瘦素、生长素释放肽、胰岛淀粉样多肽、C肽、生长抑素、生长抑素类似物包括奥曲肽(octreotide)、血管加压素、促卵泡激素(FSH)、伊米苷酶(imiglucerase)、流感疫苗、胰岛素样生长因子(IGF)、促胰岛激素、巨噬细胞集落刺激因子(M-CSF)、纤溶酶原激活剂包括阿替普酶(alteplase)、尿激酶、瑞替普酶(reteplase)、链激酶、帕米替普酶(pamiteplase)、拉替普酶(lanoteplase)和替替普酶(teneteplase);神经生长因子(NGF)、骨保护素、血小板衍生生长因子、组织生长因子、转化生长因子-1、血管内皮生长因子、白血病抑制因子、角质形成细胞生长因子(KGF)、神经胶质生长因子(GGF)、T细胞受体、CD分子/抗原、肿瘤坏死因子(TNF)(例如TNF-α和TNF-β)、TNF受体(例如TNF-α受体和TNF-β受体)、CTLA4、CTLA4受体、单核细胞趋化蛋白-1、内皮生长因子、甲状旁腺激素(PTH)、胰高血糖素样肽、生长激素、胸腺素α1、拉布立酶(rasburicase)、胸腺素α1IIb/IIIa抑制剂、胸腺素β10、胸腺素β9、胸腺素β4、α-1抗胰蛋白酶、磷酸二酯酶(PDE)化合物、VLA-4(极晚抗原4)、VLA-4抑制剂、双膦酸盐、呼吸道合胞病毒抗体、囊性纤维化跨膜调节剂(CFTR)基因、脱氧核糖核酸酶(Dnase)、杀菌/通透性增加蛋白(BPI),和抗CMV抗体。示例性的单克隆抗体包括依那西普(etanercept)(一种二聚体融合蛋白、由与IgG1的Fc部分相连的人75kD TNF受体的细胞外配体辍合部分组成)、阿昔单抗(abciximab)、阿达木单抗(adalimumab)、阿非木单抗(afelimomab)、拉布立酶(rasburicase)、针对B淋巴细胞的抗体、阿利珠单抗(atlizumab)、巴利昔单抗(basiliximab)、贝伐单抗(bevacizumab)、比西罗单抗(biciromab)、柏替木单抗(bertilimumab)、CDP-484、CDP-571、CDP-791、CDP-860、CDP-870、西妥昔单抗(cetuximab)、克立诺昔单抗(clenoliximab)、达克珠单抗(daclizumab)、依库珠单抗(eculizumab)、埃德考洛单抗(edrecolomab)、依法珠单抗(efalizumab)、依帕妥珠单抗(epratuzumab)、芳妥珠单抗(fontolizumab)、加维莫单抗(gavilimomab)、吉妥珠单抗奥唑米星(gemtuzumabozogamicin)、替伊莫单抗(ibritumomab tiuxetan)、英夫利昔单抗(infliximab)、伊诺莫单抗(inolimomab)、凯里昔单抗(keliximab)、拉贝妥珠单抗(labetuzumab)、乐地单抗(lerdelimumab)、奥利珠单抗(olizumab)、放射性标记的lym-1、美他莫单抗(metelimumab)、美泊珠单抗(mepolizumab)、米托玛单抗(mitumomab)、莫罗莫纳德-CD3(muromonad-CD3)、那巴珠单抗(nebacumab)、那他珠单抗(natalizumab)、奥杜林单抗(odulimomab)、奥马珠单抗(omalizumab)、奥列戈马单抗(oregovomab)、帕利珠单抗(palivizumab)、培美他单抗(pemtumomab)、派克珠单抗(pexelizumab)、贝伐单抗(rhuMABVEGF)、利妥昔单抗(rituximab)、舒达妥单抗(satumomabpendetide)、司韦单抗(Sevirumab)、西利珠单抗(Siplizumab)、托西莫单抗(tositumomab)、131I-托西莫单抗(I.sup.131tositumomab)、曲妥珠单抗(trastuzumab)、妥韦单抗(tuvirumab)、维西珠单抗(Visilizumab)及其片段和模拟物。
在一个实施方式中,该肽是融合蛋白。例如但不限于,该肽可以是与一种或多种某些有用的肽序列融合的免疫球蛋白或免疫球蛋白的一部分。例如,该肽可以包含抗体Fc片段。在一个实施方式中,该肽是CTLA4融合蛋白。例如,该肽可以是Fc-CTLA4融合蛋白。在另一个实施方式中,该肽是因子VIII融合蛋白。例如,该肽可以是Fc因子VIII融合蛋白。
在一个特别有用的实施方案中,该肽是人蛋白质或人多肽,例如,异源产生的人蛋白质或人多肽。本文公开了许多蛋白质和多肽,其具有相应的人源形式(即,蛋白质或肽通常在人体内的人源细胞中产生)。因此,在一个实施例中,所述肽是在此公开的每个蛋白质和多肽的人源形式,为此,所述肽具有人源形式。此类人源蛋白质的实例包括但不限于,人源抗体、人源酶、人源激素和人源细胞因子,例如粒细胞集落刺激因子、粒细胞巨噬细胞集落刺激因子、干扰素(例如α干扰素和β干扰素)、人源生长激素和促红细胞生成素。
治疗性蛋白质的其他实例包括但不限于,因子VIII、b结构域缺失的因子VIII、因子VIIa、因子IX、抗凝剂;水蛭素(hirudin)、阿替普酶(alteplase)、tpa、瑞替普酶(reteplase)、tpa、5个结构域中的3个已缺失的tpa、胰岛素,赖脯胰岛素、门冬胰岛素、甘精胰岛素、长效胰岛素类似物、hgh、胰高血糖素、tsh、促卵泡素-β、fsh、gm-csf、pdgh、ifnα2、ifnα2a、ifnα2b,inf-α1、复合ifn、ifn-β、ifn-β1b、ifn-β1a、ifn-γ(例如1和2)、ifn-λ、ifn-δ、il-2、il-11、hbsag、ospa、针对t淋巴细胞抗原的鼠单克隆抗体、针对tag-72的鼠单克隆抗体、肿瘤相关糖蛋白、衍生自抗血小板表面受体gpII(b)/III(a)的嵌合单克隆抗体的fab片段、抗肿瘤相关抗原cal 25的鼠单克隆抗体片段,抗人癌胚抗原的鼠单克隆抗体片段、cea、抗人心脏肌球蛋白的鼠单克隆抗体片段、抗肿瘤表面抗原psma的鼠单克隆抗体片段、抗hmw-maa的鼠单克隆抗体片段(fab/fab2混合)、抗癌相关抗原的鼠单克隆抗体片段(fab),抗nca 90的单克隆抗体片段(fab)、一种表面粒细胞非特异性交叉反应抗原、针对b淋巴细胞表面的cd20抗原嵌合单克隆抗体、抗il2受体的α链的人源化单克隆抗体片段、抗il2受体的α链的嵌合单抗、抗tnf-α的嵌合单克隆抗体、抗呼吸道合胞病毒表面抗原决定簇的人源化单克隆抗体、抗her2的人源化单克隆抗体、人表皮生长因子受体2的人源化单克隆抗体、抗细胞角蛋白肿瘤相关抗原ctla4的人源化单克隆抗体、抗b淋巴细胞链道酶α核酸酶(dornase-αdnase)表面抗原cd 20的嵌合单抗、β葡萄糖脑苷脂酶、tnf-α、il-2-白喉毒素融合蛋白、tnfr-lgg片段融合蛋白拉罗尼酶(laronidase)、DNA脱氧核糖核酸酶(dnaases)、阿法西普(alefacept)、达贝泊汀α(darbepoetinα)(集落刺激因子)、托西莫单抗(tositumomab)、鼠单克隆抗体、阿仑单抗(alemtuzumab)、拉布立酶(rasburicase)、半乳糖苷酶β(agalsidaseβ)、特立帕肽(teriparatide)、甲状旁腺激素衍生物、阿达木单抗(lgg1)、阿那白滞素(anakinra)、生物修饰剂、奈西立肽(nesiritide)、人b型利钠肽(hbnp)、集落刺激因子、培维索孟(pegvisomant)、人生长激素受体拮抗剂、重组活化蛋白c、奥马珠单抗(omalizumab)、免疫球蛋白e(lge)阻断剂、替伊莫单抗(lbritumomabtiuxetan)、ACTH、胰高血糖素、生长抑素、生长激素、胸腺素、甲状旁腺激素、色素激素、生长激素、促红细胞生成素、促黄体生成激素、绒毛膜促性腺激素、下丘脑释放因子、依那西普、抗利尿激素、催乳素和促甲状腺激素。任何一种蛋白都可以利用天然氨基酸(例如,丝氨酸对半胱氨酸的取代)(例如,红木生物科学公司的甲醛方法)或非天然氨基酸修饰成具有位点特异性的辍合点(N端、C端或其他位置)。
本发明中有用的治疗性抗体(或其各自的scFv或Fab片段)的例子包括但不限于、抗TNF抑制剂、例如TNF受体诱饵依那西普(etanercept)和单克隆抗体阿达木单抗(adalimumab)、英夫利昔单抗(infliximab)、戈利木单抗(golimumab)和赛妥珠单抗(certolizumab)、IL-6单克隆抗体抑制剂siltuximab、IL-17单克隆抗体抑制剂苏金单抗(secukinumab)和ixekizumab、IL-12/23单克隆抗体抑制剂优特克单抗(ustekinumab)、整联蛋白受体拮抗剂(如单克隆抗体抑制剂那他珠单抗(natalizumab)和埃特罗珠单抗(etrolizumab)、CLTA受体拮抗剂abatacept、IL-13单克隆抗体抑制剂初妥克单抗(tralokinumab)、趋化因子抑制剂(例如单克隆抗体埃尔德单抗(eldelumab)和百替路单抗(bertilumab)、和IL-1抑制剂、例如受体诱饵利纳西普(rilonacept)、和单克隆抗体康纳单抗(canakinumab)。
可用于本发明的治疗性抗体(或其各自的scFv或Fab片段)的其他实例包括但不限于,HERCEPTINTM(曲妥珠单抗)(Trastuzumab)(基因泰克,加利福尼亚州),其为人源抗HER2单克隆抗体,用于转移性乳腺癌患者的治疗;REOPROTM阿昔单抗(Abciximab)(森托科公司),它是血小板上的一种抗糖蛋白IIb/IIIc受体,用于防止血块形成;ZENAPAXTM达利珠单抗(daclizumab)(罗氏制药,瑞士),是一种免疫抑制性人源化抗CD25单克隆抗体,用于预防急性肾移植排斥反应;PANOREXTM是鼠抗17-IA细胞表面抗原IgG2a抗体(葛兰素史克/森托科公司);BEC2是鼠类抗独特型(GD3表位)IgG抗体(ImClone系统公司);IMC-C225是嵌合的抗EGFR IgG抗体(ImClone系统公司);IMC-C225为嵌合抗EGFR IgG抗体(ImClone系统公司);VITAXINTM是人源化的抗αVβ3整联蛋白抗体(应用分子进化/医学免疫公司);坎帕特(Campath);坎帕特1H/LDP-03,为人源化的抗CD52 IgG1抗体(Leukosite公司);Smart M195是人源化抗CD33 IgG抗体(蛋白质设计实验室/佳丽宝);RITUXANTM是嵌合的抗CD2O IgG1抗体(IDEC制药/基因泰克,罗氏/赛诺根);LYMPHOCIDETM是人源化的抗CD22 IgG抗体(免疫医学);ICM3是人源化的抗ICAM3抗体(ICOS制药);IDEC-114是灵长类动物抗CD80抗体(IDEC制药/三菱);ZEVALINTM是一种放射性标记的鼠抗CD20抗体(IDEC/先灵葆雅公司);IDEC-131是一种人源化抗CD40L抗体(IDEC/卫材);IDEC-151是灵长类抗CD4抗体(IDEC);IDEC-152是灵长类化抗CD23抗体(IDEC/IDEC/先灵葆雅公司);SMART抗CD3是一种人源化抗CD3 IgG(蛋白质设计实验室);5G1.1是一种人源化的抗补体因子5(CS)抗体(亚力兄制药);D2E7是人源化的抗TNF-α抗体(CATIBASF);CDP870是人源化的抗TNF-αFab片段(塞尔泰克公司);IDEC-151是灵敏的抗CD4 IgG1抗体(IDEC制药/史克必成);MDX-CD4是人源抗CD4 IgG抗体(美达瑞/卫材/Genmab公司);CDP571是人源化的抗TNF-αIgG4抗体(塞尔泰克公司);LDP-02是人源化的抗α4β7抗体(LeukoSite公司/基因泰克);OrthoClone OKT4A是人源化的抗CD4 IgG抗体(奥多生物技术公司);ANTOVATM是人源化的抗CD40L IgG抗体(渤健);ANTEGRENTM是人源化的抗VLA-4IgG抗体(Elan公司);CAT-152、人抗TGF-β2抗体(剑桥Ab泰克);西妥昔单抗(Cetuximab)(BMS)是单克隆抗EGF受体(EGFr)抗体;贝伐单抗(Bevacizuma)(基因泰克)是抗VEGF人源单克隆抗体;英利昔单抗(Infliximab)(Centocore公司,JJ)是一种嵌合的(小鼠和人)单克隆抗体,用于治疗自身免疫性疾病;吉妥单抗(Gemtuzumab ozogamicin)(惠氏)是用于化疗的单克隆抗体;雷珠单抗(Ranibizumab)(基因泰克)是一种嵌合的(小鼠和人的)单克隆抗体,用于治疗黄斑变性。
