CN114652825A - 稳定的抗体制剂及其制备方法和应用 - Google Patents
稳定的抗体制剂及其制备方法和应用 Download PDFInfo
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- CN114652825A CN114652825A CN202111574249.XA CN202111574249A CN114652825A CN 114652825 A CN114652825 A CN 114652825A CN 202111574249 A CN202111574249 A CN 202111574249A CN 114652825 A CN114652825 A CN 114652825A
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- methionine
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- 239000003381 stabilizer Substances 0.000 claims abstract description 34
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 claims abstract description 20
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Abstract
本发明属于生物制剂领域,提供一种稳定的抗体制剂,包括抗IL‑17抗体、缓冲剂、稳定剂和表面活性剂,其中,所述稳定剂选自甲硫氨酸或甲硫氨酸和糖醇的组合,所述抗体制剂的pH值为5.4~6.6。本发明的抗体制剂在高温和室温下均有较好的稳定性,能够以液态形式保持,方便使用。
Description
技术领域
本发明属于生物制剂领域,涉及一种稳定的抗体制剂。
背景技术
抗IL-17抗体在治疗各种自身免疫疾病,如类风湿性关节炎、银屑病关节炎、糖尿病、哮喘、慢性斑块型银屑病、多发性硬化症等有显著疗效。作为一种蛋白产品,抗IL-17抗体易降解,稳定性差,需要制备成稳定的制剂才能保证其效果。目前已有多种抗IL-17抗体制剂存在,但本领域依然有针对抗IL-17抗体的稳定制剂的需求。
发明内容
本发明的目的是提供一种稳定的抗IL-17抗体制剂,以解决现有技术存在的问题。
第一个方面,本发明提供一种稳定的抗体制剂,包括抗IL-17抗体、缓冲剂、稳定剂和表面活性剂,其中,所述稳定剂选自甲硫氨酸或甲硫氨酸和糖醇的组合。
在一种实施方式中,所述甲硫氨酸的浓度为0.15%-1%。在一种实施方式中,所述甲硫氨酸的浓度为0.4%或1%。在一种实施方式中,所述糖醇的浓度为3%-5%。在一种实施方式中,所述糖醇的浓度为3%或4%。
在一种实施方式中,所述抗体制剂的pH值为5.4~6.6。在一种实施方式中,所述抗体制剂的pH值为5.8~6.6。在一种实施方式中,所述抗体制剂的pH值为5.8~6.4。在一种实施方式中,所述抗体制剂的pH值为6.1。
在一种实施方式中,所述缓冲剂为柠檬酸盐缓冲液或磷酸盐缓冲液。在一种实施方式中,所述缓冲剂的浓度为10mM~30mM。在一种实施方式中,所述缓冲剂为20mM柠檬酸盐缓冲液。在一种实施方式中,所述缓冲剂为20mM磷酸盐缓冲液。在一种实施方式中,所述缓冲剂为10mM磷酸盐缓冲液和10mM柠檬酸盐缓冲液的组合。
在一种实施方式中,所述稳定剂是甲硫氨酸和山梨醇的组合。在一种实施方式中,所述甲硫氨酸的浓度为0.15%-1%。在一种实施方式中,所述甲硫氨酸的浓度为1%或0.4%。在一种实施方式中,所述山梨醇的浓度为3%-5%。在一种实施方式中,所述山梨醇的浓度为3%或4%。
在一种实施方式中,所述表面活性剂为吐温80或吐温20。在一种实施方式中,所述表面活性剂的浓度为0.01%-0.04%。在一种实施方式中,所述表面活性剂的浓度为0.02%。在一种实施方式中,所述表面活性剂为吐温80。在一种实施方式中,所述吐温80的浓度为0.02%。
在一种实施方式中,所述抗IL-17抗体的浓度为8mg/mL-300mg/mL。在一种实施方式中,所述抗IL-17抗体的浓度为20mg/mL-300mg/mL。在一种实施方式中,所述抗IL-17抗体的浓度为100mg/mL-300mg/mL。在一种实施方式中,所述抗IL-17抗体的浓度为150mg/mL。
在一种实施方式中,所述抗IL-17抗体的轻链序列如SEQ ID NO:1所示,重链序列如SEQ ID NO:2所示。在一种实施方式中,所述抗IL-17抗体为IgG1/kappa亚型的单克隆抗体。在一种实施方式中,所述抗IL-17抗体由CHO细胞表达。
