CN113713094A - 一种抗il-6r抗体药物组合物及其用途 - Google Patents
一种抗il-6r抗体药物组合物及其用途 Download PDFInfo
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Abstract
本披露涉及一种抗IL‑6R抗体药物组合物及其用途。具体地,本披露涉及一种药物组合物,其包含抗IL‑6R抗体或其抗原结合片段以及缓冲液。进一步地,该药物组合物还包含稳定剂和表面活性剂。特别地,本披露中的药物组合物可用于治疗IL‑6相关的疾病或病症。
Description
技术领域
本披露属于药物制剂领域,具体涉及一种包含抗IL-6R抗体或其抗原结合片段的药物组合物,以及其作为药物的用途。
背景技术
这里的陈述仅提供与本披露有关的背景信息,而不必然地构成现有技术。
白介素6(IL-6)是一种多效性炎症细胞因子,能调节细胞生长和分化,在介导炎症反应及免疫应答中起着重要作用。白介素6和其受体(IL-6R)与许多疾病的发病机理相关,如多发性骨髓瘤、自身免疫性疾病、中枢神经系统(CNS)炎症、慢性类风湿性关节炎、血管炎和前列腺癌症等。
IL-6R是最早被发现的造血细胞因子受体超家族的成员,又被称为CD126,包括IL-6Rα及IL-6Rβ即IL-6家族成员共有信号转导蛋白gp130。IL-6只有与IL-6Rα结合形成IL-6/IL-6Rα复合物后才能与gp130结合形成高亲和力复合物(免疫学杂志,2006,25(5):475-479)。
IL-6Rα主要表达在肝细胞、中性粒细胞、巨噬细胞及某些淋巴细胞表面;gp130表达于所有细胞表面(Rheumatology(Oxford,England),2010,49(1):15-24)。另外还存在一种可溶形式的IL-6R(即sIL-6R)。sIL-6R在体液中运输,因此增加了对IL-6起反应的细胞的种类。例如,内皮细胞、滑膜细胞表达gp130,却不表达IL-6R。只有在sIL-6R存在时,才能对IL-6起反应(Rheumatology(Oxford,England),2010,49(1):15-24)。另外,还存在一种由gp130胞外区组成的可溶性片段(sgp130),它能与IL-6及sIL-6R复合物发生结合,具有拮抗IL-6生物学活性的作用。已有研究表明,IL-6R在多种疾病中均有异常高表达,比如多发性骨髓瘤、肝癌以及几乎所有的髓系白血病等(Journal of Experimental Hematology2001:9(2)184-187)。
为了保持抗体有效,抗体必须在生产、纯化、运输和储存期间维持其生物活性。已开发出新的生产和纯化技术可以生产大量的高度纯化的单克隆抗体。然而,仍然存在使这些抗体稳定以便运输和储存的难题,并且甚至还存在提供适合于给药的剂型的抗体的难题。变性、聚集、污染和粒子形成是抗体配制和储存中的重大障碍。由于抗体的多种多样性,没有适合于所有抗体的储存的通用配方或条件。一种抗体的最佳配制品对于该抗体通常是特定的。另外,取决于抗体的浓度,和/或抗体配制品的期望的物理性质,通常需要进一步定制抗体制剂以适应特异性抗体。抗体的制剂通常是商业抗体研究和开发过程的重要部分,因此,存在开发稳定的抗体制剂的需要。
目前已有WO1996011020A、WO200905245、WO2005061000、WO2010100135、WO2014066468、WO2016062766和CN101454345B等专利报道了IL-6R的抗体及IL-6R抗体制剂。
发明内容
本披露提供一种药物组合物,其包含抗IL-6R抗体或其抗原结合片段,以及缓冲剂,所述缓冲剂选自醋酸盐、组氨酸盐缓冲剂,所述缓冲剂优选为组氨酸-醋酸盐缓冲剂。
在一些实施方案中,药物组合物中所述缓冲剂的pH为4.5至6.0,优选4.5至5.0,优选为5.0至5.5,优选为5.0至6.0,优选为5.5至6.0,非限制的实施例包括约4.5、约4.6、约4.7、约4.8、约4.0、约5.0、约5.1、约5.2、约5.3、约5.4、约5.5、约5.6、约5.7、约5.8、约5.9、约6.0,优选为约5.5。
本披露中的药物组合物的最终pH与缓冲液pH几乎一致。但本领域技术人员公知,在制备药物制剂的过程中,可能会存在pH飘移,本披露药物制剂的最终pH的飘移在±0.3范围内。
在一些实施方案中,药物组合物中所述缓冲液浓度为5mM至30mM,优选为10mM至20Mm或5Mm至16mM,非限制性实施例包括约5mM、约7mM、约8mM、10mM、约12mM、约14mM、约16mM、约18mM、约20mM,最优选为约10mM。
在一些实施方案中,药物组合物中所述抗IL-6R抗体或其抗原结合片段浓度为1mg/mL至180mg/mL,优选为80mg/mL至120mg/mL,或优选为100mg/mL至120mg/mL,非限制性的实施例包括约约80mg/mL、约82mg/mL、约84mg/mL、约86mg/mL、约88mg/mL、约90mg/mL、约92mg/mL、约94mg/mL、约96mg/mL、约98mg/mL、约100mg/mL、约102mg/mL、约104mg/mL、约106mg/mL、约108mg/mL、约110mg/mL、约112mg/mL、约114mg/mL、约116mg/mL、约118mg/mL、约120mg/mL,最优选为约100mg/mL。
在一些实施方案中,药物组合物中还包含表面活性剂,优选为非离子型表面活性剂,如聚山梨醇酯,优选为聚山梨醇酯80或聚山梨醇酯20。本披露的药物制剂中包含的非离子型表面活性剂的量可以根据制剂所需的特定性质以及意图使用制剂的具体情况和目的而变化。
在一些实施方案中,药物组合物中所述的非离子型表面活性剂的浓度为0.01mg/mL至1.2mg/mL,优选为0.4mg/mL至1.2mg/mL,优选为0.4mg/mL至1.0mg/mL,优选为0.8mg/mL至1.0mg/mL,非限制性实施例包括:约0.4mg/mL、约0.5mg/mL、约0.6mg/mL、约0.7mg/mL、约0.8mg/mL、约0.9mg/mL、约1.0mg/mL,约1.1mg/mL、约1.2mg mL;最优选为约1.0mg/mL。
在一些实施方案中,药物组合物中还包括稳定剂,所述稳定剂优选为海藻糖或蔗糖,最优选为蔗糖。
在一些实施方案中,药物组合物中所述稳定剂的浓度为60mg/mL至90mg/mL,优选为70mg/mL至80mg/mL,非限制性实施例包括:约60mg/mL、约65mg/mL、约70mg/mL、约75mg/mL和约80mg/mL,优选为约75mg/mL。
在一些实施方案中,所述的药物组合物包含:
(a)5mM至15mM的组氨酸盐缓冲剂,pH为4.5至6.0;(b)80mg/mL至120mg/mL的抗IL-6R抗体或其抗原结合片段;(c)0.01mg/mL至1.2mg/mL的聚山梨醇酯80或聚山梨醇酯20;和(d)60mg/mL至90mg/mL的海藻糖或蔗糖;优选地,所述药物组合物包含:
(a)约10mM的组氨酸-醋酸盐缓冲剂,pH为约5.0至6.0;(b)100mg/mL至120mg/mL的抗IL-6R抗体或其抗原结合片段;(c)0.8mg/mL至1.0mg/mL的聚山梨醇酯80;和(d)70mg/mL至80mg/mL的蔗糖。
在一些实施方案中,所述的药物组合物包含:
(a)5mM至30mM的组氨酸盐缓冲剂,pH为4.5至6.0;(b)1mg/mL至180mg/mL的抗IL-6R抗体或其抗原结合片段;(c)0.01mg/mL至1.2mg/mL的聚山梨醇酯80;和(d)60mg/mL至90mg/mL的海藻糖或蔗糖;优选地,所述药物组合物包含:
(a)5mM至15mM的组氨酸盐缓冲剂,pH为5.0至6.0;(b)80mg/mL至120mg/mL的抗IL-6R抗体或其抗原结合片段;(c)0.4mg/mL至1.2mg/mL的聚山梨醇酯80;和(d)60mg/mL至90mg/mL的蔗糖。
在一些实施方案中,药物组合物包含:(a)约10mM的组氨酸-醋酸盐缓冲剂,pH为约5.5;(b)约100mg/mL的抗IL-6R抗体或其抗原结合片段;(c)约1.0mg/mL的聚山梨醇酯80;和(d)约75mg/mL的蔗糖。
在一些实施方案中,药物组合物中所述的抗IL-6R抗体或其抗原结合片段包含SEQID NO:15所示的CDR1,SEQ ID NO:16所示的CDR2,和SEQ ID NO:17所示的CDR3。
在一些实施方案中,药物组合物中所述的抗IL-6R抗体或其抗原结合片段为羊驼源抗体或嵌合抗体;优选地,所述抗IL-6R抗体或其抗原结合片段包含SEQ ID NO:14所示的VHH。
在一些实施方案中,药物组合物中所述的抗IL-6R抗体或其抗原结合片段为人源化抗体,其中所述的人源化抗体包含SEQ ID NO:14所示VHH的变体。
在一些实施方案中,药物组合物中所述变体是在SEQ ID NO:14所示的VHH的FR区上具有一个或多个选自A14P,E23A,Q44G,V78L,K86R,N96A,A97F和Q116L突变;优选地,所述变体的氨基酸序列如SEQ ID NO:20、21、22、23、24、25、26、27或28所示。
在一些实施方案中,药物组合物中所述的抗IL-6R抗体或其抗原结合片段包含人抗体Fc区;优选地,所述人抗体Fc区的序列如SEQ ID NO:19所示。
在一些实施方案中,药物组合物中所述的抗IL-6R抗体或其抗原结合片段的序列如SEQ ID NO:29、30、31、32、33、34、35、36、37或38所示;优选地,所述的抗IL-6R抗体或其抗原结合片段的序列如SEQ ID NO:32所示。