本文公开的蛋白质和肽可以通过任何有用的方法生产,包括通过体外合成生产和通过生物系统生产。本领域众所周知的体外合成方法的典型实例包括固相合成(“SPPS”)和固相片段缩合(“SPFC”)。用于产生蛋白质的生物系统也是本领域众所周知的。细菌(例如,大肠杆菌(E.coli)和芽孢杆菌属(Bacillus sp.))、酵母(例如,酿酒酵母(Saccharomycescerevisiae)和巴斯德毕赤酵母(Pichia pastoris))、烟草叶(通过烟草花叶病毒(tobaccomosaic virus))被广泛用于产生异源蛋白质。另外,本公开中用于生产肽的异源基因表达可以通过动物细胞系例如哺乳动物细胞系(例如CHO细胞)来完成。在一个特别有用的实施方案中,所述肽在转基因或克隆的动物如牛、绵羊、山羊和鸟(例如鸡、鹌鹑、鸭和火鸡)中产生,如本领域所理解的。参见,例如,2004年8月24日授权的美国专利号6,781,030中,其全部公开内容通过引用合并于此。
除了在蛋白质和多肽中发现的常见天然氨基酸之外,可用于本发明的蛋白质或多肽还可以包含非天然存在的氨基酸。除了为了改变多肽或蛋白质的性质而存在之外,还可以引入非天然存在的氨基酸来提供官能团,用于将蛋白质或多肽直接连接到无规共聚物上。此外,可以以这种方式使用天然存在的氨基酸,例如半胱氨酸,酪氨酸,色氨酸。
可以通过多种方式将非天然存在的氨基酸引入蛋白质和肽中。引入非天然氨基酸的一些技术见美国专利号5,162,218,其公开内容通过引用整体并入本文。首先,可以通过在氨基酸侧链上或氨基末端或羧基末端化学修饰多肽或蛋白质来引入非天然存在的氨基酸。蛋白质或肽的化学修饰的非限制性实例可以是通过诸如重氮甲烷之类的试剂作甲基化,或在赖氨酸侧链上的氨基、肽或蛋白质的氨基末端中引入乙酰化。蛋白质/多肽氨基基团修饰制备非天然氨基酸的另一个例子是使用3-巯基丙酸甲酯或2-亚氨基硫烷引入具有功能的硫醇(巯基,-SH),连接到含有伯胺的蛋白质或多肽的位置。一旦引入,这些基团就可以被用来与蛋白质或多肽形成共价连接键。
第二,可以在化学合成过程中将非天然存在的氨基酸引入蛋白质和多肽。通常使用合成方法来制备具有少于约200个氨基酸,通常具有少于约150个氨基酸,并且更通常具有100个或更少氨基酸的多肽。可以通过化学合成制备具有少于约75个氨基酸或少于约50个氨基酸的较短的蛋白质或多肽。
通过合成制备方法将非天然氨基酸插入所需位置,这一特别方便的方法是本领域已知的。合适的合成多肽制备方法可以基于Merrifield固相合成方法进行,其中氨基酸被顺序添加到增长链中(Merrifield(1963)美国化学会志85:2149-2156)。用于这种技术合成多肽的自动化系统现在可以从供应商那里购买到,例如应用生物系统公司,福斯特城,加州,94404;新布伦瑞克科学公司,爱迪生市,新泽西州,08818;和法玛西亚公司,生物技术集团,皮斯卡塔韦,新泽西州,08854。
在多肽的化学合成中引入的非天然氨基酸的例子包括但不限于:D-氨基酸以及20种天然氨基酸、N-甲酰基甘氨酸、鸟氨酸、正亮氨酸、羟脯氨酸、β-丙氨酸、羟基缬氨酸、正缬氨酸、苯甘氨酸、环己基丙氨酸、叔丁基甘氨酸(叔亮氨酸,2-氨基-3,3-二甲基丁酸)、羟基叔丁基甘氨酸、氨基丁酸、环亮氨酸、4-羟基脯氨酸、焦谷氨酸(5-氧代脯氨酸)、氮杂环丁烷羧酸、哌嗪酸、二氢吲哚-2-羧酸、四氢-3-异喹啉羧酸、2,4-二氨基丁酸、2,6-二氨基庚二酸、2,4-二氨基丁酸、2,6-二氨基庚二酸、2,3-二氨基丙酸、5-羟基赖氨酸、神经氨酸和3,5-二碘酪氨酸的D型和L型的混合物。
第三,非天然存在的氨基酸可通过在编码多肽的DNA序列(例如基因)中对应于非天然氨基酸插入位置的密码子处插入无义密码子(例如琥珀或赭色密码子),从而通过体内或体外生物合成引入。此类技术在例如美国专利第5,162,218号和第6,964,859号中被公开,其公开内容通过引用整体并入本文。可以使用多种方法来插入突变密码子,包括寡核苷酸定向的诱变。被改变的序列随后被转录和翻译,在提供抑制性tRNA的体内或体外的系统中,该系统针对已被所需非天然存在的氨基酸化学或酶促酰化的无义密码子。合成氨基酸将插入在无义密码子对应的位置。为了制备更大和/或糖基化的多肽,通常优选这种类型的重组制备技术。可以这种方式引入的氨基酸是:甲酰基甘氨酸、氟丙氨酸、2-氨基-3-巯基-3-甲基丁酸、高半胱氨酸、高精氨酸等。在蛋白质中获得非天然氨基酸的其他类似方法包括甲硫氨酸取代方法。
当非天然存在的氨基酸具有易于选择性修饰的功能结构时,它们对于形成与蛋白质或多肽的共价交联特别有用。功能结构易被选择性修饰的情况包括:该功能结构是独一的,或可能在感兴趣的条件下反应的其他功能结构被立体化学或其他因素阻碍。
其他抗体,例如单域抗体可用于本发明。单域抗体(sdAb,被Ablynx命名为Nanobody)是由单个单体可变抗体结构域组成的抗体片段。像完整抗体一样,sdAb能够选择性结合特定抗原。单域抗体的分子量仅为12-15kDa,比普通的完整抗体(150-160kDa)小得多。单结构域抗体是长度约为110个氨基酸的肽链,包含重链抗体一个可变域(VH)或常见IgG。
与完整抗体不同,单结构域抗体(sdAbs)(例如VHH)不显示补体系统触发的细胞毒性,因为它们缺少Fc区。骆驼科动物和鱼类衍生的sdAb能够与完整抗体无法接触的隐藏抗原辍合,例如与酶的活性位点辍合。
sdAb可通过用所需抗原免疫单峰骆驼、骆驼、美洲驼、羊驼或鲨鱼,然后分离编码重链抗体的mRNA来获得。或者,可以通过筛选合成文库来制备。骆驼科动物是骆驼科生物家族的成员,骆驼科是胼足亚目中唯一的存活家族。骆驼、单峰骆驼,双峰驼、美洲驼、羊驼、骆马和原驼属于这一类。
可用于本发明的肽还包括但不限于:大环肽、环氧化物、LDL受体A结构域、可溶性受体、酶、肽多聚体、结构域多聚体、抗体片段多聚体、和融合蛋白。
在一些实施方式中,该肽调节免疫细胞功能的活性。在一些实施方式中,该肽抑制肿瘤坏死因子-α、白介素-1β、白介素-6或干扰素-γ。在一些实施方式中,该肽抑制肿瘤坏死因子-α。在一些实施方式中,该肽是单克隆IgG抗体、IgG抗体片段、单链可变区抗体、单结构域重链抗体、adnectin、亲和体、抗铁蛋白、DARPin、Kunitz型抑制剂或受体诱饵。
在一些实施方式中,该肽可以是抗TNFα单结构域重链(VHH)抗体。在一些实施方式中,该肽可以是抗TNFα亲和体。在一些实施方式中,该肽可以是抗TNFα设计的锚蛋白重复蛋白(Anti-TNFa designed ankyrin repeat protein,DARPin)。在一些实施方式中,该肽可以是抗IL-1B单链(scFv)抗体。在一些实施方式中,该肽可以是可溶性白介素受体2(sILR2)。在一些实施方式中,该肽具有SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:6、SEQ IDNO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10或SEQ ID NO:11的氨基酸序列。在一些实施方式中,该肽具有SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9或SEQ ID NO:10的氨基酸序列。在一些实施方式中,该肽具有的氨基酸序列为SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:9、SEQ ID NO:10或SEQID NO:11。在一些实施方式中,该肽具有氨基酸序列,该氨基酸序列为SEQ ID NO:6、SEQ IDNO:7、SEQ ID NO:9或SEQ ID NO:11。在一些实施方式中,该肽具有氨基酸序列为SEQ IDNO:6、SEQ ID NO:7或SEQ ID NO:9。在一些实施方式中,该肽具有SEQ ID NO:6的氨基酸序列。在一些实施方式中,该肽具有SEQ ID NO:7的氨基酸序列。在一些实施方式中,该肽具有SEQ ID NO:9的氨基酸序列。
可用于本发明的肽可具有至少2kDa的分子量并显示三级结构。例如,肽的分子量可以为约2kDa至约150kDa、约5kDa至约150kDa、约5kDa至约100kDa、约2kDa至约50kDa、约5kDa至约50kDa、约5kDa至约30kDa、约10kDa至约30kDa或约10kDa至约20kDa。肽的代表性分子量包括约2kDa,或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、35、40、45、50、60、70、80、90、100、110、120、130、140或大约150kDa。
辍合物
本发明的辍合物可以描述为如式I的化合物:
(X-Y)n-Z (I)
其中X是如上所述的肽,Z是如上所述的生物相容性聚合物,Y是任选的接头,并且下标n是5至500。
本发明的肽-聚合物辍合物可以包括肽与生物相容性聚合物的任何合适的组合,其中肽与聚合物的摩尔比为至少5:1。可用于本发明的肽与生物相容性聚合物的代表性摩尔比包括5∶1至约1000∶1、5∶1至约500∶1、5∶1至约400∶1、约10∶1至约500:1、约10:1至约400:1、约10:1至约300:1、约10:1至约200:1、约10:1至约100:1、约20:1至约100:1、约30:1至约100:1、约50:1至约100:1、约10:1至约50:1、约20:1至约50:1,或大约30:1到大约50:1。可用于本发明的肽与生物相容性聚合物的其他摩尔比包括约50∶1至约500∶1、约50∶1至约400∶1、约50∶1至约300∶1或约50:1至大约200:1。肽与生物相容性聚合物的代表性摩尔比包括约10:1或15:1、20:1、25:1、30:1、35:1、40:1、45:1、50:1、60:1、70:1、80:1、90:1、100:1、125:1、150:1、175:1、200:1、250:1、300:1、350:1、450:1或约500:1。
每个肽都可以通过用于形成抗体-药物辍合物的本领域通常已知的各种接头与生物相容性聚合物连接,例如加州圣地亚哥的BroadPharm公司提供的连接物。形成生物辍合键的方法在《生物辍合技术》,第3版,GregT.Hermanson著中有所描述。接头可以与胺、羰基、羧基和活化的酯反应,可以通过点击化学反应(有或没有铜)反应,或与硫醇反应。
例如,该肽可以直接共价连接至生物相容性聚合物而无需任何接头。或者,可以通过形成离子键,例如通过羧酸根和铵离子,将肽连接到生物相容性聚合物上。当接头用于将肽与生物相容性聚合物共价连接时,该接头的代表性接头包括酰胺或二硫化物,或由反应性基团形成,例如琥珀酸酐、琥珀酰亚胺、N-羟基琥珀酰亚胺、N-氯琥珀酰亚胺、N-溴代琥珀酰亚胺、马来酸酐、马来酰亚胺、乙内酰脲、邻苯二甲酰亚胺等。可用于本发明的接头很小,并且分子量通常为约100Da至约500Da,其包含两个官能团,所述两个官能团由马来酰亚胺和胺或酰肼组成。在一些实施方式中,所述肽经由硫化物键和分子量为约100Da至约500Da的接头共价连接至聚合物。在一些实施方式中,接头具有约100Da至约300Da的分子量。在一些实施方式中,接头包含琥珀酰亚胺。在一些实施方式中,使用N-β-马来酰亚胺基丙酸酰肼(BMPH)、N-ε-马来酰亚胺基己酸酰肼(EMCH)、N-氨基乙基马来酰亚胺、N-κ-马来酰亚胺基癸酸酰肼(KUMH)、酰肼-PEG2-马来酰亚胺、胺-PEG2-马来酰亚胺、酰肼-PEG3-马来酰亚胺或胺-PEG3-马来酰亚胺形成接头。