在一种实施方式中,本发明的制剂包括150mg/mL抗IL-17抗体、20mM柠檬酸盐缓冲液、3%糖醇、0.4%甲硫氨酸、0.02%吐温80,pH值5.8~6.4。在一些实施方式中,pH值为6.1。
在一种实施方式中,本发明的制剂包括150mg/mL抗IL-17抗体、20mM柠檬酸盐缓冲液、3%山梨醇、0.4%甲硫氨酸、0.02%吐温80,pH值5.8~6.4。在一些实施方式中,pH值为6.1。
在一种实施方式中,本发明的制剂不包含糖。
在第二个方面,本发明提供所述制剂的制备方法,包括:取指定量的抗IL-17抗体、缓冲剂、稳定剂和表面活性剂,加水溶解并混匀上述物质。在一些实施方案中,本发明提供所述制剂的制备方法,包括:取指定量的抗IL-17抗体、柠檬酸一水合物、山梨醇、甲硫氨酸和吐温80,加水溶解并混匀上述物质,调节到指定量体积,并用NaOH调节pH值至5.8~6.6,优选5.8~6.4。在一些实施方案中,本发明提供所述制剂的制备方法,包括:取指定量的抗IL-17抗体、柠檬酸一水合物、柠檬酸钠二水合物、山梨醇、甲硫氨酸和吐温80,加水溶解并混匀上述物质,调节到指定量体积。
在第三个方面,本发明提供所述制剂在制备用于治疗自身免疫疾病的产品中的应用,所述自生免疫疾病包括但不限于类风湿性关节炎、银屑病关节炎、糖尿病、哮喘、慢性斑块型银屑病和多发性硬化症。
在第四个方面,本发明提供了一种治疗IL-17相关疾病的抗体药物制品,包括如前文所述的抗IL-17抗体制剂以及用于保存所述制剂的容器。所述药物制品还可以包括使用说明书。所述容器可以是本领域常规使用的用于保存药品的任何容器,如预灌封容器、预填充注射器、小瓶、安瓿、小袋等。本发明的抗体制剂在高温和室温下均有较好的稳定性,能够以液态形式保持,方便使用。
附图说明
图1:高温条件下抗体在不同缓冲液中SEC-HPLC单体纯度随时间的变化趋势;
图2:高温条件下抗体在不同缓冲液中SEC-HPLC聚体随时间的变化趋势;
图3:高温条件下抗体在不同缓冲液中IEC-HPLC主峰随时间的变化趋势;
图4:高温条件下抗体在不同缓冲液中CE-SDS(NR)主峰随时间的变化趋势;
图5:光照条件下抗体在不同缓冲液中SEC-HPLC单体含量随时间的变化趋势;
图6:光照条件下抗体在不同缓冲液中SEC-HPLC多聚体含量随时间的变化趋势;
图7:光照条件下抗体在不同缓冲液中IEC-HPLC主峰随时间的变化趋势;
图8:光照条件下抗体在不同缓冲液中CE-SDS(NR)主峰含量随时间的变化趋势。
具体实施方案
下面将通过具体实施方案来说明本发明,但本发明的内容不限于此。
需要说明的是,本发明中,涉及到液体制剂组分的“%”指重量体积(w/v)百分比,其中重量单位可以为g,体积单位可以为mL。比如溶液中含1%稳定剂表示100mL溶液中含有1g稳定剂,或稳定剂含量为0.01g/mL。
“约”指相关技术领域技术人员容易知道的相应数值的常规误差范围。在一些实施方式中,本文中提到“约”指所描述的数值以及其±10%、±5%或±1%的范围。
“包括”或“包含”指组合物和方法等等包括所列举的元素(如组合物中的组分,方法中的步骤等),但不排除其它元素。当“基本上由……组成”用于定义组合物和方法时,指排除对用于预期用途的组合有根本影响的其它元素,但不排除不会本质上影响组合物或方法的特征的元素。“由……组成”指排除未特别列举的元素。由这些过渡术语中的每一者定义的实施方案均在本发明的范围内。举例来说,当组合物被描述为包括成分A、B以及C时,基本上由A、B以及C组成的组合物和由A、B以及C组成的组合物独立地在本发明的范围内。
术语“缓冲剂”也被称为缓冲系统或缓冲体系,其包括但不限于有机酸盐,如琥珀酸、醋酸、柠檬酸、抗坏血酸、葡糖酸、碳酸、酒石酸或苯二甲酸的盐;Tris,或无机酸盐,如磷酸盐缓冲剂。此外,氨基酸组分也可以用作缓冲剂。这样的氨基酸组分包括但不限于甘氨酸、组氨酸、精氨酸、赖氨酸、鸟氨酸、异亮氨酸、亮氨酸、丙氨酸、谷氨酸或天冬氨酸。在一些实施方案中,缓冲剂为组氨酸盐缓冲剂。
本发明中缓冲剂的量,是指组成缓冲剂的缓冲体系中缓冲对的总量。在一些实施方式中,采用摩尔浓度作为缓冲剂的量的单位,其数值指缓冲剂的缓冲体系中缓冲对的摩尔浓度。如,由柠檬酸和柠檬酸钠组成的柠檬酸盐缓冲液作为缓冲剂时,给定浓度的柠檬酸盐缓冲液(如20mM)是柠檬酸和柠檬酸钠的组合浓度(如柠檬酸为2.8mM,柠檬酸钠为17.2mM等。)
本发明所述的制剂可以用所述辅料或其水合物配制。比如柠檬酸,可以是无水柠檬酸,也可以是柠檬酸水合物,如柠檬酸一水合物;如0.59mg柠檬酸一水合物,包括0.59mg柠檬酸一水合物或相应量的柠檬酸。
术语“糖醇”包括但不限于甘露醇、木糖醇、麦芽糖醇、乳糖醇、山梨醇(又名山梨糖醇或葡萄糖醇)等。