在一些实施方案中,所述的药物组合物包含:
(i)约10mM的组氨酸盐缓冲剂,pH为4.5至6.0;0.4mg/mL至1.0mg/mL的聚山梨醇酯80或聚山梨醇酯20;60mg/mL至90mg/mL的蔗糖或海藻糖;和20mg/mL至162mg/mL的序列如SEQ ID NO:32所示的抗IL-6R抗体或其抗原结合片段;
(ii)约10mM的组氨酸盐缓冲剂,pH为5.0至6.0;0.8mg/mL至1.0mg/mL的聚山梨醇酯80或聚山梨醇酯20;70mg/mL至80mg/mL的蔗糖或海藻糖;和100mg/mL至120mg/mL的序列如SEQ ID NO:32所示的抗IL-6R抗体或其抗原结合片段;
(iii)约10mM组氨酸盐缓冲剂,pH5.0至6.0;约0.2mg/mL聚山梨醇酯80;和约50mg/mL序列如SEQ ID NO:32所示的抗IL-6R抗体或其抗原结合片段;
(iv)约10mM组氨酸盐缓冲剂,pH 5.0至6.0,约0.4mg/mL聚山梨醇酯80;和约20mg/mL的序列如SEQ ID NO:32所示的抗IL-6R抗体或其抗原结合片段;
(v)约10mM组氨酸-醋酸盐缓冲剂,pH约5.5;和100mg/mL至162mg/mL的序列如SEQID NO:32所示的抗IL-6R抗体或其抗原结合片段;
(vi)约10mM组氨酸-醋酸缓盐冲剂,pH约5.5;0.4mg/mL至1.0mg/mL聚山梨醇酯80;约80mg/mL蔗糖;和100mg/mL至120mg/mL的序列如SEQ ID NO:32所示的抗IL-6R抗体或其抗原结合片段;
(vii)约10mM的组氨酸-醋酸盐缓冲剂,pH约5.5;约1.0mg/mL的聚山梨醇酯80;约75mg/mL的蔗糖;和约100mg/mL的序列如SEQ ID NO:32所示的抗IL-6R抗体或其抗原结合片段;
(viii)10mM的组氨酸-醋酸盐缓冲剂,pH 5.5;1.0mg/mL的聚山梨醇酯80;约75mg/mL的蔗糖;和100mg/mL的序列如SEQ ID NO:32所示的抗IL-6R抗体或其抗原结合片段;或
(viii)约10mM的组氨酸-醋酸盐缓冲剂,pH约5.8;约1.0mg/mL的聚山梨醇酯80;约75mg/mL的蔗糖;和约99mg/mL的序列如SEQ ID NO:32所示的抗IL-6R抗体或其抗原结合片段。
在一些实施方案中,所述的药物组合物包含:约10mM醋酸钠盐缓冲液,pH约4.5,约50mg/mL IL-6R抗体h1764-mu3,和约0.2mg/mL聚山梨醇酯80。
在一些实施方案中,所述的药物组合物包含:约10mM醋酸钠盐缓冲液,pH约5.0,约50mg/mL IL-6R抗体h1764-mu3,和约0.2mg/mL聚山梨醇酯80。
在一些实施方案中,所述的药物组合物包含:约10mM醋酸钠盐缓冲液,pH约5.5,约50mg/mL IL-6R抗体h1764-mu3,和约0.2mg/mL聚山梨醇酯80。
在一些实施方案中,所述的药物组合物包含:约10mM琥珀酸钠盐缓冲液,pH约5.0,约50mg/mL IL-6R抗体h1764-mu3,和约0.2mg/mL聚山梨醇酯80。
在一些实施方案中,所述的药物组合物包含:约10mM琥珀酸钠盐缓冲液,pH约5.5,约50mg/mL IL-6R抗体h1764-mu3,和约0.2mg/mL聚山梨醇酯80。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-盐酸盐缓冲液,pH约5.5,约50mg/mL IL-6R抗体h1764-mu3,和约0.2mg/mL聚山梨醇酯80。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-盐酸盐缓冲液,pH约6.0,约50mg/mL IL-6R抗体h1764-mu3,和约0.2mg/mL聚山梨醇酯80。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-醋酸盐缓冲液,pH约5.0,约20mg/mL IL-6R抗体h1764-mu3,和约0.4mg/mL聚山梨醇酯80。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-醋酸盐缓冲液,pH约5.5,约20mg/mL IL-6R抗体h1764-mu3,和约0.4mg/mL聚山梨醇酯80。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-醋酸盐缓冲液,pH约6.0,约20mg/mL IL-6R抗体h1764-mu3,和约0.4mg/mL聚山梨醇酯80。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-盐酸盐缓冲液,pH约5.5,约20mg/mL IL-6R抗体h1764-mu3,和约0.4mg/mL聚山梨醇酯80。
在一些实施方案中,所述的药物组合物包含:约10mM醋酸钠盐缓冲液,pH约5.5,约20mg/mL IL-6R抗体h1764-mu3,和约0.4mg/mL聚山梨醇酯80。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-醋酸盐缓冲液,pH约5.5,和约100mg/mL IL-6R抗体h1764-mu3。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-醋酸盐缓冲液,pH约5.5,和约120mg/mL IL-6R抗体h1764-mu3。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-醋酸盐缓冲液,pH约5.5,和约162mg/mL IL-6R抗体h1764-mu3。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-醋酸盐缓冲液,pH约5.5,约100mg/mL IL-6R抗体h1764-mu3,约1.0mg/mL聚山梨醇酯80,和约80mg/mL蔗糖。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-醋酸盐缓冲液,pH约5.5,约120mg/mL IL-6R抗体h1764-mu3,约1.0mg/mL聚山梨醇酯80,和约80mg/mL蔗糖。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-醋酸盐缓冲液,pH约5.5,约100mg/mL IL-6R抗体h1764-mu3,约0.4mg/mL聚山梨醇酯80,和约80mg/mL蔗糖。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-醋酸盐缓冲液,pH约5.5,约100mg/mL IL-6R抗体h1764-mu3,约0.6mg/mL聚山梨醇酯80,和约80mg/mL蔗糖。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-醋酸盐缓冲液,pH约5.5,约100mg/mL IL-6R抗体h1764-mu3,约0.8mg/mL聚山梨醇酯80,和约80mg/mL蔗糖。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-醋酸盐缓冲液,pH约5.5,约100mg/mL IL-6R抗体h1764-mu3,约1.0mg/mL聚山梨醇酯80,和约80mg/mL蔗糖。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-醋酸盐缓冲液,pH5.5,约100mg/mL IL-6R抗体h1764-mu3,约1.0mg/mL聚山梨醇酯80,和约75mg/mL蔗糖。
在一些实施方案中,所述的药物组合物包含:约10mM组氨酸-醋酸盐缓冲液,pH约5.5,约99mg/mL IL-6R抗体h1764-mu3,约1.0mg/mL聚山梨醇酯80,和约75mg/mL蔗糖。
本披露还提供一种包含抗IL-6R抗体或其抗原结合片段的冻干制剂,其中所述的冻干制剂通过将权前述的药物组合物经冷冻干燥获得。
本披露还提供一种冻干制剂,所述冻干制剂由液体制剂:约10mM组氨酸-醋酸盐缓冲液,pH约5.5,约100mg/mL IL-6R抗体h1764-mu3,约1.0mg/mL聚山梨醇酯80,和约75mg/mL蔗糖冻干获得。
本披露还提供一种制备前述的药物组合物的方法,包括将抗IL-6R抗体或其抗原结合片段原液经缓冲液置换的步骤。
本披露还提供一种含有抗IL-6R抗体或其抗原结合片段的复溶溶液,其特征在于所述复溶溶液是通过将前述的冻干制剂经复溶制备获得;优选地,所述复溶溶液的pH为4.5至6.3,优选为约5.0至6.0,最优选为约5.8。
本披露还提供一种制品,其包括容器,该容器中装有如前任一项所述的药物组合物或前述的冻干制剂或前述的复溶溶液。
本披露还提供前述任一项的药物组合物,或前述的冻干制剂,或前述的复溶溶液在制备治疗或预防疾病的药物中的用途;优选地,所述的疾病为与IL-6相关的疾病。
本披露还提供一种抗IL-6R抗体,其包含如SEQ ID NO:29、30、31、32、33、34、35、36、37或38所示的序列或与SEQ ID NO:29、30、31、32、33、34、35、36、37或38所示的序列具有至少90%的同源性。其中所述的“至少90%同源性”包括但不限于至少91%、92%、93%、94%、95%、96%、97%、98%、99%和100%的同源性。