式I中的代表性连接基团Y包括但不限于:
在一些实施方式中,连接基团Y可以是N-ε-马来酰亚胺基己酸酰肼(EMCH):
可用于本发明的辍合物的接头也可以是短肽。柔性、半柔性、刚性肽接头可以作为抗炎肽序列的一部分包括在内。
与未辍合的肽相比,本发明的生物相容性聚合物多肽的辍合物可具有更长的扩散半衰期。例如,辍合物的扩散半衰期比肽的扩散半衰期长至少2倍,或比肽长3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、60、70、80、90或至少100倍。辍合物的扩散半衰期可比肽长约2至约100倍,或比肽长约2至约50倍、约10至约100倍、约25至约100倍、约50至约100倍。在一些实施方式中,辍合物的扩散半衰期比肽长至少约2倍。在一些实施方式中,辍合物的扩散半衰期比肽长约2至约100倍。
与未辍合的肽相比,本发明的辍合物还可具有更长的关节内半衰期。例如,辍合物的关节内半衰期比未辍合的肽长至少20%,或比未辍合的肽长至少50、75、100、150、200、250、300、350、400、450、500、600、700、800、900、1000或1000%。辍合物的关节内半衰期可以比未辍合的肽长约20%至约1000%、或约100%至约1000%、或约100%至约500%,或比未辍合的肽长约100%至约300%。在一些实施方式中,辍合物的关节内半衰期比肽长至少约20%。在一些实施方式中,辍合物的关节内半衰期比肽长约20%至约1000%。
在一些实施方式中,生物相容性聚合物具有约0.8MDa至约3MDa的分子量;每个肽的分子量为约5kDa至约50kDa。其中每个肽与聚合物共价连接,并且辍合物中肽与聚合物的摩尔比至少为约10:1。在一些实施方式中,生物相容性聚合物具有约0.8MDa至约2MDa的分子量;每个肽的分子量为约5kDa至约50kDa;其中每个肽与聚合物共价连接,并且辍合物中肽与聚合物的摩尔比至少为约10:1。在一些实施方式中,生物相容性聚合物具有约1MDa至约2MDa的分子量;每个肽的分子量为约5kDa至约50kDa;其中每个肽与聚合物共价连接,并且辍合物中肽与聚合物的摩尔比至少为约10:1。在一些实施方式中,生物相容性聚合物具有约1MDa至约2MDa的分子量;每个肽的分子量为约5kDa至约50kDa;其中每个肽与聚合物共价连接,并且辍合物中肽与聚合物的摩尔比至少为约20:1。在一些实施方式中,生物相容性聚合物具有约2MDa的分子量;每个肽的分子量为约5kDa至约50kDa;其中每个肽与聚合物共价连接,并且辍合物中肽与聚合物的摩尔比至少为约50:1。
在一些实施方式中,本发明提供了以下的辍合物:(抗TNFαVHH抗体-EMCH)13-HyA(200kDa)、(抗TNFαVHH抗体-EMCH)17-HyA(350kDa)、抗TNFαVHH抗体-EMCH)23-HyA(750kDa)、(抗TNFαVHH抗体-EMCH)46-HyA(850kDa)、(抗TNFαVHH抗体-EMCH)88-HyA(1350kDa)、(抗TNFαVHH抗体-EMCH)184-HyA(2000kDa)、(抗-(小鼠)TNFαVHH抗体-EMCH)273-HyA(2000kDa)、(抗-TNFαVHH抗体-EMCH)41-CMC(90kDa)、(抗TNFαVHH抗体-EMCH)37-CMC(250kDa)、(抗TNFαVHH抗体-EMCH)42-CMC(700kDa)、(抗TNFαVHH抗体-EMCH)5-CM壳聚糖(200kDa)、(抗TNFαVHH抗体-EMCH)13-HyA(200kDa)、(抗TNFα抗体)-EMCH)21-HyA(850kDa)、(抗TNFα亲和体-EMCH)22-CMC(700kDa)、(抗IL-1scFv抗体-EMCH)15-HyA(2000kDa)或(抗IL-1scFv抗体(EMCH)13-CMC(700kDa)。在一些实施方式中,本发明提供了以下的辍合物:(抗TNFαVHH抗体-EMCH)13-HyA(200kDa)、(抗TNFαVHH抗体-EMCH)17-HyA(350kDa)、抗TNFαVHH抗体-EMCH)23-HyA(750kDa)、(抗TNFαVHH抗体-EMCH)46-HyA(850kDa)、(抗TNFαVHH抗体-EMCH)88-HyA(1350kDa)、(抗TNFαVHH抗体-EMCH)184-HyA(2000kDa)、(抗-(小鼠)TNFαVHH抗体-EMCH)273-HyA(2000kDa)、(抗-TNFαVHH抗体-EMCH)37-CMC(250kDa)、(抗TNFαVHH抗体-EMCH)42-CMC(700kDa)、(抗TNFαVHH抗体-EMCH)5-CM壳聚糖(200kDa)、(抗TNFαVHH抗体-EMCH)13-HyA(200kDa)、(抗TNFα亲和体-EMCH)21-HyA(850kDa)、(抗TNFα亲和体-EMCH)22-CMC(700kDa)、(抗IL-1scFv抗体-EMCH)15-HyA(2000kDa)或(抗IL-1scFv抗体-EMCH)13-CMC(700kDa)。在一些实施方式中,本发明提供了以下的辍合物:(抗TNFαVHH抗体-EMCH)46-HyA(850kDa)、(抗TNFαVHH抗体-EMCH)88-HyA(1350kDa)、(抗TNFαVHH抗体-EMCH)184-HyA(2000kDa)、(抗(小鼠)TNFαVHH抗体-EMCH)273-HyA(2000kDa)、(抗TNFαaffibody-EMCH)21-HyA(850kDa)或(抗IL-1scFv抗体-EMCH)15-HyA(2000kDa)。在一些实施方式中,本发明提供了以下辍合物:(抗TNFαVHH抗体-EMCH)46-HyA(850kDa)、(抗TNFαVHH抗体-EMCH)88-HyA(1350kDa)、(抗TNFαVHH抗体-EMCH)184-HyA(2000kDa)、(抗-(小鼠)TNFαVHH抗体-EMCH)273-HyA(2000kDa)、(抗-TNFα亲和体-EMCH)21-HyA(850kDa)或(抗IL-1scFv抗体-EMCH)15-HyA(2000kDa)。
IV.药物组合物
在一些实施方式中,本发明提供了包含本发明的辍合物和药学上可接受的赋形剂的药物组合物。
A.制剂
为从本发明的辍合物制备药物组合物,药学上可接受的载体可以是固体或液体。固体形式的制剂包括粉剂、扁囊剂和可分散的颗粒。固体载体可以是一种或多种物质,它们也可以用作稀释剂、粘合剂、防腐剂、崩解剂或包囊材料。关于配制和给药技术的细节在科学和专利文献中有很好的描述,参见例如《雷明顿的医药科学》的最新版本,迈克出版公司,宾夕法尼亚伊斯顿(“雷明顿”)。
在粉剂中,载体是细碎的固体,其与细碎的活性成分混合。在片剂中,将活性成分与具有必要粘合性质的载体以合适的比例混合,并压制成所需的形状和大小。优选地,散剂和片剂包含5%或10%至70%的本发明的辍合物。
液体形式的制剂包括溶液、悬浮液和乳液,例如水或水/丙二醇溶液。对于肠胃外注射,可以将液体制剂配制在聚乙二醇水溶液中。
适用于口服的水溶液可通过将本发明的辍合物溶解于水中并根据需要添加合适的着色剂、调味剂、稳定剂和增稠剂来制备。适用于口服的水溶液可以通过将细碎的活性成分分散在具有粘性物质的水中,粘性物质例如天然或合成胶、树脂、甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、海藻酸钠、聚乙烯基吡咯烷酮、黄蓍胶和阿拉伯胶,以及天然磷脂等分散或润湿剂例如天然磷脂(如卵磷脂)、环氧烷与脂肪酸的缩合产物(如聚氧乙烯硬脂酸酯)、环氧乙烷与长链脂族醇的缩合产物(如十七亚乙基氧基鲸蜡醇)、环氧乙烷与脂肪酸和己糖醇(如聚氧乙烯山梨醇单油酸酯)的缩合产物、或环氧乙烷与脂肪酸和己糖酐的部分酯的缩合产物(如聚氧乙烯山梨醇单油酸酯)。水悬浮液还可以含有一种或多种防腐剂,如乙基或正丙基对羟基苯甲酸酯,一种或多种着色剂、一种或多种调味剂和一种或多种甜味剂,如蔗糖、阿斯巴甜或糖精。配方可以根据渗透压进行调整。
本发明还包括固体剂型,计划在使用前不久将其转变成用于口服的液体剂型。这种液体形式包括溶液、悬浮液和乳剂。除活性成分外,这些制剂还可能含有着色剂、风味剂、稳定剂、缓冲剂、人工和天然甜味剂、分散剂、增稠剂、增溶剂等。
油悬浮液可通过将本发明的辍合物悬置在植物油中来配制,例如花生油,橄榄油,芝麻油或椰子油;或在矿物油中配制油悬浮液,例如液体石蜡;或是这些的混合物。油悬浮液可以包含增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。通过添加甜味剂以提供可口的口服制剂,例如甘油、山梨糖醇或蔗糖。这些制剂可以通过添加抗氧化剂例如抗坏血酸来保存。作为可注射油状载体的示例,参见Minto,J.Pharmacol.Exp.Ther.281:93-102,1997。本发明的药物制剂也可以是水包油乳剂的形式。油相可以是如上所述的植物油或矿物油,或它们的混合物。合适的乳化剂包括天然树胶,例如阿拉伯树胶和黄蓍胶;天然磷脂,例如大豆卵磷脂;衍生自脂肪酸和己糖醇酐的酯或偏酯,例如脱水山梨醇单油酸酯;以及这些酯与环氧乙烷缩合的产物,如聚氧乙烯乙烯山梨醇单油酸酯。乳剂还可以包含甜味剂和调味剂,如在糖浆和酏剂的配方中。这类制剂还可以含有镇静剂、防腐剂或着色剂。
本发明的组合物还可以作为微球递送,以便在体内缓慢释放。例如,微球可以通过皮下注射含有药物的微球来调配给药,该药物在皮下缓慢释放(参见Rao,J.BiomaterSci.Polym.Ed.7:623-645,1995);作为可生物降解和可注射的凝胶制剂(参见,如GaoPharm.Res.12:857-863,1995);或作为口服微球(参见,如Eyles,J.Pharm.Pharmacol.49:669-674,1997)。透皮途径和皮内途径均可以持续递送数周或数月。
在另一个实施方式中,本发明的组合物可以配制用于肠胃外给药到体腔中,例如关节的关节内空间。用于给药的剂型通常包括溶解在药学上可接受的载体中的本发明组合物的溶液。在可接受的载体和溶剂中,可以采用水和林格氏溶液,一种等渗氯化钠。此外,无菌不挥发性油通常可作为溶剂或悬浮液使用。为此,可以使用任何温和的不挥发性油,包括合成的甘油单酯或甘油二酯。另外,脂肪酸如油酸同样可以用于注射剂的制备中。这些溶液是无菌的,并且通常没有不良物质。这些制剂可以通过常规的,众所周知的灭菌技术进行灭菌。制剂中可能含有药物上可接受的近似生理条件的辅助物质,如pH调节剂和缓冲剂、毒性调节剂,如醋酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。这些制剂中本发明组合物的浓度可以在很大范围内变化,并且将根据所选择的特定给药方式和患者的需要,主要根据体液量、粘度、体重等来选择。对于静脉注射,制剂可以是无菌可注射制剂,例如无菌可注射水性或油质悬浮液。该悬浮液可以根据已知工艺配置,使用合适的分散剂或湿润剂和悬浮剂。无菌注射制剂也可以是非毒性非肠道可接受的稀释剂或溶剂配制的无菌注射溶液或悬浮液,例如1,3-丁二醇的溶液。
在另一个实施方式中,本发明的组合物的制剂可以通过使用与细胞膜融合或内吞的脂质体来递送,通过利用附着在脂质体上的配体,或直接附着在寡核苷酸上,寡核苷酸辍合到细胞表面膜蛋白受体上,导致内吞作用。通过使用脂质体,特别是脂质体表面携带靶细胞特异性配体或以其他方式优先定向于特定器官时,可以将本发明的组合物集中递送到体内的靶细胞中(参见,例如Al-Muhammed,微囊法杂志13:293-306,1996;生物技术现状述评6:698-708,1995;Ostro,美国医院药学杂志46:1576-1587,1989)。