术语“表面活性剂”包括但不限于吐温(Tween,如吐温20和吐温80);泊洛沙姆(例如泊洛沙姆188);Triton;十二烷硫酸钠(SDS);月桂硫酸钠;辛基配糖物钠盐;月桂基磺基甜菜碱、肉豆蔻基磺基甜菜碱、亚油烯基磺基甜菜碱或硬脂基磺基甜菜碱;月桂基肌氨酸、肉豆蔻基肌氨酸、亚油烯基肌氨酸或硬脂基肌氨酸;亚油烯基甜菜碱、肉豆蔻基甜菜碱或鲸蜡基甜菜碱;月桂酰胺基丙基甜菜碱、椰油酰胺基丙基甜菜碱、亚油酰胺基丙基甜菜碱、肉豆蔻酰胺基丙基甜菜碱、棕榈酰胺基丙基甜菜碱或异硬脂酰胺基丙基甜菜碱(例如月桂酰胺基丙基);肉豆蔻酰胺基丙基二甲胺、棕榈酰胺基丙基二甲胺或者异硬脂酰胺基丙基二甲胺;甲基椰油酰基牛磺酸钠或甲基油基牛磺酸二钠;聚乙二醇,聚丙二醇,和乙烯与丙烯二醇的共聚物(例如Pluronics,PF68等);等等。在一些实施方式中,表面活性剂为吐温80(Tween 80)。
吐温也称作聚山梨酯(例如,吐温20称作聚山梨酯20,吐温80称作聚山梨酯80)。
患者疾病“治疗”指的是(1)阻止疾病在有倾向性或还没表现疾病症状的患者中出现;(2)抑制疾病或其症状或阻止其发展;或(3)减轻疾病或其症状或致其退化消除。
本文的“稳定性”、“稳定”,是指包含抗体的液体制剂中,抗体(包括其抗体片段)在给定的生产、制备、运输和/或贮存条件下不发生、或仅极少地发生聚集、降解或片段化。“稳定”制剂在给定的生产、制备、运输和/或贮存条件下保持生物学活性。可通过例如SEC-HPLC、IEC-HPLC、CE-SDS(NR)、灯检及浑浊度、不溶性颗粒、DLS检测粒子粒径等技术对所述制剂的聚集、降解或片段化程度等进行测量,从而评估所述抗体的稳定性。
本发明的制剂中的活性成分是抗IL-17抗体,包括但不限于单克隆抗体、嵌合抗体、dAb(结构域抗体)、单链抗体、Fab、Fab-和F(ab')2片段、Fv、scFvs和Fab表达库。在一些实施方案中,抗IL-17抗体是重组抗IL-17单克隆抗体,该抗体由一种高效表达重组抗IL-17单克隆抗体的细胞经细胞培养、抗体分离和高度纯化后制成。在一些实施方案中,所述抗IL-17抗体的轻链的氨基酸序列如SEQ ID NO:1所示,重链的氨基酸序列如SEQ ID NO:2所示。在一些实施方案中,所述抗IL-17抗体为secukinumab,如中的抗体及其生物类似物。
在一些实施方案中,所述抗IL-17抗体的含量约为100mg/mL-300mg/mL。在一些实施方案中,所述抗IL-17抗体的含量约为120mg/mL-200mg/mL。在本发明的一些实施方案中,所述抗IL-17抗体的含量约为140mg/mL-160mg/mL。例如约100mg/mL、约120mg/mL、约140mg/mL、约145mg/mL、约150mg/mL、约155mg/mL、约160mg/mL、约180mg/mL、约200mg/mL、约250mg/mL、约300mg/mL,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,所述抗IL-17抗体的含量约为150mg/mL。
在一些实施方案中,本发明提供的制剂的pH约为5.0-7.0。在一些实施方案中,本发明提供的制剂的pH约为5.4-6.6。在一些实施方案中,pH约为5.8-6.6。在一些实施方案中,pH约为6.0-6.4。例如约5.0、约6.0、约6.1、约6.2、约6.3、约6.4、约6.5、约6.6、约7.0,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,pH约为6.1。
在一些实施方案中,本发明的缓冲剂,包括柠檬酸盐缓冲液、磷酸盐缓冲液、琥珀酸盐缓冲液和醋酸盐缓冲液中的一种或多种。在一些实施方案中,缓冲剂为柠檬酸盐缓冲液。在一些实施方案中,缓冲剂为磷酸盐缓冲液和柠檬酸盐缓冲液的组合。
在一些实施方案中,缓冲剂的浓度范围约为10mM-30mM。在一些实施方案中,缓冲剂的浓度约为15-25mM。在一些实施方案中,缓冲剂的浓度约为18-22mM;例如约10mM、约15mM、约18mM、约19mM、约20mM、约21mM、约22mM、约25mM、约30mM,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方式中,缓冲剂为20mM的柠檬酸盐缓冲液。
在一些实施方案中,制剂还包含稳定剂。在一些实施方案中,所述稳定剂选自氯化钠、甘露醇、山梨醇、蔗糖、海藻糖、精氨酸盐酸盐和甲硫氨酸中的一种或多种。在一些实施方案中,稳定剂为山梨醇和甲硫氨酸的组合。
在一些实施方案中,稳定剂的浓度约为0.1%-10%,在一些实施方案中,稳定剂的浓度约为0.2%-5%,例如为约0.2%、约0.4%、约1%、约2%、约3%、约4%,约5%,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,稳定剂为约4%的山梨醇。在一些实施方案中,稳定剂为约4%的山梨醇和约1%的甲硫氨酸的组合。在一些实施方案中,稳定剂为约3%的山梨醇和约0.4%的甲硫氨酸的组合。