本披露还提供一种治疗或预防疾病的方法,所述方法包括向受试者施用治疗有效量的前述任一项的药物组合物,或前述的冻干制剂,或前述的复溶溶液,或前述的抗IL-6R抗体;优选地,所述的疾病为与IL-6相关的疾病。
本披露的前述任一项的药物组合物,或前述的冻干制剂,或前述的复溶溶液可用作治疗疾病的药物,或前述的抗IL-6R抗体;优选用作治疗与IL-6相关的疾病的药物。
在一些实施方式中,其中所述的疾病选自:脓毒症、多发性骨髓瘤、肾细胞癌、浆细胞白血病、淋巴瘤、B-淋巴组织增生、前列腺癌、骨质疏松症、恶病质、银屑病、肾小球系膜增生性肾小球肾炎、卡波西肉瘤、艾滋病相关的淋巴瘤、类风湿性关节炎、全身发作的青少年特发性关节炎、高丙球蛋白血症、局限性回肠炎、溃疡性大肠炎、系统性红斑狼疮、多发性硬化病、Castleman病、IgMγ-球蛋白病、心脏粘液瘤、哮喘、自体免疫性胰岛素-依赖型糖尿病和炎性贫血。
本披露的药物组合物可以用于预防和治疗与IL-6R、IL-6相关的和/或与IL-6/IL-6R复合体(任选地在与gp130的进一步复合体中)相关的、和/或与其中涉及IL-6和/或IL-6/IL-6R复合体(任选地在与gp130的进一步复合体中)的信号传导途径和/或生物学功能和反应相关的疾病和病症,并且特别用于预防和治疗与IL-6R、IL-6相关的和/或与IL-6/IL-6R复合体(任选地在与gp130的进一步复合体中)相关的、和/或与其中涉及IL-6R、IL-6和/或IL-6/IL-6R复合体(任选地在与gp130的进一步复合体中)的信号传导途径和/或生物学功能和反应相关的疾病和病症,所述疾病和病症的特征在于由IL-6R或由其中涉及IL-6R的途径介导的过量的和/或不需要的信号传导。基于本披露公开的内容,所述与IL-6R、IL-6相关的和/或与IL-6/IL-6R复合体相关的、和/或与其中涉及IL-6和/或IL-6/IL-6R复合体的信号传导途径和/或生物学功能和反应相关的疾病和病症的实例,对于熟练的技术人员将是清楚的。所述疾病和病症在本文通常还称为“IL-6相关的病症”或“IL-6R相关的疾病”。
附图说明
图1A至1C显示1764及其人源化抗体阻断IL-6和IL-6R结合的实验结果。
图2A至2B显示1764及其人源化抗体阻断gp130与IL-6/IL-6R结合的实验结果。
图3显示1764与U266B1细胞结合实验结果。
图4显示1764抗体抑制IL-6诱导的TF-1增殖检测实验结果。
具体实施方式
一.术语
为了更容易理解本披露,以下具体定义了某些技术和科学术语。除非在本文中另有明确定义,本文使用的所有其它技术和科学术语都具有本披露所属领域的一般技术人员通常理解的含义。
本披露将申请PCT/CN2018/105180中的全部内容引入本申请。
“缓冲剂”指通过其酸-碱共轭组分的作用而耐受pH变化的缓冲剂。将pH控制在适当范围中的缓冲剂的例子包括醋酸盐、琥珀酸盐、葡萄糖酸盐、组氨酸盐、草酸盐、乳酸盐、磷酸盐、枸橼酸盐、酒石酸盐、延胡索酸盐、甘氨酰甘氨酸和其它有机酸缓冲剂。
“组氨酸盐缓冲剂”是包含组氨酸根离子的缓冲剂。组氨酸盐缓冲剂的实例包括组氨酸-盐酸盐,组氨酸-醋酸盐,组氨酸-磷酸盐,组氨酸-硫酸盐等缓冲剂,优选组氨酸-醋酸盐缓冲剂,组氨酸-醋酸盐缓冲剂是组氨酸与醋酸配制而成。
“枸橼酸盐缓冲剂”是包括枸橼酸根离子的缓冲剂。枸橼酸盐缓冲剂的实例包括枸橼酸-枸橼酸钠、枸橼酸-枸橼酸钾、枸橼酸-枸橼酸钙、枸橼酸-枸橼酸镁等。优选的枸橼酸盐缓冲剂是枸橼酸-枸橼酸钠。
“琥珀酸盐缓冲剂”是包括琥珀酸根离子的缓冲剂。琥珀酸盐缓冲剂的实例包括琥珀酸-琥珀酸钠、琥珀酸-琥珀酸钾、琥珀酸-琥珀酸钙盐等。优选的琥珀酸盐缓冲剂是琥珀酸-琥珀酸钠。
“磷酸盐缓冲剂”是包括磷酸根离子的缓冲剂。磷酸盐缓冲剂的实例包括磷酸氢二钠-磷酸二氢钠、磷酸氢二钠-磷酸二氢钾、磷酸氢二钠-枸橼酸等。优选的磷酸盐缓冲剂是磷酸氢二钠-磷酸二氢钠。
“醋酸盐缓冲剂”是包括醋酸根离子的缓冲剂。醋酸盐缓冲剂的实例包括醋酸-醋酸钠、醋酸组氨酸盐、醋酸-醋酸钾、醋酸-醋酸钙、醋酸-醋酸镁等。优选的醋酸盐缓冲剂是醋酸-醋酸钠。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,所述其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是保持抗体活性成分的稳定性,促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
本文中,“药物组合物”和“制剂”并不互相排斥。
本披露中所述药物组合物的溶液形式,若无特殊说明,其中的溶剂均为水。
术语“表面活性剂(surfactant)”是指表面活性剂(surface-activeagent),优选非离子表面活性剂。使用表面活性剂可以降低制剂中蛋白质的聚集和/或降低颗粒的形成。添加的表面活性剂的量是使得其可以在制剂中降低蛋白质的聚集并最小化颗粒形成的量。
本披露的表面活性剂可选自聚山梨醇酯20、聚山梨醇酯80、聚羟亚烃、Triton、十二烷基磺酸钠、月桂基磺酸钠、辛基糖甙钠、月桂基/肉豆蔻基/亚油基/硬脂基-磺基甜菜碱、月桂基/肉豆蔻基/亚油基/硬脂基-肌氨酸、亚油基/肉豆蔻基/鲸蜡基-甜菜碱、月桂酰胺基丙基/柯卡酰胺基丙基/亚油酰胺基丙基/肉豆蔻酰胺基丙基/棕榈酰胺基丙基/异硬脂酰胺基丙基-甜菜碱、肉豆蔻酰胺基丙基/棕榈酰胺基丙基/异硬脂酰胺基丙基-二甲基胺、甲基可可酰基钠、甲基油基牛磺酸钠、聚乙二醇、聚丙二醇、乙烯与丙烯二醇的共聚物等等。优选的表面活性剂是聚山梨醇酯80或聚山梨醇酯20,更优选为聚山梨醇酯80。
“稳定剂”是指有助于维持生物制药药物的结构完整性的组分,特别是在冷冻和/或冻干和/或储存期间(特别是当暴露于应激(stress)时)。这种稳定作用可以由于多种原因而产生,通常这种稳定剂可起到减轻蛋白质变性的渗透剂的作用。如在本文中所使用的,稳定剂可以是糖、或者多种形式的氨基酸赖氨酸(例如,赖氨酸单盐酸盐、乙酸盐或一水合物)或者盐(例如,氯化钠)。
本披露的“糖”包含常规组合物(CH2O)n及其衍生物,包括单糖,二糖,三糖,多糖,糖醇,还原性糖,非还原性糖等等。可选自葡萄糖,蔗糖,海藻糖,乳糖,果糖,麦芽糖,右旋糖苷,甘油,赤藻糖醇,丙三醇,阿拉伯糖醇,木糖醇,山梨糖醇,甘露醇,密里二糖,松三糖,蜜三糖,甘露三糖,水苏糖,麦芽糖,乳果糖,麦芽酮糖,山梨醇,麦芽糖醇,乳糖醇,异-麦芽酮糖等等。优选的糖是非还原性二糖,更优选为海藻糖或蔗糖,最优选为蔗糖。
“置换”是指溶解抗体蛋白的溶剂体系的置换,例如,使用稳定制剂的缓冲体系经物理操作方式将含抗体蛋白的高盐或高渗溶剂体系置换,从而使抗体蛋白存在于稳定制剂中。所称物理操作方式包括但不限于超滤、透析或离心后复溶。
“冻干制剂”表示液体或溶液形式的药物组合物或液体或溶液制剂经真空冷冻干燥步骤之后获得的制剂或药物组合物。
术语“粘度”可以是“运动粘度”或“绝对粘度”。“运动粘度”是在重力影响下流体的阻止流动的量度。当将两个等体积的流体置于相同的毛细血管粘度计中并允许其借助重力流动时,粘的流体比更不粘的流体需要更长的时间流过该毛细管。例如,如果一种流体花200秒完成其流动,而另一流体花400秒,则第二种流体的运动粘度度量是第一种的两倍。“绝对粘度”有时也称为动力学或简单粘度,是运动粘度和流体密度的结果(绝对粘度=运动粘度×密度)。运动粘度的单位是L2/T,其中L是长度,T为时间。通常,运动粘度表示为厘沱(cSt)。运动粘度的SI单位是mm2/s,其为1cSt。绝对粘度表示为厘泊(cP)单位。绝对粘度的SI单位是毫帕斯卡-秒(mPa-s),其中1cP=1mPa-s。
本文所用术语“约”、“大约”是指数值在由本领域一般技术人员所测定的具体值的可接受误差范围内,所述数值部分取决于怎样测量或测定(即测量体系的限度)。例如,在本领域每一次实行中“约”可意味着在1内或超过1的标准差。或者,“约”或“基本上包含”可意味着其后所示的具体数值±30%的范围。此外,特别对于生物学系统或过程而言,该术语可意味着至多一个数量级或数值的至多5倍。除非另外说明,否则当具体值在本申请和权利要求中出现时,“约”或“基本上包含”的含义应该假定为在该具体值的可接受误差范围内。
本披露所述的药物组合物能够达到一种稳定的效果:其中的抗体在贮藏后基本上保留其物理稳定性和/或化学稳定性和/或生物学活性的药物组合物,优选地,药物组合物在贮藏后基本上保留其物理和化学稳定性以及其生物学活性。贮藏期一般基于药物组合物的预定保存期来选择。目前有多种测量蛋白质稳定性的分析技术,可测量在选定温度贮藏选定时间段后的稳定性。
稳定的药物抗体制剂是在下述情况下没有观察到显著变化的制剂:在冷藏温度(2-8℃)保存至少3个月、优选6个月、更优选1年,且甚至更优选地多达2年。另外,稳定的液体制剂包括这样的液体制剂:其在包括25℃的温度保存包括1个月、3个月、6个月在内的时段后表现出期望的特征。稳定性的典型的可接受的标准如下:通过SEC-HPLC测得,通常不超过约10%、优选不超过约5%的抗体单体发生降解。通过视觉分析,药物抗体制剂是淡黄色近无色澄明液体或者无色,或澄清至稍微乳白色。所述制剂的浓度、pH和重量克分子渗透压浓度具有不超过±10%变化。通常观察到不超过约10%、优选不超过约5%的减少。通常形成不超过约10%、优选不超过约5%的聚集。