基于脂质的药物递送系统包括脂质溶液、脂质乳剂、脂质分散体、自乳化药物输送系统(SEDDS)和自微乳化药物输送系统(SMEDDS)。特别地,SEDDS和SMEDDS是脂质、表面活性剂和助表面活性剂的各向同性混合物,它们可以自发地分散在水性介质中,形成细乳液(SEDDS)或微乳液(SMEDDS)。可用于本发明制剂的脂质包括任何天然或合成脂质,包括但不限于芝麻籽油、橄榄油、蓖麻油、花生油、脂肪酸酯、甘油酯、 和
B.施用
本发明的辍合物和组合物可以通过任何合适的方式递送,包括口服、肠外和局部方法。在一些实施方式中,递送方法是关节内的。
药物制剂优选为单位剂型。以这种形式,将制剂细分为包含适当量的本发明的辍合物和组合物的单位剂量。该单位剂型可以是包装的制剂,该包装包含离散量的制剂,如小瓶或安瓿中的包装片剂、胶囊和粉末。
本发明的辍合物和组合物可以与其他试剂共同施用。共同施用包括在另一种药物的0.5、1、2、4、6、8、10、12、16、20或24小时内施用本发明的辍合物或组合物。共同施用还包括同时,近似同时(例如,在彼此之间约1、5、10、15、20或30分钟内)或以任何顺序依次施用。此外,本发明的辍合物和组合物可以每天一次给药,或者每天两次,三次或更多次给药,以便提供每天优选的剂量水平。
在一些实施方式中,共同给药可以通过共同制剂来实现,即,制备包括本发明的辍合物和组合物以及任何其他试剂的单一药物组合物。另外,各种组分可以分开配制。
本发明的辍合物和组合物以及任何其他试剂可以任何合适的量存在,并且可以取决于各种因素,包括但不限于:受试者的体重和年龄、疾病状态等。剂量范围包括约0.1mg至约10,000mg、或约1mg至约1000mg、或约10mg至约750mg、或约25mg至约500mg、或约50mg至约250mg。合适的剂量还包括约1mg,5、10、20、30、40、50、60、70、80、90、100、200、300、400、500、600、700、800、900或1000mg。该组合物还可包含其他相容的治疗剂。本文所述的辍合物可以彼此联用,也可以与对调节糖皮质激素受体有用的其他已知活性物质联用,或者与可能不单独有效但有助于活性物质功效的辅助剂联用。
V.方法
本发明提供了一种使用本发明的肽-聚合物辍合治疗关节疾病或病症的方法。在一些实施方式中,本发明提供了一种治疗关节中关节疾病或病症的方法,该方法包括将有效量的辍合物注射到关节中,所述辍合物包括:分子量为约0.1MDa至约3MDa的生物相容性聚合物;以及多个肽,其中所述肽的分子量为约5kDa至约150kDa;其中每个肽与聚合物共价连接,并且辍合物中肽与聚合物的摩尔比为至少约5:1。在一些实施方式中,本发明提供了一种治疗关节内疾病或病症的方法,该方法包括将有效量的辍合物注射到关节中,所述辍合物包括:分子量为约0.1MDa至约2MDa的生物相容性聚合物;以及多个肽,其中所述肽的分子量为约5kDa至约100kDa;其中每个肽与聚合物共价连接,聚合物的分子量为每个肽约5kDa至约50kDa,并且辍合物中肽与聚合物的摩尔比为至少约5∶1。
本发明还提供了使用本发明的辍合物治疗关节组织的疾病和病症的方法。关节组织疾病和失调的例子包括但不限于:类风湿关节炎、磨损相关性骨关节炎、年龄相关性骨关节炎、创伤后骨关节炎、银屑病性关节炎、无菌性植入物松动、关节积液、强直性脊柱炎、粘液囊炎、痛风、反应性、关节炎、滑膜炎和缺血性坏死。在一些实施方式中,该疾病或病症是类风湿性关节炎、磨损相关的骨关节炎、年龄相关的骨关节炎、创伤后骨关节炎、银屑病关节炎以及无菌性植入物松动、关节积液、强直性脊柱炎、粘液囊炎、痛风、反应性关节炎、滑膜炎或缺血性坏死。
许多多肽被用作减弱免疫细胞功能的药物,在治疗许多关节疾病中具有实质性用途。关节组织特别容易受到伤害和疾病的侵害,因为典型的细胞对这些攻击的反应,即炎症介质的上调,也是促进关节软骨分解代谢和底层骨组织吸收的信号。关节表面的退化促进了关节组织损伤的恶化,并进一步上调炎症介质。随着时间的流逝,这些机制会产生前馈回路,从而导致对关节组织的累积损伤。
人体或动物体的任何关节都可以使用本发明的方法和辍合物进行治疗。代表性关节包括但不限于:纤维关节、软骨关节、滑膜关节、小关节、关节联关节、双关节和动关节。关节可以是有两个关节面的简单关节,有三个或三个以上关节面的复合关节,或有两个或两个以上关节面和一个膝关节或半月板关节面的复杂关节。可以使用本发明的辍合物和方法治疗的解剖学关节包括但不限于:手关节包括手指、手肘关节,腕关节,肩膀关节,关节胸骨、锁骨椎关节,下巴和头骨关节,骨盆和髋关节,膝关节、踝关节和足关节包括脚趾(包括脚趾)。关节又可分为平面关节、球窝关节、铰链关节、枢轴关节、髁突关节和鞍状关节。本发明的辍合物和方法可用于治疗关节的组织,包括但不限于结缔组织、软骨、关节面、滑膜腔、半月板和其他组织。
设计用来减弱免疫细胞功能的药物的例子包括可以干扰肿瘤坏死因子-α和IL-1β,IL-6或干扰素-γ的抗体。其他的例子包括T细胞和B细胞选择性抗体抑制剂的功能。这些抗体可以是单克隆IgG抗体、IgG抗体片段、单链scFv抗体、单域重链VHH抗体或工程化的抗体样支架,例如安耐汀(adnectin)、亲和体、安替开林(anticalin)、DARPins和工程化的Kunitz型抑制剂。其他例子还包括免疫调节细胞因子的受体诱饵,例如肿瘤坏死因子-α和IL-1β,IL-6或干扰素-γ。
使用上述抗炎药的一种常见副作用是较高的感染风险。由于它们会减弱人体的免疫反应,因此免疫系统将无法抵抗细菌、病毒和寄生虫。因此,需要仔细权衡全身使用这些药物的益处与全身免疫抑制相关的风险。对于整个人体都受到高免疫性疾病影响的疾病,例如类风湿关节炎,应适当使用全身免疫衰减药物。然而,对于只影响一个或有限数量的关节的情况,全身感染的风险往往不值得全身使用这些药物。
作为替代,关节内(IA)施用免疫调节药物已被提议,以预防或抑制与骨关节炎相关的炎症的长期影响。但是,这些药物会迅速从关节间隙中清除,并且在IA给药后不能提供足够的治疗时间。IA注射后,滑膜中抗炎蛋白的半衰期很短(<1.5小时)。这从临床研究中可以明显看出,在该研究中,通过IA注射剂已在人类中针对多种关节疾病施用了炎症抑制剂,包括英夫利昔单抗(infliximab)和依那西普(etanercept)。这些研究中的一些报道了关节炎症的显著减少,但是公认成功的结果需要频繁(例如每周一次)给药。因此,使用现有药物进行IA抗炎治疗将受到成本高和频繁给药不便的限制。显然,在滑膜液中扩展抗炎药物生物活性的方法是必要的,以使这种治疗方法能够治疗关节疾病。
与关节疾病相关的主要症状是疼痛、积液、活动范围受限和关节解剖的病理重塑。治疗关节疾病的疗效可能包括通过广义评估(如视觉评估评分)来衡量的疼痛减轻。疗效也可以根据针对特定关节疾病的改进评分来确定,如骨关节炎的WOMAC评分、类风湿关节炎的ACR20评分、银屑病关节炎的生活质量评分或强直性脊柱炎的SASSS评分。疗效也可以通过功能输出来衡量,如无疼痛行走距离的增加或关节活动范围的增加。也可以根据显示正常关节解剖恢复的放射学证据来检测疗效。
上述讨论的辍合物可以以任何合适的频率或数量施用。将辍合物注射到关节内的时间不超过每月一次。在一些实施例中,该辍合物大约每月注射一次到每6个月注射一次到关节内。在一些实施例中,将辍合物每2个月一次或每3个月一次注射到关节中。
A.骨关节炎
2015年,估计有775万美国人经历了可能与已知的关节损伤相关的骨关节炎(OA)症状。创伤后骨性关节炎(PTOA)至少占所有骨性关节炎病例的15%,尽管公认为许多其他骨性关节炎的诊断也可能与先前的关节创伤有关。由于缺乏疾病改良疗法,关节置换手术通常是消除相关不适和恢复活动能力的唯一治疗选择。但是,经常在年轻患者中诊断出PTOA,对于这些患者而言,关节置换术不是一个可行的选择。总体而言,每年治疗这些PTOA患者的费用超过40亿美元。
短期抑制与损伤有关的炎症会限制PTOA的长期症状。许多类型的关节损伤都与PTOA相关,包括脱位、韧带撕裂、半月板损伤和关节内骨折。尽管最初的损伤可能是急性的,但损伤足以引发一系列炎症介质。所导致的慢性全关节炎症可促进关节软骨的分解代谢,导致进一步的组织损伤,随着时间的推移而累积,并表现为PTOA。TNF和αIL-1在介导β关节炎症中具有众所周知的作用。这些细胞因子相互作用以促进软骨的破坏,这通过下调软骨基质成分的表达和上调基质金属蛋白酶(MMP)的表达而发生。TNFα还刺激破骨细胞募集,并在炎性环境中诱导成骨成骨细胞的凋亡,这有助于关节软骨组织的侵蚀。TNFα和IL-1β是缓解关节损伤的炎症反应中引人注目的靶标。在关节环境中抑制这些关键的急性炎性细胞因子被认为可用于早期干预以阻止PTOA的进展。
B.由于关节内微粒的免疫反应引起的炎症
关节的关节表面之间发生的磨损会产生微米级的颗粒,从而导致关节发炎和骨溶解。磨损颗粒可能是由于内生表面之间的磨损而产生的,例如骨化的软骨病变、骨赘(骨刺)或软骨下骨病变。这种类型的磨损颗粒的产生经常发生在OA的后期,从而导致严重的关节疼痛和无法活动。这种额外的炎症反应加快了OA中关节组织变性的速度。
磨损颗粒也可能在人造关节的表面之间形成。2015年,超过700万美国人生活在植入人工关节的状态中。由于设备周围骨骼的骨溶解,这些患者中将近250,000名最终将需要进行翻修手术,最终导致设备松动和故障。
磨损相关的炎症源于异物对关节表面掉落的惰性微粒的反应。滑膜内的巨噬细胞很容易识别磨损微粒为异物,释放促炎因子,将其他活跃的免疫细胞招募到滑膜内,刺激破骨细胞扩张,同时抑制骨形成。因此,持续的炎症会引发前传循环,软骨变性和骨溶解导致关节表面更多的磨损,更多的运动和物理压力,从而产生更多的颗粒。
在一些实施方式中,该肽调节免疫细胞功能的活性。在一些实施方式中,该肽抑制肿瘤坏死因子-α,白介素-1β,白介素-6或干扰素-γ。在一些实施方式中,该肽抑制肿瘤坏死因子-α。
肿瘤坏死因子α(TNF)是控制异物反应的引人注目的靶标。TNF在α介导关节炎症中具有众所周知的作用。TNFα还刺激破骨细胞募集,诱导成骨细胞的成骨细胞在炎症环境中凋亡,导致软骨下骨的骨质溶解。尽管全身性α抗TNF相关的风险在局部条件下通常不被接受,但已证明使用全身性受体拮抗剂(依那西普)(etanercept)对TNFα的抑制作用可减少小鼠中的磨损颗粒诱导的骨吸收。作为替代方案,已经提出了IA抗TNFα治疗来预防或抑制对关节内磨损颗粒的溶骨反应。
在一些实施方式中,该肽是单克隆IgG抗体、IgG抗体片段、单链可变区抗体、单域重链抗体、安耐汀(adnectin)、亲和体、安替开林(anticalin)、DARPins和Kunitz型抑制剂受体诱饵。
本发明的方法包括肽-聚合物辍合物,其包含分子量为约0.1MDa至约2MDa的生物相容性聚合物;以及分子量分别为约5kDa至约100kDa的多个肽,其中每个肽与聚合物共价连接,其中每个肽对应约50kDa至约5kDa的聚合物,其中肽与聚合物的摩尔比为至少5∶1。
在一些实施方式中,辍合物包含具有CDR为SEQ ID NO:3至SEQ ID NO:5的肽:
DHSGYTYTIG(SEQ ID NO:3),
ARIYWSSGNTYYADSVKG(SEQ ID NO:4),和
RDGIPT(SEQ ID NO:5)。
在一些实施方式中,辍合物包含具有氨基酸序列为SEQ ID NO:1的肽:QVQLQESGGGLVQPGGSLRLSCAASGRTFSDHSGYTYTIGWFRQAPGKEREFVARIYWSSGNTYYADSVKGRFAISRDIAKNTVDLTMNNLEPEDTAVYYCAARDGIPTSRSVESYNYWGQGTQVTVSS(SEQ ID NO:1)。