在一些实施方案中,制剂还包括表面活性剂。在一些实施方案中,表面活性剂为吐温80、吐温20或泊洛沙姆188。在一些实施方案中,表面活性剂为吐温80。
在一些实施方案中,表面活性剂的浓度为约0.01%-0.04%,或约0.01%-0.03%,或约0.015%-0.025%,或约0.02%。在一些实施方案中,表面活性剂的浓度为约0.01%、约0.015%、约0.02%、约0.025%、约0.03%、约0.04%,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,表面活性剂为约0.02%的吐温80。
在一些实施方式中,所述制剂含有以下组分:约100mg/mL-300mg/mL的抗IL-17抗体、约10mM-30mM的缓冲剂、约0.1%-10%的稳定剂、约0.01%-0.04%的表面活性剂,pH为约5.0-7.0。在一些实施方式中,所述抗体制剂含有以下组分:约120mg/mL-200mg/mL的抗IL-17抗体、约15mM-25mM的缓冲剂、0.2%-5%的稳定剂、0.01%-0.03%的表面活性剂,pH为约5.8-6.6。在一些实施方式中,所述抗体制剂含有以下组分:约140mg/mL-160mg/mL的抗IL-17抗体、约15mM-25mM的柠檬酸盐缓冲液、约3%-5%的山梨醇和/或约0.4%-1%的甲硫氨酸、约0.01%-0.03%的吐温80,pH为约5.8-6.6。在一些实施方式中,所述抗体制剂含有以下组分:约140mg/mL-160mg/mL的secukinumab、约18mM-22mM的柠檬酸盐缓冲液、约3%-5%的山梨醇和/或约0.4%-1%的甲硫氨酸、约0.015%-0.025%的吐温80,pH为约5.8-6.6。在一些实施方式中,所述抗体制剂含有以下组分:约150mg/mL的secukinumab、约20mM的柠檬酸盐缓冲液、约4%的山梨醇、约0.02%的吐温80,pH为约5.8-6.6。在一些实施方式中,所述抗体制剂含有以下组分:约150mg/mL的secukinumab、约20mM的柠檬酸盐缓冲液、约4%的山梨醇、约1%的甲硫氨酸、约0.02%的吐温80,pH为约5.8-6.6。在一些实施方式中,所述抗体制剂含有以下组分:约150mg/mL的secukinumab、约20mM的柠檬酸盐缓冲液、约3%的山梨醇、约0.4%的甲硫氨酸、约0.02%的吐温80,pH为约5.8-6.6。在一些实施方式中,所述抗体制剂含有以下组分:约150mg/mL的secukinumab、约0.59mg/mL的柠檬酸一水合物、约5.06mg/mL的柠檬酸钠二水合物、约30mg/mL的山梨醇、约4mg/mL的甲硫氨酸、约0.2mg/mL的吐温80,pH为约5.8-6.6。
综上所述,本发明提供优选的液体制剂组合方案中,所述制剂缓冲体系包括柠檬酸盐缓冲液,所述制剂的稳定剂包括山梨醇、甲硫氨酸,所述制剂的表面活性剂包括吐温80或吐温20。所述制剂的pH值范围在5.0~7.0之间。
本发明提供液体含水药物制剂,包括适合治疗用途的抗体,这种药物制剂便于施用,并且含有高蛋白浓度,主要用于治疗由IL-17引起的病症。在一些实施方案中,所述药物制剂具有增强稳定性的作用。在另一些实施方案中,本发明的制剂在经过至少5次冻融循环后是稳定的。在另一些实施方案中,本发明的制剂,经过40℃高温放置1周、2周、3周或4周后保持稳定,如IEC主峰保持在65%以上。在另一些实施方案中,本发明的制剂,经过25℃放置1个月、2个月或3个月后保持稳定,如IEC主峰保持在65%以上。在另一些实施方案中,本发明的制剂,在4000lx光照条件下,放置一段时间,仍能保持稳定。
本发明提供的制剂包括有效量的所述抗体成分。在本发明的一种实施方案中,所述制剂是制剂,例如适合于进行静脉注射或皮下注射。在本发明的一种实施方案中,所述抗体在所述液体含水药物制剂中的浓度为约150mg/mL。
本发明还提供一种治疗IL-17相关疾病的方法,所述方法包括对患者施用所述抗体制剂。
在一些实施方式中,针对IL-17相关疾病,抗体的用量为约10mg/次~500mg/次。在一些实施方式中,针对IL-17相关疾病,抗体的用量为约100mg/次~350mg/次,或约150mg/次~300mg/次。在一些实施方式中,针对IL-17相关疾病,抗体的用量为约10mg/次、约100mg/次、约150mg/次、约200mg/次、约300mg/次、约400mg/次,或约500mg/次。在一些实施方式中,向患者施用所述抗体制剂的频率为约1周/次至6周/次。在一些实施方式中,向患者施用所述抗体制剂的频率为1周/次,4周后调整为4周/次。在一些实施方式中,向患者施用所述抗体制剂,抗体用量为约150mg/次,1周/次,4周后调整为4周/次。在一些实施方式中,向患者施用所述抗体制剂,抗体用量为约300mg/次,1周/次,4周后调整为4周/次。