如果在目检颜色和/或澄清度后,或者通过UV光散射、尺寸排阻色谱法(SEC)和动态光散射(DLS)测得,抗体没有显示出显著的聚集增加、沉淀和/或变性,那么所述抗体在药物制剂中“保留它的物理稳定性”。蛋白构象的变化可以通过荧光光谱法(其确定蛋白三级结构)和通过FTIR光谱法(其确定蛋白二级结构)来评价。
如果抗体没有显示出显著的化学改变,那么所述抗体在药物制剂中“保留它的化学稳定性”。通过检测和定量化学上改变的形式的蛋白,可以评估化学稳定性。经常改变蛋白化学结构的降解过程包括水解或截短(通过诸如尺寸排阻色谱法和SDS-PAGE等方法来评价)、氧化(通过诸如与质谱法或MALDI/TOF/MS结合的肽谱法等方法来评价)、脱酰胺作用(通过诸如离子交换色谱法、毛细管等电聚焦、肽谱法、异天冬氨酸测量等方法来评价)和异构化(通过测量异天冬氨酸含量、肽谱法等来评价)。
如果抗体在给定时间的生物活性是在制备药物制剂时表现出的生物活性的预定范围内,那么所述抗体在药物制剂中“保留它的生物活性”。抗体的生物活性可以例如通过抗原结合测定来确定。
本披露所用氨基酸三字母代码和单字母代码如J.biol.chem,243,p3558(1968)中所述。
常规的免疫球蛋白是四聚体,由两条重链和两条轻链组成,组合分子量约150kDa。在骆驼科(Camelidae)成员中,相当比例的血清抗体是同源二聚体IgG,分子量约80kD(Hamers-Casterman等人.1993Nature,363,446-448)。这些重链免疫球蛋白(Ig)包含三个结构域,其可变区被称为VHH(variable domain of heavy chain of heavy-chainantibody)。重组VHH(约12至14kD)构成完整的抗原结合结构域并显示出广阔的抗原结合谱。扩大它们的高变区,并表现出独特的特性,如三至四个(与常规抗体VL相互作用的)疏水框架残基被更多亲水性氨基酸取代。为了稳定扩大的CDR,除了常规的二硫键以外,在单峰骆驼CDR1和CDR3之间,在美洲驼的CDR2和CDR3之间,VHH可具有额外的二硫键(Harmsen和DeHaard2007Appl Microbiol Biotechnol.,77,13-22;Muyldermans 2001JBiotechnol.,74,277-302)。扩大的CDR3环可以采取凸面构象,而常规的互补位被限制在凹的或者平面结构(Muyldermans 2001J Biotechnol.,74,277-302)。这些特征允许VHH识别对于常规抗体而言免疫原性较差的独特表位(Lafaye等人.2009Mol Immuno.,46,695-704;Wernery 2001JVet Med B Infect Dis Vet Public Health.,48,561-568)。尽管VHH被定义为单价抗体,默认排除任何亲合力效果,被测量表示为体外IC50的生物活性可类似于常规的二价抗体分子(Thys等人.2010Antiviral Res.,87:257-264)。
术语“单克隆抗体”是指由一群基本同源的抗体获得的抗体,即包含在该群体中的各个抗体是相同的(除了可能以少量存在的可能的天然突变以外)。单克隆抗体针对单个抗原位点具有高度特异性。此外,与常规的多克隆抗体制剂(其通常包括针对抗原上不同决定簇(表位)的不同抗体)不同的是,每个单克隆抗体只针对抗原上的单个决定簇或表位。
在某些实施方式中,本披露可涉及嵌合的骆驼科动物/人抗体,特别是其中VH和/或VL结构域完全是骆驼科动物序列(例如大羊驼或阿尔帕卡羊驼),而抗体的其余部分完全是人序列的嵌合抗体。在本披露的一些优选实施方式中,还包括“人源化”或“种系化”的骆驼科抗体以及骆驼科/人嵌合抗体,其中VH和/或VL结构域相对于通过主动免疫获得的骆驼科VH和/或VL结构域来说在框架区包含一个或多个氨基酸替换。用人种系VH或VL结构域中的对应残基来取代起始骆驼科VH或VL结构域中的不匹配氨基酸残基,这样的“人源化”过程提高了与人种系VH或VL结构域的序列一致性百分比。
“重组”涉及采用遗传工程的方法(克隆、扩增)来生产所述VHH或VH。
根据本披露的VHH能够是单体的形式或者同源多聚体的形式,如同源二聚体或同源三聚体。
抗体重链和轻链靠近N端的约110个氨基酸的序列变化很大,为可变区(Fv区);靠近C端的其余氨基酸序列相对稳定,为恒定区。可变区包括3个高变区(HVR)和4个序列相对保守的骨架区(FR)。3个高变区决定抗体的特异性,又称为互补性决定区(CDR)。每条轻链可变区(LCVR)和重链可变区(HCVR)各由3个CDR区4个FR区组成,从氨基端到羧基端依次排列的顺序为:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。轻链的3个CDR区指LCDR1、LCDR2、和LCDR3;重链的3个CDR区指HCDR1、HCDR2和HCDR3。本披露所述的抗体或抗原结合片段的LCVR区和HCVR区的CDR氨基酸残基在数量和位置符合已知的Kabat编号规则(LCDR1-3,HCDR1-3)。
本披露的抗体包括羊驼源抗体、嵌合抗体、人源化抗体,优选人源化抗体。
术语“羊驼源抗体”为根据本领域知识和技能制备的针对人IL-6R来源于羊驼的单克隆抗体。制备时,用IL-6R抗原注射实验对象,然后分离表达具有所需序列或功能特性的抗体的杂交瘤,或者建立免疫文库,通过噬菌体展示技术分离具有所需功能的抗体。在本披露一个具体的实施方式中,所述的羊驼源IL-6R抗体或其抗原结合片段,可进一步包含羊驼的重链Fc区。
术语“嵌合抗体(chimeric antibody)”,是将羊驼源性抗体的可变区与人抗体的恒定区(或Fc区)融合而成的抗体,可以减轻羊驼源性抗体诱发的免疫应答反应。建立嵌合抗体,要先建立分泌羊驼源性特异性单抗的杂交瘤或抗体文库,然后将羊驼抗体可变区基因与人恒定区基因(或Fc区基因)连接成嵌合基因后插入表达载体中,最后在真核系统或原核系统中表达嵌合抗体分子。在本披露一个具体的实施方式中,所述的IL-6R嵌合抗体的抗体重链进一步包含人源IgG1、IgG2、IgG3、IgG4或其变体的重链恒定区(或Fc区),优选包含人源IgG1、IgG2或IgG4重链恒定区(或Fc区),或者包含氨基酸突变(如YTE突变或回复突变)的IgG1、IgG2或IgG4重链恒定区(或Fc区)变体。
术语“人源化抗体(humanized antibody)”,是指将羊驼的CDR序列移植到人的抗体可变区框架,即不同类型的人种系抗体框架序列中产生的抗体。可以克服嵌合抗体由于携带大量羊驼蛋白成分,从而诱导的异源性反应。此类构架序列可以从包括种系抗体基因序列的公共DNA数据库或公开的参考文献获得。如人重链和轻链可变区基因的种系DNA序列可以在“VBase”人种系序列数据库(www.mrccpe.com.ac.uk/vbase)中获得,以及在Kabat,E.A.等人,1991Sequences of Proteins of Immunological Interest第5版中找到。为避免免疫原性下降的同时,引起的活性下降,可对所述的人抗体可变区框架序列进行最少反向突变或回复突变,以保持活性。本披露的人源化抗体也包括进一步由噬菌体展示对CDR进行亲和力成熟后的人源化抗体。为避免免疫原性下降的同时,引起的活性下降,采用基于1764序列渐进式向人源突变模式,逐渐替换1764的FR区羊驼来源残基为人源残基,以保持活性。在本申请中,“人源化抗体”也包含通过对羊驼单域抗体的FR渐进式向人源突变获得单域抗体。
术语“VHH”涉及来自骆驼科(骆驼、单峰骆驼、美洲驼、羊驼等)重链抗体的可变抗原结合结构域(参见Nguyen等人.2000EMBO J.,19,921-930;Muyldermans 2001JBiotechnol.,74,277-302以及综述Vanlandschoot等人.2011Antiviral Res.92,389-407)。
通常纳米抗体可以定义为具有下述(通用)结构的氨基酸序列:
FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4
其中,FR1-FR4分别是指构架区(Frame)1-4,并且其中CDR1-CDR3分别是指互补决定区1-3。
本文中使用的术语“抗体构架区”或“抗体框架区”,是指可变结构域VH的一部分,其用作该可变结构域的抗原结合环(CDR)的支架。从本质上讲,其是不具有CDR的可变结构域。
术语抗体的“抗原结合片段”或“功能片段”是指抗体的保持特异性结合抗原(例如,IL-6R)的能力的一个或多个片段。已显示可利用全长抗体的片段来实现抗体的抗原结合功能。术语抗体的“抗原结合片段”中包含的结合片段的实例包括:
(i)Fab片段,由VL、VH、CL和CH1结构域组成的单价片段;
(ii)F(ab')2片段,包含通过铰链区上的二硫桥连接的两个Fab片段的二价片段,
(iii)由VH和CH1结构域组成的Fd片段;
(iv)由抗体的单臂的VH和VL结构域组成的Fv片段;
(v)单结构域或dAb片段(Ward等人,(1989)Nature 341:544-546),其由VHH结构域组成;
(vi)VHH与Fc形成的融合蛋白;
(vii)VHH与抗体重链恒定区形成的融合蛋白。
此外,“抗原结合片段”还包括含有VHH中三个CDR的可结合IL-6R的其他抗原结合形式。
本披露还进一步延伸至这样的抗原结合多肽,其中VHH结构域的高变环或CDR来自于骆驼科,但相对于骆驼科动物编码的序列来说,其中至少一个所述(骆驼科动物来源的)高变环或CDR被改造成包含一个或多个氨基酸替换、添加或缺失。这些变化包括高变环/CDR的“人源化”。以这种方式改造的骆驼科动物来源之HV/CDR仍可以表现出与由骆驼科动物编码的HV/CDR之氨基酸序列“基本一致”的氨基酸序列。在这种情况下,“基本一致”可允许与骆驼科动物编码的HV/CDR含有不超过一个,或不超过两个,或不超过三个氨基酸序列不匹配。