在一些实施方式中,辍合物包含具有氨基酸序列为SEQ ID NO:2的肽:SNAQVQLQESGGGLVQPGGSLRLSCAASGRTFSDHSGYTYTIGWFRQAPGKEREFVARIYWSSGNTYYADSVKGRFAISRDIAKNTVDLTMNNLEPEDTAVYYCAARDGIPTSRSVESYNYWGQGTQVTVSSSPSTPPTPSPSTPPGGC(SEQ ID NO:2)。
本发明的辍合物被适当定位以减轻在关节附近发生的炎症,从而抑制随后的软骨变性和骨溶解。这些辍合物被设计成与关节内的滑液大分子相匹配的生物物理属性。另外,辍合多个拷贝或生物活性多肽足以通过使其靶标进行多价相互作用来增加其效力。因此,本发明非常适合于实现将长效药物局部施用至关节以治疗各种疾病的方法。
生物辍合药物的一个示例目标市场是约25%的患者,他们在关节损伤后出现慢性炎症和积液,因此有发展为PTOA的风险。目前,这些患者的选择仅限于全身镇痛和局部糖皮质激素治疗。如果不能解决长期的炎症阶段,就会导致关节软骨的分解代谢,并随着时间的推移导致进一步的损伤。基于抗炎生物辍合物的治疗,每三个月(甚至更少)一次给药,可以减轻长期关节炎症的影响,从而减轻疼痛,推迟或避免昂贵的手术。这些好处可能会超过重复注射IA(每年多达4次)的不利影响,其中可能包括感染的风险,给患者带来的不便以及手术成本。
生物辍合物药物的另一个示例目标市场是由于钙化软骨病变,骨刺或软骨下骨病变的发展而遭受慢性炎症和疼痛的患者。尽管手术修复可以消除疼痛的急性病因,但现有的炎症、由于手术引起的炎症以及其他磨损颗粒的炎症都会加速关节损伤和变性。这些患者的长期选择目前仅限于全身镇痛和局部糖皮质激素治疗。如果不能解决长期的炎症阶段,可能导致关节表面衰竭,这就需要进行关节置换手术以使患者恢复体力活动。基于抗炎生物辍合物的治疗方法设计为每三个月(甚至更少)一次给药,可以减轻长期关节炎症的影响,从而减轻疼痛,推迟或避免昂贵的手术。这些好处可能会超过重复注射IA(每年多达4次)的不利影响,其中可能包括感染的风险,给患者带来的不便以及手术成本。
生物辍合药物的另一个示例目标市场是约25%的具有人工关节的患者,在关节置换后出现疼痛和积液,但没有显示出种植体周围感染的证据来解释这些症状。目前,这些患者的选择仅限于镇痛和临床监测,直到随后的骨溶解导致器械故障为止。基于抗炎生物辍合物的治疗,设计为每三个月或更低给药频率,可以减轻对磨损颗粒的反应,从而减轻疼痛并延迟或避免进行昂贵的修复手术。这些好处可能会超过长期IA注射(每年多达4次)的不利影响,其中可能包括感染的风险,给患者带来的不便以及手术费用。
多价抗体辍合物能够很好地改善关节损伤或暴露于磨损颗粒而引起的炎症,并抑制随后的分解代谢组织损伤。除了表现出高效力外,还可对辍合物进行改造,使其具有特定的大分子特性,并将其保留在关节内。通过将抗炎肽辍合至足够大从而能被滑膜保留的HyA,与等效的未辍合抗体相比,辍合抗体的生物活性半衰期可以显著延长。
VI.实施例
实施例1辍合物的制备
一般方法。按照先前描述的方法制备抗炎生物辍合物(PMID:28679037)。按制造商所述,获得了分子量范围从150kDa–2.0MDa的聚合物,本文以它们的重均MW指代。将聚合物放入含有0.1-1M适当缓冲液的水溶液中以维持pH在5.5-8.5的范围内,所用的缓冲液例如MES、磷酸盐缓冲液、His缓冲液、MOPS、葡萄糖醛酸、柠檬酸盐、乙酸盐HEPES。
将以下一种或多种赋形剂添加到溶液中,以促使聚合物溶解:50-500mMNaCl、0.0001-0.1%吐温-20、0.0001-0.1%吐温-80、1-10%蔗糖、1-10%蔗糖、1-10%海藻糖、1-10%、1-10%甘露醇、1-10%的山梨糖醇、1-10%的甘油等。使用以下一种或多种搅拌方法促使它们进入溶液:振动、轨道摇动、旋转或搅拌(例如,使用搅拌棒或立式搅拌器)。
通过碳二亚胺取代聚合物上的羧酸侧基团,以生产抗炎肽的辍合柄。对于每3毫克的聚合物,向溶液中添加以下物质:1-10mg/mL的1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)以下之一:0.25-2.5mg/mLN-ε-马来酰亚胺基己酸酰肼(EMCH)、0.25-2.5mg/mLBMPH、0.25-2.5mg/mL酰肼-PEG2-马来酰亚胺或0.25-2.5mg/mL胺-PEG2-马来酰亚胺。添加以下物质之一以促进碳二亚胺反应:0.1-3mg/mL磺基-NHS、0.1-3mg/mL Oxyma或0.01-0.1mg/mLHOBt。使溶液在4℃或环境温度下反应2小时。通过50kDa MWCO膜对所列缓冲溶液之一进行透析,以清除未反应的辍合反应(物)。4小时后两次更换透析缓冲液,然后24小时后更换一次。该反应的产物是以0.5-5%的可用羧酸反应基团添加马来酰亚胺反应基团生成的聚合物。
然后使马来酰亚胺活化的聚合物与抗炎肽反应。抑制炎症的可接受靶标和肽部分在说明书的其他地方列出。对肽进行了改造,使其包括用于辍合的C端或N端的半胱氨酸。可作为抗炎肽序列的一部分包括柔性、半柔性、刚性肽接头。还可以在抗炎肽序列中添加其他肽,以促进肽纯化,如HIS6、FLAG或链霉亲和素,这些肽可能在辍合前裂解,也可能不裂解。使用合适的重组表达系统这些肽是使用合适的重组表达系统产生的,例如大肠杆菌,酵母,CHO细胞,烟叶等。
为了获得肽在一定价态范围内辍合的抗炎生物辍合物,将固定浓度的肽与聚合物以各种确定的进料比在PBS中混合,并使其在4℃或环境温度下反应4小时。在辍合反应过程中,增加以下一种或多种方法以提高反应效率:0.5-5mMTCEP可最大程度地减少肽之间的二硫键和/或0.5-5mM EDTA可以最大程度地减少游离硫醇的氧化。通过以下一种或多种方法从肽-聚合物辍合物中除去未反应的肽:用50-100kDa MWCO对上述缓冲液之一透析,在4℃透析两次,24小时一次;对上述缓冲液之一进行切向流过滤,使用尺寸排阻柱进行FPLC抛光,使用亲和层析柱进行FPLC抛光,亲和层析柱设计用于结合辍合物的聚合物组分,或乙醇沉淀辍合物。
表1中描述的所有示例性辍合物的制备通过以下方法合成(图1)。首先,在MES缓冲液(0.1M,pH 5.7)中制备各生物聚合物的4mg/mL溶液,在室温旋转(~5RPM)搅拌溶液24小时,以确保聚合物充分溶解。对于每4毫克聚合物,向溶液中添加以下物质:8.8毫克/毫升的1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)、0.8毫克/毫升的N-ε-马来酰亚胺基己酸酰肼(EMCH)和0.04毫克/毫升的HOBt。使溶液在室温下通过旋转(~5RPM)搅拌,反应2小时。使用50kDa MWCO膜在以下各种缓冲溶液中依次进行渗析,以去除未反应的辍合试剂:首先,加入含50mM甘氨酸的磷酸盐缓冲盐水(pH 6.5)4小时,其次加入磷酸盐缓冲盐水(pH6.5)过夜,第三,加入含10%甘油的磷酸盐缓冲盐水(pH 6.5)4小时。向EMCH活化的聚合物的每种溶液中,以60:1的肽:聚合物的摩尔进料比添加肽,将吐温-20添加至0.01%的最终浓度。溶液在环境温度下通过旋转(~5RPM)搅拌,反应2小时。通过使用100kDa MWCO膜依次对以下每种缓冲液进行透析来去除未反应的肽:首先是含0.01%吐温-20的磷酸盐缓冲盐水(pH 7),4小时,然后是含0.01%吐温-20的磷酸盐缓冲盐水(pH7),过夜,和含0.01%吐温-20的磷酸盐缓冲盐水(pH 7),4小时。
实施例2辍合物的表征
通过多种方法来评估在公开的治疗方法中适合于患有炎性关节疾病或病症的个人的物质组成。使用标准的蛋白质浓度方法,例如BCA,Bradford和/或A280处的UV吸收,确定辍合反应中肽含量的浓度。使用A204处的UV吸收来确定辍合反应中聚合物含量的浓度。聚合物含量的浓度也可以通过用硫酸消化,然后与苯酚温育来测定,得到的产物可以通过比色分析法进行分析,并与标准曲线进行比较。通过酶或酸的消化使聚合物组分完全解聚后,肽和聚合物的浓度也可以通过质谱分析法分析。通过浓度测量确定的聚合物与肽的摩尔比,用于估计每种辍合物的化合价。
通过在还原和非还原条件下在SDS-PAGE凝胶上电泳反应产物,可以证实肽与聚合物之间的共价化学辍合。这些方法足以确定辍合反应的产物是否包含任何未辍合的肽或在不稳定的、脱靶反应位点与聚合物反应的肽。可以使用考马斯蓝染色剂或更高分辨率的SYPRO红宝石色染色剂对凝胶进行染色。辍合的蛋白质将保留在上样孔的顶部附近,而未辍合的或不稳定辍合的肽将以所预期分子量的通过凝胶。通过这种方法,可以使未辍合的肽的进行粗略的近似,将其降至辍合反应产物中检测到的肽总浓度的0.1%左右。或者,也可以将辍合反应产物通过尺寸排除柱(SEC),使用高效液相色谱分离和量化未辍合肽中的辍合肽。这种方法还将提供对肽-聚合物辍合物的大小的粗略估计
使用光散射方法来测定肽-聚合物辍合物的大小。例如,在通过SEC分离之后对辍合物使用静态多角度激光散射(MALLS)方法来确定肽-聚合物辍合物的数量和重均分子量。此外,通过使用直线紫外检测器和差示折光计测量尺寸分离的共轭物的吸收折射率,可以估计由肽或聚合物组成的共轭物的比例。因此,SEC-MALLS分析可以提供对肽化合价的独立估计(即,每个聚合物的肽比例),以及对辍合聚合物的最终数均和重均分子量的估计。SEC-MALLS分析还将得出辍合物的平均回转半径(Rg)和Rg分布。采用动态光散射估计辍合物的平均流体动力学半径(Rh)和Rh的分布。
表1辍合物
为了验证每个样品中的肽都与生物聚合物主链共价辍合,辍合反应的产物通过SDS-PAGE(Mini Protean System,伯乐公司)进行分析,使用12%的丙烯酰胺凝胶在还原条件下,添加2.5%的巯基乙醇。由于非共价键的存在,这些条件能够分离肽之间的相互作用。使用SYPRO红宝石染料(伯乐公司)目测观察凝胶中的肽。如基于肽参考梯所预期的,未辍合的肽迁移通过凝胶,而每种生物辍合物的主蛋白带太大而无法进入分离凝胶。在生物辍合物泳道中仅出现痕量的未辍合肽(每个样品少于总肽的2%)。因此,肽被共价辍合到生物聚合物的主链上。
肽分子量(图3A),HyA MW(图3B),体积排阻色谱(图3C),采用所建立的尺寸排阻色谱多角度光散射方法测量旋转半径(Rg,z)(SEC-MALS;Bioconjug Chem.2012;23(9):1794)。一种分支分析方法被用来假设蛋白质从线性生物聚合物中分支出来,以更准确地计算HyAMW范围内的蛋白质化合价的分布(生物大分子.2016;17(10):3162)。基于先前的实验,经验数据可用于预测实现目标辍合价的必要进料比。
实施例3抗炎生物缀合物的生物活性
以下一种或多种方法用于测量蛋白质-聚合物辍合物的生物活性。作为一个例子,生物层干涉法(BLI;ForteBio Octet Red)用于确定每种肽和肽-聚合物辍合物与其靶标的辍合亲和力。在该测定中,将肽靶标吸附到玻璃BLI探针上。最常见的靶标为已与生物素辍合或表达含生物素的融合肽,可将其吸附到BLI探针上,该探针用共价辍合的链霉亲和素表面层对其进行预处理。然后将吸附有靶标的探针置于已知浓度的肽或肽-聚合物辍合物溶液中。然后使激光沿着BLI探针的长度方向通过,在肽或辍合物与探针尖端的靶标辍合而产生的激光干涉可直接与已辍合的肽或辍合物的质量相关。随时间的干涉数据可用于计算k-on辍合动力学。然后,通过将探针放置在不包含任何肽或辍合物的溶液中,激光干涉将逆转,其动力学可用于确定k-off。因此,该BLI方法能够测量每种肽和辍合物与其靶标的辍合亲和力(kD)。