以下实施例中,如无特别说明,所使用的试剂和仪器为本领域常规试剂和仪器,可通过商购的方式获得;所使用的方法为本领域常规技术方法,本领域技术人员根据实施例的内容可以毫无疑义地实施所述方法并获得相应的结果。
部分设备的信息如下:
蠕动泵厂家:Longer Pump,型号:BT300-1F
超滤膜厂家:Millipore,50cm2,30KD,Cat No.:PXB030A50;Lot No.:C8AA16209-0026
培养箱:SFS-160药品强光稳定性试验箱,LHS-250SC恒温恒湿箱
以下实验中所使用的方法可以如下所示:
SEC-HPLC的分析方法:
1)用液相色谱系统和TOSOH生物科技TSK-GEL G3000SWXL色谱柱(柱规格为7.8*300mm,5μm)。柱温设定为室温,流速0.5mL/min,平衡30-60min至基线平稳。
2)进样,记录色谱图,积分后按照峰面积归一法计算供试液的单体或多聚体百分含量。
IEC-HPLC的分析方法:
1)液相色谱系统和色谱柱
仪器:Agilent 1260 Infinity/Waters e2695;色谱柱:Thermo ProPacTM WCX-104×250mm,10μm;流速:0.8mL/min;柱温30℃。
进样,记录色谱图,积分后按照峰面积归一法计算供试液的酸峰,主峰和碱峰百分含量。
CE-SDS(NR)的分析方法:
毛细管电泳仪采用Agilent CE7100,样品进样后,记录色谱图,积分处理数据,采用面积归一化方法计算单体峰的百分含量。
轻链序列:
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPCTFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQID NO:1);
重链序列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMNWVRQAPGKGLEWVAAINQDGSEKYYVGSVKGRFTISRDNAKNSLYLQMNSLRVEDTAVYYCVRDYYDILTDYYIHYWYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:2)。
实施例中所用secukinumab由CHO细胞表达,经细胞培养、分离和高度纯化后制成。CHO细胞、抗体表达方法、质粒构建及纯化方法等均按照常规方式购买和操作。
以下实施例采用的抗体均为纯化后的secukinumab。
实施例1:pH筛选实验
分别配制20mM pH为5.4、5.6、5.8、6.0、6.2、6.4、6.6的七种柠檬酸盐缓冲液。分别配制20mM柠檬酸缓冲液(称取4.2g柠檬酸一水合物,溶于1L水中)和20mM柠檬酸盐缓冲液(称取5.89g柠檬酸钠二水合物,溶于1L水中),再将上述两种缓冲液互调成pH5.3和pH6.6的20mM柠檬酸盐缓冲液。将secukinumab样品分别置换到pH5.3和pH6.6的缓冲液中,然后两种pH样品互调,可以得到相同浓度的其他pH的样品。最终获得抗体浓度均为150mg/mL的pH分别为5.4、5.6、5.8、6.0、6.2、6.4、6.6的抗体制剂。
对上述制剂置于40℃恒温箱放置,并在1周、2周、3周、4周取样,考察其稳定性。
表1:高温实验下不同pH值缓冲液对抗体的影响
从表1中的数据可以看出,在pH5.4-pH6.6的范围内,抗IL-17抗体具有一定的稳定性,且整体上,随着pH的升高,稳定性更好。以SEC-单体和IEC-主峰(%)两个指标来评价,在pH5.8~6.6范围内,抗IL-17抗体的稳定性较好,如pH5.8、pH6.0、pH6.2、pH6.4和pH6.6。
实施例2:缓冲体系筛选
制备不同成分的缓冲液,在相同的条件下,考察不同缓冲液对蛋白的稳定性。其中,各缓冲液的成分和配制方法如表2所示。使用所述缓冲液对培养制备的抗体进行超滤,得到表3所示的用于本实施例的处方。
表2:缓冲液配制
表3:配制的处方
处方编号 | PB-CB | CB | PB |
缓冲液 | 20mM PB-CB | 20mM CB | 20mM CB |
抗IL-17抗体浓度(mg/mL) | 8 | 8 | 8 |
体积(mL) | 10 | 10 | 10 |
将各处方在40℃恒温箱放置4周,考察各组样品的聚体、片段的变化情况。
由图1的SEC-HPLC单体纯度变化趋势可知,3组样品的变化趋势基本一致,但是下降幅度有显著差异,CB缓冲液明显优于其他组,其次是PB-CB较好。