本披露的抗体可以是任何同种型。用于人类治疗用途的抗体类型通常为IgA、IgD、IgE、IgG、IgM型。通常是IgG型,在这种情况下,它们可以属于IgG1、IgG2a和IgG2b、IgG3或IgG4四个亚类中的任何一种。在这些亚类中,允许在Fc部分进行一个或多个氨基酸的替换、插入或缺失,或进行其它结构修饰,从而例如提高或降低Fc依赖的功能。
本披露的抗体可以通过以下步骤来生产:获得本披露的特异性识别人IL-6R并与胞外区(氨基酸序列或其三维结构)结合的单克隆抗体的VHH的编码cDNA,构建编码VHH的DNA,以使肽接头的氨基酸序列长度为8个残基或更少,将所述DNA插入到原核生物表达载体或真核生物表达载体中,然后将所述表达载体导入到原核生物或真核生物中以表达抗体。
术语“表位”或“抗原决定簇”是指抗原上免疫球蛋白或抗体特异性结合的部位(例如,IL-6R分子上的特定部位)。表位通常以独特的空间构象包括至少3、4、5、6、7、8、9、10、11、12、13、14或15个连续或非连续的氨基酸。参见,例如,Epitope Mapping Protocols inMethods in Molecular Biology,第66卷,G.E.Morris编(1996)。
术语“特异性结合”、“选择性结合”、“选择性地结合”和“特异性地结合”是指抗体对预先确定的抗原上的表位的结合。通常,抗体以大约小于10-7M,例如大约小于10-8M、10-9M或10-10M或更小的亲和力(KD)结合。
术语"KD"或“Kd”是指特定抗体-抗原相互作用的解离平衡常数。通常,本披露的抗体以小于大约10-7M,例如小于大约10-8M、10-9M或10-10M或更小的解离平衡常数(KD)结合IL-6R,如使用表面等离子体共振(SPR)技术在BIACORE仪中测定的。
当术语“竞争”用于竞争相同表位的抗原结合蛋白(例如中和抗原结合蛋白或中和抗体)的情况中时,意指在抗原结合蛋白之间竞争,其通过以下测定法来测定:待检测的抗原结合蛋白(例如抗体或其免疫学功能片段)防止或抑制(例如降低)参考抗原结合蛋白(例如配体或参考抗体)与共同抗原(例如IL-6R抗原或其片段)的特异性结合。众多类型的竞争性结合测定可用于确定一种抗原结合蛋白是否与另一种竞争,这些测定例如:固相直接或间接放射免疫测定(RIA)、固相直接或间接酶免疫测定(EIA)、夹心竞争测定(参见例如Stahli等,1983,Methodsin Enzymology 9:242-253);固相直接生物素-亲和素EIA(参见,例如Kirkland等,1986,J.Immunol.137:3614-3619)、固相直接标记测定、固相直接标记夹心测定(参见例如Harlow和Lane,1988,Antibodies,A Laboratory Manual(抗体,实验室手册),Cold Spring Harbor Press);用I-125标记物的固相直接标记RIA(参见例如Morel等,1988,Molec.Immunol.25:7-15);固相直接生物素-亲和素EIA(参见例如Cheung,等,1990,Virology176:546-552);和直接标记的RIA(Moldenhauer等,1990,Scand.J.Immunol.32:77-82)。通常所述测定法涉及,使用能与带有未标记的检测抗原结合蛋白及标记的参考抗原结合蛋白结合的纯化抗原(所述抗原在固态表面或细胞表面)。在待测抗原结合蛋白存在下,测量结合于固态表面或细胞的标记的量,来测量竞争性抑制。通常,待测抗原结合蛋白是过量存在的。由竞争性测定(竞争抗原结合蛋白)鉴定的抗原结合蛋白包括:与参考抗原结合蛋白相同的表位发生结合的抗原结合蛋白;以及,与充分接近参考抗原结合蛋白结合的表位所邻近的表位发生结合的抗原结合蛋白,所述两个表位在空间上互相妨碍结合的发生。在本文实施例中提供关于用于测定竞争性结合的方法的其它详细资料。通常当竞争的抗原结合蛋白过量存在时,其将抑制(例如降低)至少40-45%、45-50%、50-55%、55-60%、60-65%、65-70%、70-75%或75%或更多参考抗原结合蛋白与共同抗原的特异性结合。在某些情况下,结合被抑制至少80-85%、85-90%、90-95%、95-97%或97%或更多。
本文中使用的术语“核酸分子”是指DNA分子和RNA分子。核酸分子可以是单链或双链的,但优选是双链DNA。当将核酸与另一个核酸序列置于功能关系中时,核酸是“有效连接的”。例如,如果启动子或增强子影响编码序列的转录,那么启动子或增强子有效地连接至所述编码序列。
术语“载体”是指能够运输与其连接的另一个核酸的核酸分子。在一个实施方式中,载体是“质粒”,其是指可将另外的DNA区段连接至其中的环状双链DNA环。在另一个实施方式中,载体是病毒载体,其中可将另外的DNA区段连接至病毒基因组中。本文中公开的载体能够在已引入它们的宿主细胞中自主复制(例如,具有细菌的复制起点的细菌载体和附加型哺乳动物载体)或可在引入宿主细胞后整合入宿主细胞的基因组,从而随宿主基因组一起复制(例如,非附加型哺乳动物载体)。
现有技术中熟知生产和纯化抗体和抗原结合片段的方法,如冷泉港的抗体实验技术指南,5-8章和15章。例如,鼠可以用人IL-6R或其片段免疫,所得到的抗体能被复性、纯化,并且可以用常规的方法进行氨基酸测序。抗原结合片段同样可以用常规方法制备。发明所述的抗体或抗原结合片段用基因工程方法在非人源的CDR区加上一个或多个人源FR区。人FR种系序列可以通过比对IMGT人类抗体可变区种系基因数据库和MOE软件,从ImMunoGeneTics(IMGT)的网站http://imgt.cines.fr得到,或者从免疫球蛋白杂志,2001ISBN012441351上获得。
术语“宿主细胞”是指已向其中引入了表达载体的细胞。宿主细胞可包括微生物(例如细菌)、植物或动物细胞。易于转化的细菌包括肠杆菌科(enterobacteriaceae)的成员,例如大肠杆菌(Escherichia coli)或沙门氏菌(Salmonella)的菌株;芽孢杆菌科(Bacillaceae)例如枯草芽孢杆菌(Bacillus subtilis);肺炎球菌(Pneumococcus);链球菌(Streptococcus)和流感嗜血菌(Haemophilus influenzae)。适当的微生物包括酿酒酵母(Saccharomyces cerevisiae)和毕赤酵母(Pichia pastoris)。适当的动物宿主细胞系包括但不限于CHO(中国仓鼠卵巢细胞系)HEK细胞(非限制性实施例HEK293E细胞)和NS0细胞等。
本披露工程化的抗体或抗原结合片段可用常规方法制备和纯化。比如,编码重链和轻链的cDNA序列,可以克隆并重组至GS表达载体。重组的免疫球蛋白表达载体可以稳定地转染CHO细胞。作为一种更推荐的现有技术,哺乳动物类表达系统会导致抗体的糖基化,特别是在Fc区的高度保守N端位点。通过表达与人IL-6R特异性结合的抗体得到稳定的克隆。阳性的克隆在生物反应器的无血清培养基中扩大培养以生产抗体。分泌了抗体的培养液可以用常规技术纯化。比如,用含调整过的缓冲液的A或G Sepharose FF柱进行纯化。洗去非特异性结合的组分。再用PH梯度法洗脱结合的抗体,用SDS-PAGE检测抗体片段,收集。抗体可用常规方法进行过滤浓缩。可溶的混合物和多聚体,也可以用常规方法去除,比如分子筛、离子交换。得到的产物需立即冷冻(如-70℃)或者冻干。
“给予”、“施用”和“处理”当应用于动物、人、受试者、细胞、组织、器官或生物流体时,是指外源性药物、治疗剂、诊断剂或组合物与动物、人、受试者、细胞、组织、器官或生物流体的接触。“给予”、“施用”和“处理”可以指例如治疗、药物代谢动力学、诊断、研究和实验方法。细胞的处理包括试剂与细胞的接触,以及试剂与流体的接触,其中所述流体与细胞接触。“给予”、“施用”和“处理”还意指通过试剂、诊断、结合组合物或通过另一种细胞体外和离体处理细胞。“处理”当应用于人、兽医学或研究受试者时,是指治疗处理、预防或预防性措施,研究和诊断应用。
“治疗”意指给予患者内用或外用治疗剂,例如包含本披露的任一种抗体或其片段的组合物,所述患者具有一种或多种疾病症状,而已知所述治疗剂对这些症状具有治疗作用。通常,在受治疗患者或群体中以有效缓解一种或多种疾病症状的量给予治疗剂,以诱导这类症状退化或抑制这类症状发展到任何临床右测量的程度。有效缓解任何具体疾病症状的治疗剂的量(也称作“治疗有效量”)可根据多种因素变化,例如患者的疾病状态、年龄和体重,以及药物在患者产生需要疗效的能力。通过医生或其它专业卫生保健人士通常用于评价该症状的严重性或进展状况的任何临床检测方法,可评价疾病症状是否已被减轻。尽管本披露的实施方式(例如治疗方法或制品)在缓解每个目标疾病症状方面可能无效,但是根据本领域已知的任何统计学检验方法如Student t检验、卡方检验、依据Mann和Whitney的U检验、Kruskal-Wallis检验(H检验)、Jonckheere-Terpstra检验和Wilcoxon检验确定,其在统计学显著数目的患者中应当减轻目标疾病症状。