抗炎抗体的多价呈递足以增强效力。作为一个例子,抗-TNFα蛋白用对人TNFα有反应的单域(VHH)骆驼抗体的公开序列生成(IC50=20nM,该序列与现有的TNF抑制剂相当(例如英夫利昔单抗(infliximab):IC50=12nM;Ann Rheum Dis.2010;69(2):443)。将这些抗体被辍合到HyA上,在不同的MWHyA主链(215和860kDa)上产生抗TNF生物缀合物,然后使用生物层干涉仪(BLI;ForteBio Octet Red)测定其生物活性。通过将TNFα以固定浓度吸附到探针上,在一系列抗体/辍合物浓度下,测量抗TNFα抗体或抗TNF生物缀合物的结合亲和力(图4A)。在抗TNFα与任一MW HyA主链多价辍合后,与未辍合抗体相比,抗TNF生物辍合物对结合TNFα表现出更高的效力。表2提供了其他生物活性数据。
表2生物活性数据
备选地,竞争性ELISA测定法被用于验证每种肽和肽-聚合物辍合物对其靶标的辍合亲和力(图4B)。对于该测定,使用了夹心ELISA系统,该系统设计用于以低检测限检测肽靶标。在开始测定之前,将每种肽或辍合物在一定浓度范围内(例如50-0.005ng/mL)与目标肽在固定浓度(例如0.5ng/mL)下孵育。已被抗炎肽或辍合物辍合的靶标肽不能夹在ELISA抗体中间被ELISA检测,因此该方法可以独立验证肽段和辍合物的生物活性,也可以比较肽段和辍合物的相对结合活性。
最后,抗炎肽和肽-聚合物辍合物的生物活性可通过细胞的药理测定法进行定量。例如,基于L929成纤维细胞的细胞存活测定可用于测试抗炎肽的生物活性,该抗炎肽通过阻断TNFα的单一活性而发挥作用(图4C)。对于该测定,将细胞以固定浓度(50ng/mL)的TNFα、和TNFα肽抑制剂或TNFα肽-聚合物辍合抑制剂在一定范围的肽浓度(例如500-0.05ng/mL)中处理,然后检测24-72小时后的细胞存活率。检测细胞存活的方法可以包括细胞凋亡的标准检测方法,例如TUNEL、放线菌素D、半胱天冬酶检测等。细胞存活还可以通过比较暴露于不同浓度TNFα的抑制剂的细胞群体的相对生长速率来检测。每种处理的IC50可以通过将数据拟合为4-参数模型拟合来计算(图4D)。
作为第二个例子,可采用基于D10淋巴细胞的细胞增殖试验来测试阻断IL-1β的信号传导活性发挥作用的抗炎肽的生物活性。对于该实验,细胞通过固定浓度(1ngβ/mL)的IL-1β、和IL-1β肽抑制剂或IL-1β肽-聚合物辍合抑制剂在一定范围的肽浓度范围内(例如100-0.01ng/mL)处理,然后检测24-72小时后的细胞增殖率(图2B)。检测细胞存活的方法可以包括用于细胞定量的标准测定法,例如CyQuant、细胞计数或流式细胞术。
实施例4抗炎生物缀合物在有孔膜上的扩散
多价辍合物在有孔膜上的扩散速度较慢。滑液包含高分子量大分子,其被糖胺聚糖分子的膜保留在关节空间内。该膜包含开孔,该开孔允许小分子和蛋白质从关节间隙中通过,但保留了大分子。
使用台式测定法测量肽-聚合物辍合物通过有孔膜的速率。在这些实验中,获得体积约为1mL的圆柱室,由平均直径约为10-100nm的穿孔膜构成。空腔被已知浓度的抗炎肽或蛋白质聚合物的溶液充满,并将膜置于至少有200mL缓冲液的容器中。用搅拌棒搅动容器,以促进肽或辍合物跨膜运输。每隔24小时(最多7天)从容器内的溶液中取样,并使用典型的蛋白质定量方法(例如BCA、Bradford或A260处的UV吸收)测量肽浓度。腔室内的肽质量下降的速率与一阶段指数衰减一致。因此,使用肽浓度来估计每种肽或辍合物在腔室内的半衰期。
将多价抗TNFa VHH生物辍合物(40VHH:1860kDa HyA)或未辍合的抗TNFa VHH溶液置于如上所述的由膜组成的小室中,然后随时间测量VHH辍合物和未辍合的VHH的浓度扩散穿过该屏障的变化(图5A)。与未辍合的蛋白质相比,多价辍合物在膜上的扩散要慢得多。此外,辍合物扩散的速率取决于孔径(图5B)。
实施例5抗炎生物辍合物的药代动力学
使用众所周知的大鼠模型评估关节中蛋白质的清除率,以测量抗TNF生物缀合物的IA半衰期(类风湿性关节炎.1999;42(10):2094)。对于该测定,将大鼠麻醉并准备将其后肢膝盖进行无菌注射。使用30号的针头,通过每个膝关节的滑膜进行注射,然后将40μL无菌缓冲液注射到滑液中。在每个右膝中,注射液还包含抗炎肽或与其总肽浓度相同的抗炎肽。通常,用于该实验的肽通过常规的肽标记方法被近红外荧光团(例如Alexa Fluor 750)标记。在注射后长达10天的各个时间点,使用体内成像系统(例如Perkin Elmer IVIS光谱)对大鼠成像,以确定膝盖处的荧光信号强度(例如平均辐射效率)。将每个左膝盖用作对侧成像对照。使用体内成像系统可以高灵敏度地在大鼠膝盖中检测近红外报道分子,这能使关节中的蛋白质含量检测降至皮克级。IA注射后,使用已建立的用于光学体内成像的指数衰减计算来确定每种治疗的半衰期(药物研究.2013;30(1):257)。因此,肽浓度用于估计给药后关节内每种肽或辍合物的关节内半衰期。在实验结束时收集滑液,通过质谱法进行蛋白质组学分析,以测量膝关节中肽的最终浓度。给药前,按照制造商的实验方法,用AlexaFluor 750近红外探针(赛默飞世尔公司)标记肽。简而言之,将肽与磺基(Sulfo)-Cy7-NHS酯以探针:肽比为2:1的比例混合。使探针与肽在室温下反应1小时,然后通过向每10份反应溶液中加入1份1.5M Tris淬灭反应。使用NAP-10脱盐柱纯化肽,并用pH 7.0的PBS洗脱。
所有组按照IA的注射方法,在每个右膝盖接受相同总剂量的抗TNFα抗体(40-μL的250μg/mL溶液:总计10μg)。在临床研究中用于改善关节炎症的超适应症评估时,此IA抗TNFα抗体浓度(~80μg/mL或4.5μM)与抗TNF剂(如英夫利昔单抗(infliximab)和依那西普(etanercept))的初始IA浓度相当(通常为1.5-17.5μM)。
在一组实验中(图6A),将抗TNFαVHH抗体(n=4)的关节内半衰期与抗炎生物辍合物进行比较,抗炎生物辍合物由与HyA辍合的抗TNFαVHH制备,HyA分子量为350kDa(n=3)、750kDa(n=3)、850kDa(n=3)和2000kDa(n=4)。使用850kDa和2000kDa HyA制备的生物辍合物的半衰期显著长于未辍合的VHH。在独立的实验中(图6B)中,将抗TNFαVHH抗体(n=4)的关节内半衰期与抗炎生物辍合物(n=3)的关节内半衰期进行比较,该抗炎生物辍合物由与700kDa CMC辍合的抗TNFαVHH制备。该生物辍合物的半衰期与未辍合的VHH的半衰期没有显著差异。在另一个独立的实验中,将抗TNFαVHH抗体(n=3)的关节内半衰期与抗炎生物辍合物(n=3)的半衰期进行比较,该生物辍合物由与850kDa HyA辍合的抗TNFαVHH制备。该生物辍合物的半衰期明显长于未辍合的VHH。
实施例6抗炎生物缀合物给药方案的药理模型
开发了一种模型,以预测维持有效治疗剂量所需的抗炎肽的重新给药频率。该模型基于一种模型,最初开发该模型是为了在给定的局部组织半衰期不同且目标辍合亲和力不同的情况下,预测眼睛中抗VEGF药物的需求。在该模型中做出的关键假设是,该药物经过一阶段指数衰减后从靶组织中清除,这已在关节内给药后用于本发明的抗炎聚合物-肽辍合物中得到了证明(参见实施例3)。使用临床研究的结果(PMID:20642840,17216015,18415775),确定了一种抗炎肽的重新给药频率,以在人体关节中提供有效的响应(每1-2周注射一次)。
鉴于给定肽药物在关节内施用后的关节内半衰期的估计,可以相对于施药浓度预测治疗浓度。为了预测抗炎肽等效剂量(mg/关节)的给药频率,摩尔浓度的差异必须考虑到肽与临床研究中所用药物之间的大小差异(例如,VHH抗体的摩尔剂量是传统IgG抗体药物等效质量的12倍)。此外,如果肽的结合亲和力相当于模型中用作参考的市售抗炎IgG,则肽-聚合物辍合物的效力将比市售IgG高10倍。在模型中,这相当于初始摩尔浓度比对照药的剂量高10倍。综合这些因素,可以估计基于肽-聚合物辍合物的抗炎药的重新给药。
实施例7临床方案
适用于用本公开的方法治疗的受试者包括已经被诊断患有炎性关节疾病或病症,例如以上列出的任何关节疾病或病症的个体。
适用于用本公开的方法治疗的个体包括由于炎性关节疾病或病症而导致关节疼痛或关节运动范围减少的个体。适用于用本公开的方法治疗的个体包括由于炎性关节疾病或病症而有流出物的个体。适合用本公开的方法治疗的个体包括由于炎性关节疾病或病症而在关节中具有关节表面损伤的个体。适用于用本公开的方法治疗的个体包括由于炎症性关节疾病或病症,而对关节的骨刺、钙化软骨或软骨下骨病变具有关节磨损的个体。
用本公开的方法进行的治疗可以与减轻炎性关节疾病或病症的症状的其他方法组合,包括通过其他全身或关节内药物或通过外科手术进行的治疗。
适用于测量本公开方法治疗后关节疼痛的方法利用一种或多种以下方法的疼痛评分:西安大略省和麦克马斯特大学的骨关节炎指数(WOMAC),患者总体评估(PTGA),临床观察员总体评估(COGA)或视觉模拟量表(VAS)。适用于测量本公开方法治疗后关节疼痛减轻疗效的方法利用一种或多种以下方法的疼痛评分:在50英尺步行后,再次使用止痛剂的时间和通过VAS的疼痛评估。适用于测量本公开方法治疗后总体患者活动度和治疗后生活质量的方法利用一种或多种以下方法的疼痛评分:使用健康评估问卷(HAQ)或简表36(SF-36)进行评估问卷调查。适用于测量本公开方法治疗后关节损伤区域的改善的放射图法利用一种或多种以下方法的疼痛评分:总尖锐分数(TSS),关节侵蚀分数,关节间隙缩小(JSN)分数或骨矿物质定量。
在一项或多项诊断研究中显示异常的受试者(例如,超出健康关节正常范围的受试者)可以按照本公开的内容进行治疗。
实施例8评估生物辍合功效的非临床方案
如前所述,基于现有方法的治疗预防骨关节炎诱导的软骨分解代谢的有效性可通过非临床试验进行评估。本研究需要成年(>5个月大)大鼠,实现对软骨分解代谢生物标志物、软骨寡聚基质蛋白(COMP)和II型胶原C-端肽(CTX-II)准确的纵向测量。在麻醉下,将大鼠加载到由两个加载压板组成的胫骨压缩系统中:底部压板将容纳弯曲的膝盖,而顶部压板将容纳脚踝弯曲至30°的脚,轴向力测试机(Bose ElectroForce 3200)将以1mm/s的速率施加单个12-N的压缩载荷。这种加载方法足以通过相对于股骨远端胫骨的短暂前半脱位对小鼠产生持续的压迫损伤。25然后将大鼠按体重随机分为三组,每组将接受以下治疗方法之一:抗炎生物辍合物,未辍合的抗炎肽或生理盐水。
受伤后立即,和在第4、7和10周开始时,将抗TNFα治疗剂和对照通过40μLIA注射至右膝。所有治疗组将接受相同剂量的总抗TNFα抗体(250μg/mL,每个关节总共10μg总抗体),产生IA浓度约为~80μg/mL(~4.5μM)。受伤后24小时,我们将用于报告MMP活性(MMPSense750;2nmol/关节)的荧光报告基因通过IA注射到双膝,在第2、4和7天测量关节的MMP生物活性。在第1、2、3、6和9周结束时,将从每只大鼠中收集大约300μL血液。在第12周结束时(第84天),处死大鼠,采集双后肢股骨和胫骨,固定福尔马林进行以进行成像分析。标本的成像可以通过射线照相(Faxitron)或μCT扫描(Inveon MM CT)进行。然后将标本准备用于常规脱钙的组织学检查,并用苏木精/曙红和番红O快速绿染色,以评估关节中骨关节炎的程度。按照OARSI指南对大鼠OA模型进行组织形态计量学评分。