由图2的SEC-HPLC聚体随时间的变化趋势分析可知,3组样品的聚体含量变化趋势基本一致,但是增加幅度有显著差异,CB缓冲液明显优于其他组,其次是PB-CB较好。
由图3的IEC-HPLC主峰随时间的变化趋势分析可知,随着时间的延长,3组样品的主峰含量均呈现下降趋势,其中PB-CB组和CB组相当,下降较PB组小。
由图4的CE-SDS(NR)单体纯度随时间的变化趋势分析可知,3组样品的变化趋势基本一致,下降幅度差别不大,说明不同缓冲体系对蛋白的CE-SDS(NR)各项指标基本没影响。
进一步地,对上述处方进行光照试验,4000lx,25℃放置14天,检测各项指标情况。
由图5可见,抗体在光照条件下,随着时间的增加,3组样品的单体含量均有不同程度的下降,CB缓冲液最好。
由图6的多聚体含量变化趋势可以见,3组样品的聚体含量增加趋势基本一致,但是增加幅度有差异,CB缓冲液聚体增加相对最缓慢。
由图7的IEC-HPLC主峰随时间的变化趋势可知,各组差别不大。
由图8从CE-SDS(NR)主峰含量变化趋势图可以看出,与第0天相比,光照条件下3组样品的主峰含量均有不同程度的下降,3组样品间差别不大。
综合SEC-HPLC、IEC-HPLC和CE-SDS(NR)的结果可知,40℃高温及光照环境下,样品在CB缓冲液中稳定性最好;在PB或者PB-CB缓冲液中稳定性较差。故可以将CB缓冲液作为抗IL-17抗体制剂的缓冲液。
实施例3:稳定剂筛选实验
制备含不同稳定剂的样品,在相同的条件下(缓冲液为20mM柠檬酸盐缓冲液),考察不同稳定剂对抗体稳定性的影响。
20mM柠檬酸盐缓冲液配制如下:柠檬酸一水合物21.014g/4L,氢氧化钠3.68g/4L,调整pH值为6.26。与下述各处方其他成分混合。各处方中,抗IL-17抗体的浓度为150mg/mL,pH值为6.26,以及包含各种稳定剂,各处方稳定剂的具体成分为:
KB:空白对照,无添加稳定剂;
Man:4%甘露醇;
Sor:4%山梨醇;
Tre:7.5%海藻糖二水合物;
Suc:7.5%蔗糖;
Arg.HCl:1%精氨酸盐酸盐;
NaCl:1%氯化钠;
Met:1%甲硫氨酸;
EDTA:1%乙二胺四乙酸;
Sor+Met:4%山梨醇+1%甲硫氨酸;
EDTA+Fe2+:1%乙二胺四乙酸+0.5mM七水合硫酸亚铁;
EDTA+Fe3+:1%乙二胺四乙酸+0.5mM六水三氯化铁。
将各处方分别进行高温和光照处理,考察各处方中抗体的变化情况。其中,高温处理条件为:40℃下放置4周,分别于第1周、第2周、第3周、第4周取样进行SEC-HPLC、IEC-HPLC、CE-SDS(NR)检测。光照处理条件为:在4000lx光照条件下(25℃)放置10d(天),分别于第5d(天)和10d(天)取样进行SEC-HPLC、IEC-HPLC、CE-SDS(NR)检测。
表4示出了高温处理下的检测数据。经过4周的高温实验,SEC-HPLC单体含量变化趋势有差异,含有EDTA的样品单体下降较快,特别是含有Fe2+和Fe3+离子的处方,其单体含量下降得最快。含有Met以及Met和山梨醇的处方,单体下降含量相对较少。
从SEC-HPLC多聚体数据分析可知,12组处方的变化趋势基本一致,但增加幅度有所不同。含有EDTA的处方中聚体增加较多,特别是含有Fe2+和Fe3+的处方,聚体增加最多。含有Met以及Met和山梨醇的处方,聚体增加量相对较少。
从IEC-HPLC主峰数据分析可知,高温条件下放置,含有EDTA的处方其IEC主峰下降比较明显,其中含有Fe2+和Fe3+的处方下降得最明显。其它各种稳定剂的稳定效果差别不大。
从CE-SDS(NR)主峰含量变化趋势可以看出,抗体在40℃高温条件下较为稳定。但含有EDTA的处方中,抗体稳定性较差,含有Fe2+和Fe3+的处方稳定性最差。含有其它稳定剂的处方,主峰含量变化差别不大。
表4:高温处理下含不同稳定剂的处方的检测结果
表5:光照实验下含不同稳定剂的处方的检测结果
表5示出了光照条件下的实验结果。从SEC-HPLC单体含量变化趋势可以看出,随着时间的增加,12组样品的单体含量均略有下降。从下降幅度来看,含有Met以及Met和Sor的处方,经10d(天)光照后,单体含量最高。
从SEC-HPLC多聚体数据分析可知,12组样品的多聚体均有上升,但上升幅度略有不同:KB组、Tre组、Suc组、EDTA+Fe2+和EDTA+Fe3+组,多聚体增加较为明显,而含有Met以及Met和山梨醇的处方,聚体增加较少。
从IEC-HPLC主峰数据分析可知,经10天光照后,含有Sor+Met以及Met的处方,其主峰值最高,即最稳定。
从CE-SDS(NR)主峰含量变化趋势可以看出,目的蛋白在光照条件下呈现下降趋势。具体来看,同样是含有Sor+Met以及Met的处方,其主峰值最高,即最稳定。