“保守修饰”或“保守置换或取代”是指具有类似特征(例如电荷、侧链大小、疏水性/亲水性、主链构象和刚性等)的其它氨基酸置换蛋白中的氨基酸,使得可频繁进行改变而不改变蛋白的生物学活性。本领域技术人员知晓,一般而言,多肽的非必需区域中的单个氨基酸置换基本上不改变生物学活性(参见例如Watson等(1987)Molecar Biology of theGene,The Benjamin/Cummings Pub.Co.,第224页,(第4版))。另外,结构或功能类似的氨基酸的置换不大可能破环生物学活性。
“有效量”包含足以改善或预防医学疾病的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化:例如,待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
“外源性”指根据情况在生物、细胞或人体外产生的物质。“内源性”指根据情况在细胞、生物或人体内产生的物质。
“同源性(homology)”是指两个多核苷酸序列之间之间的序列相似性。当两个比较序列中的位置均被相同碱基或氨基酸单体亚基占据时,例如如果两个DNA分子的每一个位置都被腺嘌呤占据时,那么所述分子在该位置是同源的。两个序列之间的同源性百分率是两个序列共有的匹配或同源位置数除以比较的位置数×100的函数。例如,在序列最佳比对时,如果两个序列中的10个位置有6个匹配或同源,那么两个序列为60%同源;如果两个序列中的100个位置有95个匹配或同源,那么两个序列为95%同源。一般而言,当比对两个序列而得到最大的同源性百分率时进行比较。
本文使用的表述“细胞”、“细胞系”和“细胞培养物”可互换使用,并且所有这类名称都包括后代。因此,术语“转化体”和“转化细胞”包括原代受试细胞和由其衍生的培养物,而不考虑转移或传代的数目。还应当理解的是,由于故意或非有意的突变,所有后代在DNA含量方面不可能精确相同。包括具有与最初转化细胞中筛选的相同的功能或生物学活性的突变后代。在意指不同名称的情况下,其由上下文清楚可见。
本文使用的“聚合酶链式反应”或“PCR”是指其中微量的特定部分的核酸、RNA和/或DNA如在例如美国专利号4,683,195中所述扩增的程序或技术。一般来说,需要获得来自目标区域末端或之外的序列信息,使得可以设计寡核苷酸引物;这些引物在序列方面与待扩增模板的对应链相同或相似。2个引物的5’末端核苷酸可以与待扩增材料的末端一致。PCR可用于扩增特定的RNA序列、来自总基因组DNA的特定DNA序列和由总细胞RNA转录的cDNA、噬菌体或质粒序列等。一般参见Mlis等(1987)Cold Spring HarborSymp.Ouant.Biol.51:263;Erlich编辑,(1989)PCR TECHNOLOGY(Stockton Press,N.Y.)。本文使用的PCR被视为用于扩增核酸测试样品的核酸聚合酶反应法的一个实例,但不是唯一的实例,所述方法包括使用作为引物的已知核酸和核酸聚合酶,以扩增或产生核酸的特定部分。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生的场合。例如,“任选包含1-3个抗体重链可变区”意味着特定序列的抗体重链可变区可以但不必须存在。
二.实施例与测试例
以下结合实施例用于进一步描述本披露,但这些实施例并非限制本披露的范围。
本披露实施例或测试例中未注明具体条件的实验方法,通常按照常规条件,或按照原料或商品制造厂商所建议的条件。参见Sambrook等,分子克隆,实验室手册,冷泉港实验室;当代分子生物学方法,Ausubel等著,Greene出版协会,Wiley Interscience,NY。未注明具体来源的试剂,为市场购买的常规试剂。
实施例
实施例1:抗原、相关蛋白及抗体等试剂制备
编码分别带Fc、His、BP15(用于细胞内定点生物素化)标签的人源白细胞介素6受体(hIL-6R.Fc、hIL-6R.His、hIL-6R.BP15),带有Flag和His标签的食蟹猴IL-6R(cIL-6R.FH)以及带有Fc或His标签的人源IL-6(IL-6.Fc,IL-6.his),带有Fc标签的gp130序列经分子克隆构建入哺乳动物细胞瞬时表达载体中。
相关蛋白氨基酸序列如下:
hIL-6R.His(SEQ ID NO:1)
LAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNATVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLAVPEGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITVTAVARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTNKDDDNILFRDSANATSLPVQDSSSVPLPHHHHHH
hIL-6R.BP15(SEQ ID NO:2)
LAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNATVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLAVPEGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITVTAVARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTNKDDDNILFRDSANATSLPVQDSSSVPLPGSSDYKDDDDKHHHHHHGLNDIFEAQKIEWHE
hIL-6R.Fc(SEQ ID NO:3)
LAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNATVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLAVPEGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITVTAVARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTNKDDDNILFRDSANATSLPVQDSSSVPLPEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
cIL-6R.FH(cIL-6R.FlagHis SEQ ID NO:4)
LAPGGCPAQEVARGVLTSLPGDSVTLTCPGGEPEDNATVHWVLRKPAVGSHLSRWAGVGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQLSCFRKSPLSNVVCEWGPRSTPSPTTKAVLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLAVPEGDSSFYIVSMCVASSVGSKLSKTQTFQGCGILQPDPPANITVTAVARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPTQAPTTNKDDDNILSRDSANATSLPVQDSSSVPLPGSSDYKDDDDKHHHHHH
IL-6.Fc(SEQ ID NO:5)
VPPGEDSKDVAAPHRQPLTSSERIDKQIRYILDGISALRKETCNKSNMCESSKEALAENNLNLPKMAEKDGCFQSGFNEETCLVKIITGLLEFEVYLEYLQNRFESSEEQARAVQMSTKVLIQFLQKKAKNLDAITTPDPTTNASLLTKLQAQNQWLQDMTTHLILRSFKEFLQSSLRALRQMEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
IL-6.his(SEQ ID NO:6)
VPPGEDSKDVAAPHRQPLTSSERIDKQIRYILDGISALRKETCNKSNMCESSKEALAENNLNLPKMAEKDGCFQSGFNEETCLVKIITGLLEFEVYLEYLQNRFESSEEQARAVQMSTKVLIQFLQKKAKNLDAITTPDPTTNASLLTKLQAQNQWLQDMTTHLILRSFKEFLQSSLRALRQMHHHHHH
gp130.Fc(SEQ ID NO:7)
ELLDPCGYISPESPVVQLHSNFTAVCVLKEKCMDYFHVNANYIVWKTNHFTIPKEQYTIINRTASSVTFTDIASLNIQLTCNILTFGQLEQNVYGITIISGLPPEKPKNLSCIVNEGKKMRCEWDGGRETHLETNFTLKSEWATHKFADCKAKRDTPTSCTVDYSTVYFVNIEVWVEAENALGKVTSDHINFDPVYKVKPNPPHNLSVINSEELSSILKLTWTNPSIKSVIILKYNIQYRTKDASTWSQIPPEDTASTRSSFTVQDLKPFTEYVFRIRCMKEDGKGYWSDWSEEASGITYEDRPSKAPSFWYKIDPSHTQGYRTVQLVWKTLPPFEANGKILDYEVTLTRWKSHLQNYTVNATKLTVNLTNDRYLATLTVRNLVGKSDAAVLTIPACDFQATHPVMDLKAFPKDNMLWVEWTTPRESVKKYILEWCVLSDKAPCITDWQQEDGTVHRTYLRGNLAESKCYLITVTPVYADGPGSPESIKAYLKQAPPSKGPTVRTKKVGKNEAVLEWDQLPVDVQNGFIRNYTIFYRTIIGNETAVNVDSSHTEYTLSSLTSDTLYMVRMAAYTDEGGKDGPEFTFTTPKFAQGEIEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