如前所述,通过非临床前交叉韧带(ACL)横切(ACLT)模型实验测定法,可以评估基于本公开内容9的治疗方法以最小化关节炎症的疗效。简而言之,将在大鼠的右膝(300-400g)上进行囊切开术,以手术刀切开ACL,然后关闭手术部位。假手术不进行左膝盖ACLT,这将用作内部阴性对照。ACLT后24小时,将大鼠分为三组,每组将接受以下治疗之一:抗炎生物辍合物、未辍合的抗炎肽或赋形剂对照。在第4、7和10周的开始,每个治疗/对照的额外剂量将通过IA注射给双膝。在基线以及第6周和第9周结束时,将收集血液用于炎症生物标志物分析,并收集尿液用于软骨分解代谢的代谢标志物。在第12周末,将在最终采血之前收集的最终尿液样本进行生物标记分析。采集双后肢的股骨和胫骨,并通过射线照相(Faxitron)、μCT扫描(Inveon MM CT)和MRI(BioSpec7T)进行成像。然后将标本准备用于常规脱钙的组织学检查,并用苏木精/曙红和番红O/快速绿染色,以评估关节中骨关节炎的程度。按照OARSI指南对大鼠OA模型进行组织形态计量学评分。血清生物标志物分析将使用光敏复合ELISA阵列检测炎症细胞因子。该阵列可检测与炎症相关的28种血液因子,包括我们预期将显示关节炎症的因子:IL-1β,IL-6,IL-10和TNFα。血清软骨寡聚基质蛋白(COMP)和II型胶原的C端肽(CTX-II)将使用ELISA检测,以量化软骨的分解代谢。
基于本公开的方法的疗效,即预防由于关节内磨损颗粒引起的关节发炎和骨溶解,可以使用如前所述的非临床试验来评估(PMID:22275163和2460476)。股骨棒(直径15毫米x 1.5毫米)由商业纯钛制成(美国顾特服公司,将通过双酸蚀刻进行植入)。制备聚乙烯微粒(直径中值1.75μm;Ceridust VP 3610)并掺入LPS,并通过如前所述9的定量方法进行验证。将钛棒植入大鼠股骨远端(300-400g)。植入手术后一天,将每周进行40μL的LPS掺杂微粒的关节内注射(每次注射4.75x107颗粒)。然后将大鼠分为三组,每组将接受以下一种治疗方法:抗炎生物辍合物、未辍合的抗炎肽或对照剂生理盐水。在第1、4、7和10周的开始时,治疗和对照组将通过40μL IA在双膝进行注射。在基线以及第6和9周结束时,将收集血液以进行炎症性生物标志物分析。在第12周结束时,大鼠将处死大鼠以进行终末血液收集以进行生物标记分析,并收集两个后肢的股骨和胫骨进行放射线照相分析(Faxitron)。一只后肢的骨头将被固定,而另一只后肢的骨头将被冷冻以进行μCT扫描和机械测试。μCT扫描(Scanco 50型)将在垂直于植入物长轴的3个位置进行,使用1.5μm体素大小来评估骨与植入物的接触,使用10μm体素来评估植入物周围的小梁和皮质骨。机械拔出测试将按照其他地方的详细说明进行(Instron 8847测试系统)。对于静态组织形态计量学测量,将通过塑料包埋,将样品研磨至镜面光洁,然后用碱性品红和甲苯胺蓝进行表面染色来处理一半的固定样品,以进行未脱钙组织学检查。另一半标本将进行常规脱钙的组织学处理,来验证骨-植入物界面处的微粒(血凝素、伊红和偏光显微镜)的存在和分布,或通过酒石酸酸性磷酸酶(TRAP)染色检测植入物周围区域的破骨细胞数。血清生物标志物分析将使用光敏复合ELISA阵列检测炎症细胞因子。此阵列可检测与炎症相关的28种血液因子,包括我们预期将指示慢性关节炎症的那些因子:IL-1,IL-6,IL-10和TNFα。5我们有初步数据显示,在关节内暴露于LPS掺杂的微粒后,这些细胞因子如何在血清中被检测到上调。
尽管为了清楚理解起见通过示例和实施例对前述发明进行了详细描述,但是本领域技术人员将理解,可以在所附权利要求的范围内进行某些改变和修改。另外,本文提供的每个参考文献通过引用整体并入本文,其程度与每个参考文献通过引用单独并入的程度相同。在本申请与本文提供的参考文献之间存在冲突的情况下,以本申请为准。
序列
SEQ ID NO:1(抗-TNFa单域重链(VHH)抗体)
QVQLQESGGGLVQPGGSLRLSCAASGRTFSDHSGYTYTIGWFRQAPGKEREFVARIYWSSGNTYYADSVKGRFAISRDIAKNTVDLTMNNLEPEDTAVYYCAARDGIPTSRSVESYNYWGQGTQVTVSS
SEQ ID NO:2(抗-TNFa单域重链(VHH)抗体)
SNAQVQLQESGGGLVQPGGSLRLSCAASGRTFSDHSGYTYTIGWFRQAPGKEREFVARIYWSSGNTYYADSVKGRFAISRDIAKNTVDLTMNNLEPEDTAVYYCAARDGIPTSRSVESYNYWGQGTQVTVSSSPSTPPTPSPSTPPGGC
SEQ ID NO:3
DHSGYTYTIG,
SEQ ID NO:4
ARIYWSSGNTYYADSVKG
SEQ ID NO:5
RDGIPT
SEQ ID NO:6(抗-TNFa亲和体)
SNACGGGVDN KFNKEVGWAF GEIGALPNLN ALQFRAFIIS LWDDPSQSAN 50
LLAEAKKLND AQAPK 65
SEQ ID NO:7(抗-TNFa单域重链(VHH)抗体)
SNAQVQLQES GGGLVQPGGS LRLSCAASGR TFSDHSGYTY TIGWFRQAPG 50
KEREFVARIY WSSGNTYYAD SVKGRFAISR DIAKNTVDLT MNNLEPEDTA 100
VYYCAARDGI PTSRSVESYN YWGQGTQVTV SSSPSTPPTP SPSTPPGGCD 150
DDDKHHHHHH DYKDDDDK 168
SEQ ID NO:8(抗-TNFa设计的锚蛋白重复蛋白(DARPin))
SNADLGKKLL EVARAGQDDE VRILMANGAD VNAADHQSFT PLHLYAIFGH 50
LEIVEVLLKN GADVNASDWH GNTPLHLAAW IGHLEIVEVL LKYGADVNAT 100
DHSGSTPLHL AATLGHLEIV EVLLKYGADV NAQDKFGKTA FDISIDNGNE 150
DLAEILQKAA GGGSGGGSC 169
SEQ ID NO:9(抗-IL-1B单链(scFv)抗体)
SNAEIVMTQS PSTLSASVGD RVIITCQASQ SIDNWLSWYQ QKPGKAPKLL 50
IYRASTLASG VPSRFSGSGS GAEFTLTISS LQPDDFATYY CQNTGGGVSI 100
AFGQGTKLTV LGGGGGSGGG GSGGGGSGGG GSEVQLVESG GGLVQPGGSL 150
RLSCTASGFS LSSAAMAWVR QAPGKGLEWV GIIYDSASTY YASWAKGRFT 200
ISRDTSKNTV YLQMNSLRAE DTAVYYCARE RAIFSGDFVL WGQGTLVTVS 250
SSPSTPPTPS PSTPPGGC 268
SEQ ID NO:10(可溶性白介素受体2(sILR2))
HTGAARSCRF RGRHYKREFR LEGEPVALRC PQVPYWLWAS VSPRINLTWH 50
KNDSARTVPG EEETRMWAQD GALWLLPALQ EDSGTYVCTT RNASYCDKMS 100
IELRVFENTD AFLPFISYPQ ILTLSTSGVL VCPDLSEFTR DKTDVKIQWY 150
KDSLLLDKDN EKFLSVRGTT HLLVHDVALE DAGYYRCVLT FAHEGQQYNI 200
TRSIELRIKK KKEETIPVII SPLKTISASL GSRLTIPCKV FLGTGTPLTT 250
MLWWTANDTH IESAYPGGRV TEGPRQEYSE NNENYIEVPL IFDPVTREDL 300
HMDFKCVVHN TLSFQTLRTT VKESPSTPPT PSPSTPPGGC 340
SEQ ID NO:11抗-(小鼠)TNFa单域重链(VHH)抗体
SNAQVQLQDS GGGLVQAGGS LRLSCAASGG TFSSIIMAWF RQAPGKEREF 50
VGAVSWSGGT TVYADSVLGR FEISRDSARK SVYLQMNSLK PEDTAVYYCA 100
ARPYQKYNWA SASYNVWGQG TQVTVSSSPS TPPTPSPSTP PGGCDDDDKH 150
HHHHH 155
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<110> 瓦利托尔有限公司
W·M·杰克逊
M·穆罕默德
L·W·布里耶
K·E·希利
<120> 用于持久的多价肽辍合物
<130> 052566-504001WO
<150> 62/640,749
<151> 2018-03-09
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50 55 60
Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu Pro Ala Leu Gln
65 70 75 80
Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn Ala Ser Tyr Cys
85 90 95
Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn Thr Asp Ala Phe
100 105 110
Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu Ser Thr Ser Gly
115 120 125
Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg Asp Lys Thr Asp
130 135 140
Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu Asp Lys Asp Asn
145 150 155 160
Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu Leu Val His Asp
165 170 175
Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val Leu Thr Phe Ala
180 185 190
His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile Glu Leu Arg Ile
195 200 205
Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile Ser Pro Leu Lys
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Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile Pro Cys Lys Val
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Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu Trp Trp Thr Ala
245 250 255
Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly Arg Val Thr Glu
260 265 270
Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn Tyr Ile Glu Val
275 280 285
Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu His Met Asp Phe
290 295 300
Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr Leu Arg Thr Thr
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Val Lys Glu Ser Pro Ser Thr Pro Pro Thr Pro Ser Pro Ser Thr Pro
325 330 335
Pro Gly Gly Cys
340
<210> 11
<211> 155
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Ser Asn Ala Gln Val Gln Leu Gln Asp Ser Gly Gly Gly Leu Val Gln
1 5 10 15
Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Thr Phe
20 25 30
Ser Ser Ile Ile Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg
35 40 45
Glu Phe Val Gly Ala Val Ser Trp Ser Gly Gly Thr Thr Val Tyr Ala
50 55 60
Asp Ser Val Leu Gly Arg Phe Glu Ile Ser Arg Asp Ser Ala Arg Lys
65 70 75 80
Ser Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Ala Arg Pro Tyr Gln Lys Tyr Asn Trp Ala Ser Ala
100 105 110
Ser Tyr Asn Val Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Ser
115 120 125
Pro Ser Thr Pro Pro Thr Pro Ser Pro Ser Thr Pro Pro Gly Gly Cys
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Asp Asp Asp Asp Lys His His His His His His
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Claims (57)
1.一种治疗关节中关节疾病或病症的方法,该方法包括将有效量的辍合物注射到关节中,所述辍合物包括:分子量为约0.1MDa至约3MDa的生物相容性聚合物;以及多个肽,其中所述肽的分子量为约5kDa至约150kDa;
其中
每个肽都与聚合物共价连接,并且
辍合物中肽与聚合物的摩尔比为至少约5∶1。
2.如权利要求1所述的方法,其中
该生物相容性聚合物的分子量为约0.1MDa至约2MDa;以及多个肽,其中所述肽的分子量为约5kDa至约100kDa;
其中
每个肽都与聚合物共价连接,
每个肽的聚合物分子量为约5kDa至约50kDa,并且
辍合物中肽与聚合物的摩尔比为至少约5∶1。
3.如权利要求1所述的方法,其中所述生物相容性聚合物是多糖。
4.如权利要求1至3中任一项所述的方法,其中所述生物相容性聚合物是糖胺聚糖。
5.如权利要求1至4中任一项所述的方法,其中所述生物相容性聚合物是透明质酸。
6.如权利要求1至5中任一项所述的方法,其中所述生物相容性聚合物具有约0.2MDa至约1.5MDa的分子量。
7.如权利要求1至6中任一项所述的方法,其中所述生物相容性聚合物具有约0.9MDa的分子量。
8.如权利要求1至5中任一项所述的方法,其中所述生物相容性聚合物的分子量为约0.8MDa至约3MDa。
9.如权利要求1至5中任一项所述的方法,其中所述生物相容性聚合物具有约2MDa的分子量。
10.如权利要求1至7中任一项所述的方法,其中所述肽调节免疫细胞功能的活性。
11.如权利要求1至10中任一项所述的方法,其中所述肽抑制肿瘤坏死因子-α、白介素-1β、白介素-6或干扰素-γ。
12.如权利要求1至11中任一项所述的方法,其中所述肽抑制肿瘤坏死因子-α。
13.如权利要求1至12中任一项所述的方法,其中所述肽是单克隆IgG抗体、IgG抗体片段、单链可变区抗体、单结构域重链抗体、安耐汀、亲和体、安替开林、DARPin、Kunitz型抑制剂或受体诱饵。
14.权利要求1至13中任一项的方法,其中所述肽的分子量为约5kDa至约30kDa。
15.权利要求1至14中任一项的方法,其中所述肽的分子量为约10kDa至约20kDa。
16.如权利要求1至15中任一项所述的方法,其中所述肽具有选自下组的氨基酸序列:SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQID NO:10和SEQ ID NO:11。
17.如权利要求1至16中任一项所述的方法,其中所述肽具有如SEQ ID NO:1的氨基酸序列:
QVQLQESGGGLVQPGGSLRLSCAASGRTFSDHSGYTYTIGWFRQAPGKEREFVARIYWSSGNTYYADSVKGRFAISRDIAKNTVDLTMNNLEPEDTAVYYCAARDGIPTSRSVESYNYWGQGTQVTVSS(SEQ ID NO:1)。
18.如权利要求1至17中任一项所述的方法,其中所述肽与所述聚合物的摩尔比为约5∶1至约400∶1。
19.如权利要求1至18中任一项所述的方法,其中所述肽与所述聚合物的摩尔比为约10:1至约100:1。
20.如权利要求1至19中任一项所述的方法,其中所述肽与所述聚合物的摩尔比为约30:1至约50:1。
21.如权利要求1至20中任一项所述的方法,其中所述肽经由硫化物键和分子量为约100Da至约500Da的接头共价连接至所述聚合物。
22.如权利要求21所述的方法,其中所述接头的分子量为约100Da至约300Da。
23.如权利要求21至22中任一项所述的方法,其中所述接头包括琥珀酰亚胺。
24.权利要求1至23中任一项所述的方法,其中所述辍合物的扩散半衰期比所述肽长至少约2倍。
25.权利要求1至24中任一项所述的方法,其中所述辍合物的扩散半衰期比所述肽长约2至约100倍。
26.权利要求1至25中任一项所述的方法,其中所述辍合物的关节内半衰期比所述肽长至少约20%。
27.权利要求1至26中任一项所述的方法,其中所述辍合物的关节内半衰期比所述肽长约20%至约1000%。
28.如权利要求1至27中任一项所述的方法,其中所述疾病或病症是类风湿性关节炎、与磨损有关的骨关节炎、与年龄有关的骨关节炎、创伤后骨关节炎、银屑病关节炎和无菌植入物松动、关节积液、强直性脊柱炎、滑囊炎、痛风、反应性关节炎、滑膜炎或无血管坏死。
29.如权利要求1至28中任一项所述的方法,其中将所述辍合物不超过约每月一次注入所述关节。
30.如权利要求1至29中任一项所述的方法,其中将所述辍合物从约每月一次至每6个月一次注入所述关节。
31.如权利要求1至30中任一项所述的方法,其中将所述辍合物每2个月一次或每3个月一次注入所述关节。
32.一种辍合物,其包含具有约0.1MDa至约3MDa的分子量的生物相容性聚合物;以及多个肽,其中所述肽的分子量为约5kDa至约150kDa;
其中每个肽都与聚合物共价连接,并且
辍合物中肽与聚合物的摩尔比为至少约5∶1。
33.如权利要求32所述1的辍合物,其中该生物相容性聚合物的分子量为约0.1MDa至约2MDa;以及多个肽,其中所述肽的分子量为约5kDa至约100kDa;
其中
每个肽都与聚合物共价连接,
每个肽的聚合物分子量为约5kDa至约50kDa,并且
辍合物中肽与聚合物的摩尔比为至少约5∶1。
34.如权利要求32所述的辍合物,其中所述生物相容性聚合物是多糖。
35.如权利要求32至34中任一项所述的辍合物,其中所述生物相容性聚合物是糖胺聚糖。
36.如权利要求32至35中任一项所述的辍合物,其中所述生物相容性聚合物是透明质酸。
37.如权利要求32至36中任一项所述的辍合物,其中所述生物相容性聚合物具有约0.2MDa至约1.5MDa的分子量。
38.如权利要求32至37中任一项所述的辍合物,其中所述生物相容性聚合物具有约0.9MDa的分子量。
39.如权利要求32至36中任一项所述的辍合物,其中所述生物相容性聚合物的分子量为约0.8MDa至约3MDa。
40.如权利要求32至36中任一项所述的辍合物,其中所述生物相容性聚合物具有约2MDa的分子量。
41.如权利要求32至38中任一项所述的辍合物,其中所述肽调节免疫细胞功能的活性。
42.如权利要求32至41中任一项所述的辍合物,其中所述肽抑制肿瘤坏死因子-α、白介素-1β、白介素-6或干扰素-γ。
43.如权利要求32至42中任一项所述的辍合物,其中所述肽抑制肿瘤坏死因子-α。
44.如权利要求32至43中任一项所述的辍合物,其中所述肽是单克隆IgG抗体、IgG抗体片段、单链可变区抗体、单结构域重链抗体、安耐汀、亲和体、安替开林、DARPin、Kunitz型抑制剂或受体诱饵。
45.如权利要求32至44中任一项所述的辍合物,其中所述肽的分子量为约5kDa至约30kDa。
46.如权利要求32至45中任一项所述的辍合物,其中所述肽的分子量为约10kDa至约20kDa。
47.如权利要求32至46中任一项所述的辍合物,其中所述肽具有选自下组的氨基酸序列:SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9和SEQ ID NO:10。
48.权利要求32至47中任一项所述的辍合物,其中所述肽具有以下序列:QVQLQESGGGLVQPGGSLRLSCAASGRTFSDHSGYTYTIGWFRQAPGKEREFVARIYWSSGNTYYADSVKGRFAISRDIAKNTVDLTMNNLEPEDTAVYYCAARDGIPTSRSVESYNYWGQGTQVTVSS(SEQ ID NO:1)。
49.如权利要求32至46中任一项所述的辍合物,其中所述肽与所述聚合物的摩尔比为约5:1至约400:1。
50.如权利要求32至49中任一项所述的辍合物,其中所述肽与所述聚合物的摩尔比为约10:1至约100:1。
51.如权利要求32至50中任一项所述的辍合物,其中所述肽与所述聚合物的摩尔比为约30:1至约50:1。
52.如权利要求32至51中任一项所述的辍合物,其中所述肽经由硫化物键和分子量为约100Da至约500Da的接头共价连接至所述聚合物。
53.如权利要求52所述的辍合物,其中所述接头的分子量为约100Da至约300Da。
54.如权利要求52至53中任一项所述的缀合物,其中所述接头包括琥珀酰亚胺。
55.如权利要求32至54中任一项所述的辍合物,其中所述辍合物的扩散半衰期比所述肽长至少约2倍。
56.如权利要求32至55中任一项所述的辍合物,其中所述辍合物的扩散半衰期比所述肽长约2至约100倍。
57.一种药物组合物,其包含如权利要求32-56中任一项所述辍合物,和药学上可接受的载体。
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CN103119062A (zh) * | 2010-07-16 | 2013-05-22 | 埃博灵克斯股份有限公司 | 修饰的单结构域抗原结合分子及其应用 |
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CN103119062A (zh) * | 2010-07-16 | 2013-05-22 | 埃博灵克斯股份有限公司 | 修饰的单结构域抗原结合分子及其应用 |
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