综合高温、光照的实验结果,可以看出Met以及Met+Sor在SEC-HPLC、IEC-HPLC、CE-SDS(NR)等方面表现都非常好,其中,山梨醇和甲硫氨酸的联合作用的稳定性最好。甲硫氨酸或山梨醇和甲硫氨酸的组合都可以作为有效的稳定剂。
实施例4:甲硫氨酸含量的选择
制备含不同含量甲硫氨酸(Met)的样品,在相同的条件下,考察甲硫氨酸含量对抗体稳定性的影响。所述样品的缓冲液为20mM组氨酸盐酸盐缓冲液:取组氨酸(His)2.17g/L和His·HCl·H2O(盐酸组氨酸(Merck,货号104354))1.257g/L,调节pH为6.3。利用该缓冲液超滤换液制备得到的抗IL-17抗体,并配制本实施例中使用的处方,各处方中,抗IL-17抗体的浓度为20mg/mL,pH值为6.3。各处方中包含的成分如表6所示。对各处方分别进行高温实验和光照实验,考察各处方中抗体的变化情况。其中,高温处理条件为:40℃下放置4周,分别于第1周、第2周、第3周、第4周取样进行SEC-HPLC、IEC-HPLC检测。光照处理条件为:在4000lx光照条件下(25℃)放置10天,分别于第5天和第10天取样进行SEC-HPLC、IEC-HPLC检测。
表6:含有不同浓度甲硫氨酸的处方
表7示出了在高温(40℃)条件下,不同含量甲硫氨酸的样品的质量变化情况。
从SEC-HPLC单体含量变化趋势可以看出,在40℃高温下放置,不同浓度甲硫氨酸的样品单体均呈现下降趋势,各组之间差异不大。
从SEC-HPLC多聚体数据分析可知,8组样品的变化趋势基本一致,但上升幅度略有不同,总体差别不显著。
从IEC-HPLC主峰数据分析可知,高温条件下放置,不同含量甲硫氨酸样品主峰方面没有明显差别。
表7:高温实验下不同浓度Met各指标随着时间的变化情况
表8示出了光照条件下,加有不同含量甲硫氨酸的样品的检测结果。从SEC-HPLC单体含量变化趋势可以看出,随着时间的增加,8组样品的单体含量均有下降。从下降幅度以及与对照处方相比(处方7)来看,优选处方1、2、3、4(0.15%-1%的Met)。
从IEC-HPLC主峰数据分析可知,8组样品的主峰含量均随光照时间的延长,呈下降的趋势。分析可知,在光照条件下放置,与对照处方相比(处方7),优选处方1、2、3、4(0.15%-1%的Met)。
表8:光照实验下不同浓度Met处方的实验结果
综合高温、光照的实验结果,与对照处方相比(处方7),优选0.15%-1%的Met作为稳定剂。
实施例5:表面活性剂筛选实验
制备不同表面活性剂的样品和不同浓度表面活性剂的样品,通过震荡试验(200rpm,室温),考察其稳定性。配制含有不同种类及浓度的表面活性剂的处方,各处方中,抗IL-17抗体的浓度为150mg/mL,pH值为6.26,缓冲液为20mM柠檬酸盐缓冲液。各处方的成分和含量如表9所示;其中,TW20为吐温20,TW80为吐温80。
各制剂的制备方法是:先配制20mM的柠檬酸盐缓冲液(以1mL缓冲液量计,称取4.2mg柠檬酸一水合物,用5M NaOH调节pH为6.3),将抗IL-17抗体超滤换液至20mM的pH6.3柠檬酸盐缓冲液,抗体终浓度为150mg/ml。在上述抗体溶液中分别加入0.01%~0.04%表面活性剂(TW20或TW80)或不加,混匀。
表9:含有不同种类及浓度的表面活性剂的处方
震荡后,考察各处方的浊度变化情况,结果如表10所示。
表10:不同种类和含量表面活性剂样品溶液震荡后浊度(OD340)变化情况
从表10的溶液浊度变化趋势可以看出,在震荡条件下放置2小时(h)后,空白样品开始出现明显浑浊,而加有表面活性剂的样品震荡至72h仍然保持澄明,说明表面活性剂对样品在振荡条件下有一定的保护作用,可以防止蛋白聚集出现浑浊,起到增溶的作用。为了进一步对含有表面活性剂的样品进行分析,在浓度为0.01~0.02%时,在不同时间点,含有吐温80的样品浊度值明显低于含有吐温20的样品。且不同浓度的吐温80之间,浊度没有明显差别;吐温80的增溶解效果优于吐温20,故选择吐温80作为抗IL-17抗体的表面活性剂。
进一步地,将表9的处方分别置于-20℃和25℃各12小时,考察其稳定性。具体地,在-20℃和25℃分别放置12小时(h)为一次反复冻融,连续5次,取样时间点:0次、3次、5次,检测不溶性微粒情况。结果如表11所示。
表11:不同种类和含量表面活性剂样品溶液反复冻融5次的微粒变化情况
在反复冻融5次后,加有表面活性剂的样品微粒数明显比没加的样品低,说明表面活性剂在反复冻融过程中能有效地防止蛋白聚集。对于不同种类表面活性剂来说,吐温80降低微粒的能力较好。综合前面的实验数据,为了保障吐温含量足够起到保护作用又不至于太高,故选择0.02%的吐温80作为抗IL-17抗体的表面活性剂。
实施例6:制剂实验