阳性抗体为:Roche/Chugai的抗IL-6R人源化单抗tocilizumab(序列来源于WO1996011020A1);Ablynx的抗IL-6R单域抗体20A11与Fc融合蛋白;Regeneron的Salilumab(序列来源于CN101454345B)。氨基酸序列如下:
Tocilizumab(Toci)
Tocilizumab重链:(SEQ ID NO:8)
EVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Tocilizumab轻链:(SEQ ID NO:9)
DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
20A11-Fc融合蛋白(20A11,其中VHH序列来源于vobarilizumab)(SEQ ID NO:10)
EVQLVESGGGLVQPGGSLRLSCAASGSVFKINVMAWYRQAPGKGRELVAGIISGGSTSYADSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAFITTESDYDLGRRYWGQGTLVTVSSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Sarilumab(Sari)
重链(SEQ ID NO:11)
EVQLVESGGGLVQPGRSLRLSCAASRFTFDDYAMHWVRQAPGKGLEWVSGISWNSGRIGYADSVKGRFTISRDNAENSLFLQMNGLRAEDTALYYCAKGRDSFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
轻链(SEQ ID NO:12)
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYGASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFASYYCQQANSFPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
采用PEI瞬时转染HEK293E细胞(即293E细胞)进行蛋白表达后,根据不同标签或融合蛋白选择不同纯化方式如下:
1.镍柱纯化(分离含His标签的蛋白):将细胞表达上清样品高速离心去除杂质。用含有PBS缓冲液平衡镍柱,冲洗2-5倍柱体积;将上清样品以一定流速上Ni Sepharoseexcel柱(GE Healthcare,Cat#17-3712-01)。用PBS缓冲液冲洗柱子,至A280读数降至基线,再后用PBS+10mM咪唑冲洗层析柱,除去非特异结合的杂蛋白,并收集流出液;最后用含有300mM咪唑的PBS溶液洗脱目的蛋白,并收集洗脱峰。
2.色谱排阻纯化:SEC柱(superdex75)预先用PBS平衡,上样后(上样体积不能大于3%柱体积)用PBS作为流动相洗脱,收集各洗脱峰,经过SDS-PAGE鉴定目的蛋白所在组分。
3.Flag亲和层析(分离含Flag的蛋白):利用0.5×PBS平衡flag亲和填料,冲洗2-5倍柱体积。待纯化样品与填料室温共孵育2小时。用5个柱体积的0.5×PBS冲洗填料,再用含有100μg/ml 3×Flag多肽的TBS缓冲液洗脱目的蛋白,并收集,经过SDS-PAGE鉴定目的蛋白。
4.抗体的亲和层析(分离含Fc的蛋白):将细胞表达上清样品高速离心去除杂质,重组抗体表达上清用Protein A柱进行纯化。用PBS冲洗柱子,至A280读数降至基线。用100mM乙酸pH3.0洗脱目的蛋白,用1M Tris-HCl,pH8.0中和。洗脱样品适当浓缩后利用PBS平衡好的凝胶层析Superdex200(GE)进一步纯化,去聚体的峰收集好后分装备用。
实施例2:羊驼免疫、噬菌体展示文库构建及筛选
采用IL-6R.Fc或IL-6R.His作为免疫原,与弗氏完全佐剂或弗氏不完全佐剂或PBS混匀后注射羊驼,前后免疫6次。在免疫前,以及第4、5、6次免疫之后取外周血用于效价测定,最终提取脾脏细胞。
分离的淋巴细胞经过抽提RNA,反转录成cDNA。建库采用两次PCR:第一次PCR中,将3条正向引物设在FR1区,3条反向引物设在CH2区,正向和反向引物分别等比混合进行PCR,琼脂糖凝胶回收小片段;第二次PCR中,正反向引物都加入sfiI酶切位点及保护碱基,正向引物除sfiI酶切位点及保护碱基外其余序列与第一次PCR正向引物相同,反向引物设在FR4区。第二次PCR产物经过胶回收,酶切,连接到噬菌粒载体中,电转化SS320感受态。最后得到一个库容为1.74E9的噬菌体展示文库。
文库建成后,经过辅助噬菌体的包装,形成噬菌体;进一步进行淘筛及ELISA鉴定,得到需要的克隆。经液相和固相两种方式淘筛:液相方式采用生物素化的IL-6R.BP15抗原在液相中与噬菌体颗粒结合后用链霉亲和素磁珠捕获;固相方式采用ELISA板包被IL-6R.Fc,结合噬菌体颗粒的方式进行。经过两轮淘洗之后,挑取单克隆包装噬菌体,进行ELISA检测结合活性及IL-6和gp130阻断活性。
ELISA过程如下:
IL-6R结合ELISA:包被链霉亲和素2ng/μl,100μl/孔,4℃过夜;2%MPBSCaMg封闭。37℃1小时。清洗平板后,孵育1ng/μl IL-6R.BP15。37℃1小时。清洗平板后,加入50μl 2%MPBSCaMg和50μl噬菌体上清。37℃孵育1小时。清洗平板后,加入1:5000稀释的抗-M13 HRP100μl。37℃孵育1小时。清洗平板后,加入100μl TMB显色。加入100μl 1M H2SO4终止反应。测量OD450。
IL-6阻断ELISA:包被IL-6.Fc 2ng/μl,100μl/孔,4℃过夜。2%MPBSCaMg(2%milk,0.90mM CaCl2,0.49mM MgCl2,1×PBS)封闭平板,37℃孵育1小时。洗平板,加入100μl1ng/μl IL-6R.his,37℃孵育1小时。洗平板,加入50μl噬菌体上清+50μl 2%MPBSCaMg封闭液。37℃孵育1小时。洗平板,加入100μl 1:5000稀释的抗-M13 HRP(GE healthcare,Cat#27-9421-01),37℃孵育1小时。洗平板,加入100μl TMB显色。加入100μl 1M H2SO4终止反应。测量OD450。
gp130阻断ELISA:包被gp130 2ng/μl,100μl/孔,4℃过夜。2%MPBSCaMg封闭平板,37℃孵育1小时。洗平板,加入100μl 1ng/μl IL-6R.his+1ng/μl IL-6.His,37℃孵育1小时。洗平板,加入50μl噬菌体上清和50μl 2%MPBSCaMg封闭液。37℃孵育1小时。洗平板,加入100μl 1:5000稀释的抗-M13 HRP,37℃孵育1小时。洗平板,加入100μl TMB显色。加入100μl 1M H2SO4终止反应。测量OD450。
对于每个克隆,在IL-6R结合结果为阳性情况下,OD450(IL-6R结合ELISA)/OD450(IL-6阻断ELISA)(IL-6R/IL-6)值大于等于4的克隆,以及OD450(IL-6阻断ELISA)/OD450(IL-6阻断ELISA)(IL-6/gp130)值大于等于3的克隆,进行测序。
序列经过分析,去除冗余序列得到一系列克隆。
实施例3:Fc融合蛋白构建及活性鉴定
为了进一步通过分子水平,细胞水平鉴定所挑选克隆,将所挑选的克隆与Fc融合构建到哺乳动物瞬转表达载体上,进行293E细胞瞬转表达。经过亲和纯化,得到VHH-hFc融合蛋白。纯化后的融合蛋白进行如下一系列的测试。
IL-6R阻断实验(测试例1),阻断gp130结合实验(测试例2),U266B1细胞结合活性(测试例3),阻断IL-6刺激的TF-1增殖样品测试(测试例4)。最终筛选出各方面属性最优的IL-6R单域抗体1764,其核苷酸序列如下:
gaggtgcagctggtggagtctgggggagggttggtgcaggctggggggtctctgagactctcctgtgaagcctctggaaacatcttcaagatcaatgtcatgggctggtaccgccaggctccagggaagcagcgcgagtgggtcgcagctattattagtggcggtagcacaaactatgcagactccgtgaagggccgattcaccatctccagagacaacgccaagaacacggtgtatctgcaaatgaacagcctgaaacctgaggacacggccgtctattactgtaatgctattctcacctataacgactatgacctagggtctgactactggggccaggggacccaggtcaccgtctcctca(SEQ IDNO:13);
所编码氨基酸序列如下:
EVQLVESGGGLVQAGGSLRLSCEASGNIFKINVMGWYRQAPGKQREWVAAIISGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCNAILTYNDYDLGSDYWGQGTQVTVSS(SEQ ID NO:14);