综合以上所有实验的结果,本发明优选的制剂包含:150mg/mL抗IL-17抗体、20mM柠檬酸盐缓冲液、3%山梨醇、0.4%甲硫氨酸、0.02%吐温80,pH值5.8~6.4,优选6.1。
该制剂的制备方法可以是:以1mL制剂量计,取150mg抗IL-17抗体、0.59mg柠檬酸一水合物、5.06mg柠檬酸钠二水合物、30mg山梨醇、4mg甲硫氨酸、0.2mg吐温80,加水至1mL,溶解并混匀上述物质,pH约为6.1。
该制剂的制备方法可以是:
1)缓冲液配制
超滤缓冲液(5L):称取2.94g柠檬酸一水合物,25.30g柠檬酸钠二水合物,20.00g甲硫氨酸,用注射用水溶解,定容至5L。pH:6.1±0.3。
10%(w/v)聚山梨酯80母液(10mL):称取1.00g聚山梨酯80,用注射用水溶解并定容至10mL。
16×制剂缓冲液母液(50mL):称取0.0295g柠檬酸一水合物,0.2530g柠檬酸钠二水合物,0.20g甲硫氨酸,24.00g山梨醇,用注射用水溶解后加入1.6mL 10%(w/v)聚山梨酯80母液,用注射用水定容至50mL。溶液pH:6.1±0.3。
2)超滤换液及稀配
用超滤缓冲液对纯化后的抗IL-17抗体进行超滤换液,换液完成后浓缩至160mg/mL,以上即为UF。
按UF:16×制剂缓冲液母液=15:1的比例加入16×制剂缓冲液母液,获得目标制剂。
稳定性验证
配制上述处方(实施例6处方,pH6.1)的抗IL-17抗体制剂,编号为01;配制对照制剂(处方为:150mg/mL抗IL-17抗体、L-His/His-HCl(3.103mg/mL;0.71mg/mL组氨酸和2.393mg/mL盐酸组氨酸(Merck,货号104354))、0.746mg/mL甲硫氨酸、0.2mg/mL吐温80、75.67mg/mL海藻糖二水合物,pH5.8),编号为02。将上述2个制剂在25℃条件下放置5个月,考察其稳定性。SEC-HPLC结果如表12所示。
表12:抗IL-17抗体制剂室温(25℃)下的SEC-HPLC单体(%)的变化
编号 | 0天 | 1月 | 2月 | 3月 | 5月 |
01 | 98.53 | 98.03 | 96.99 | 96.65 | 95.75 |
02 | 98.42 | 97.69 | 96.83 | 96.36 | 95.52 |
根据结果可见,本发明的抗IL-17抗体制剂中,抗体的SEC-HPLC的单体含量较高。本发明的抗IL-17抗体制剂在室温的条件下具有良好的稳定性。
序列表
<110> 百奥泰生物制药股份有限公司
<120> 稳定的抗体制剂及其制备方法和应用
<150> PCT/CN2020/138273
<151> 2020-12-22
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Claims (10)
1.一种抗体制剂,包括抗IL-17抗体、缓冲剂、稳定剂和表面活性剂,其中,所述稳定剂选自甲硫氨酸或甲硫氨酸和糖醇的组合,所述抗体制剂的pH值为5.4~6.6,或5.8~6.6,或5.8~6.4,或6.1。
2.根据权利要求1所述的抗体制剂,其中,所述甲硫氨酸的浓度为0.15%-1%,或0.4%或1%;所述糖醇的浓度为3%-5%,或3%或4%;或者,所述糖醇为山梨醇。
3.根据权利要求1或2所述的抗体制剂,其中,所述缓冲剂为柠檬酸盐缓冲液和/或磷酸盐缓冲液,或柠檬酸盐缓冲液;浓度为10-30mM,或20mM。
4.根据权利要求1~3任一项所述的抗体制剂,其中,所述表面活性剂为吐温80或吐温20,或吐温80;浓度为0.01%~0.04%,或0.02%。
5.根据权利要求1~4任一项所述的抗体制剂,其中,所述抗IL-17抗体的浓度为100mg/mL~300mg/mL,或150mg/mL。
6.根据权利要求1~5任一项所述的抗体制剂,其中,所述抗IL-17抗体的轻链序列如SEQ ID NO:1所示,重链序列如SEQ ID NO:2所示;或者,所述抗IL-17抗体为单克隆抗体,由CHO细胞表达。
7.根据权利要求1~6任一项所述的抗体制剂,其中,所述制剂包括150mg/mL抗IL-17抗体、20mM柠檬酸盐缓冲液、3%糖醇、0.4%甲硫氨酸、0.02%吐温80,pH值5.8~6.4;或者,所述糖醇为山梨醇。
8.权利要求1~7任一项所述的抗体制剂的制备方法,包括,取指定量的抗IL-17抗体、缓冲剂、稳定剂和表面活性剂,加水溶解并混匀上述物质,调节到指定量体积。
9.权利要求1~7任一项所述的抗体制剂在用于制备治疗自身免疫疾病的产品中的应用。
10.根据权利要求9所述的应用,其中,所述自身免疫疾病是类风湿性关节炎、银屑病关节炎、糖尿病、哮喘、慢性斑块型银屑病或多发性硬化症。
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