其中,下划线表示该单域抗体1764的CDR1-3,序列分别为:
CDR1:INVMG(SEQ ID NO:15);
CDR2:AIISGGSTNYADSVKG(SEQ ID NO:16);
CDR3:ILTYNDYDLGSDY(SEQ ID NO:17);
上述单域抗体VHH与下述Fc片段融合形成融合蛋白:
编码人Fc片段的核苷酸序列:
gagcccaaatctagtgacaaaactcacacgtgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaagagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaatga(SEQ ID NO:18);
人Fc片段:
EPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:19)。
实施例4:1764人源化
为了避免治疗用抗体存在的抗药反应,本披露将羊驼源分子1764进行人源化改造,以降低其免疫源性。人源化采用基于1764序列渐进式向人源突变模式,逐渐替换1764FR区羊驼源氨基酸残基为人源氨基酸残基。设计序列如下。
表1.设计序列
注:如A14P表示1764第14位氨基酸残基A突变为P,此表格中氨基酸残基的位置编号为其在SEQ ID NO:14所示序列中的自然位置顺序编号。
>1764-mu1(SEQ ID NO:20)
EVQLVESGGGLVQPGGSLRLSCEASGNIFKINVMGWYRQAPGKQREWVAAIISGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLRPEDTAVYYCNAILTYNDYDLGSDYWGQGTQVTVSS
>1764-mu2(SEQ ID NO:21)
EVQLVESGGGLVQAGGSLRLSCAASGNIFKINVMGWYRQAPGKGREWVAAIISGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCNAILTYNDYDLGSDYWGQGTQVTVSS
>1764-mu3(SEQ ID NO:22)
EVQLVESGGGLVQPGGSLRLSCEASGNIFKINVMGWYRQAPGKQREWVAAIISGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLRPEDTAVYYCNAILTYNDYDLGSDYWGQGTLVTVSS
>1764-mu4(SEQ ID NO:23)
EVQLVESGGGLVQAGGSLRLSCAASGNIFKINVMGWYRQAPGKGREWVAAIISGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCNAILTYNDYDLGSDYWGQGTLVTVSS
>1764-mu5(SEQ ID NO:24)
EVQLVESGGGLVQAGGSLRLSCAASGNIFKINVMGWYRQAPGKQREWVAAIISGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAFILTYNDYDLGSDYWGQGTLVTVSS
>1764-mu6(SEQ ID NO:25)
EVQLVESGGGLVQPGGSLRLSCAASGNIFKINVMGWYRQAPGKGREWVAAIISGGSTNYADSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCNAILTYNDYDLGSDYWGQGTLVTVSS
>1764-mu7(SEQ ID NO:26)
EVQLVESGGGLVQPGGSLRLSCAASGNIFKINVMGWYRQAPGKQREWVAAIISGGSTNYADSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAFILTYNDYDLGSDYWGQGTLVTVSS
>1764-mu8(SEQ ID NO:27)
EVQLVESGGGLVQAGGSLRLSCAASGNIFKINVMGWYRQAPGKGREWVAAIISGGSTNYADSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCAFILTYNDYDLGSDYWGQGTLVTVSS
>1764-mu9(SEQ ID NO:28)
EVQLVESGGGLVQPGGSLRLSCAASGNIFKINVMGWYRQAPGKGREWVAAIISGGSTNYADSVKGRFTISRDNAKNTlYLQMNSLRPEDTAVYYCAFILTYNDYDLGSDYWGQGTlVTVSSEPKSS
将上述单域抗体与Fc(氨基酸序列如SEQ ID NO:19所示)融合,构建到哺乳动物瞬时表达载体上,进行293E细胞瞬时转染表达。经过亲和纯化,得到VHH-hFc融合蛋白。融合蛋白(IL-6R抗体)与VHH的对应关系如下:
表2.IL-6R抗体序列
融合蛋白 | 序列号 | 单域抗体VHH |
1764-Fc | SEQ ID NO:29 | 1764 |
h1764-mu1 | SEQ ID NO:30 | 1764-mu1 |
h1764-mu2 | SEQ ID NO:31 | 1764-mu2 |
h1764-mu3 | SEQ ID NO:32 | 1764-mu3 |
h1764-mu4 | SEQ ID NO:33 | 1764-mu4 |
h1764-mu5 | SEQ ID NO:34 | 1764-mu5 |
h1764-mu6 | SEQ ID NO:35 | 1764-mu6 |
h1764-mu7 | SEQ ID NO:36 | 1764-mu7 |
h1764-mu8 | SEQ ID NO:37 | 1764-mu8 |
h1764-mu9 | SEQ ID NO:38 | 1764-mu9 |
示例性的VHH-hFc融合的蛋白的序列如下:
1764-Fc(SEQ ID NO:29)
EVQLVESGGGLVQAGGSLRLSCEASGNIFKINVMGWYRQAPGKQREWVAAIISGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCNAILTYNDYDLGSDYWGQGTQVTVSSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>h1764-mu1(SEQ ID NO:30)
EVQLVESGGGLVQPGGSLRLSCEASGNIFKINVMGWYRQAPGKQREWVAAIISGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLRPEDTAVYYCNAILTYNDYDLGSDYWGQGTQVTVSSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>h1764-mu2(SEQ ID NO:31)
EVQLVESGGGLVQAGGSLRLSCAASGNIFKINVMGWYRQAPGKGREWVAAIISGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCNAILTYNDYDLGSDYWGQGTQVTVSSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>h1764-mu3(SEQ ID NO:32)
EVQLVESGGGLVQPGGSLRLSCEASGNIFKINVMGWYRQAPGKQREWVAAIISGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLRPEDTAVYYCNAILTYNDYDLGSDYWGQGTLVTVSSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>h1764-mu4(SEQ ID NO:33)
EVQLVESGGGLVQAGGSLRLSCAASGNIFKINVMGWYRQAPGKGREWVAAIISGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCNAILTYNDYDLGSDYWGQGTLVTVSSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>h1764-mu5(SEQ ID NO:34)
EVQLVESGGGLVQAGGSLRLSCAASGNIFKINVMGWYRQAPGKQREWVAAIISGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAFILTYNDYDLGSDYWGQGTLVTVSSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>h1764-mu6(SEQ ID NO:35)
EVQLVESGGGLVQPGGSLRLSCAASGNIFKINVMGWYRQAPGKGREWVAAIISGGSTNYADSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCNAILTYNDYDLGSDYWGQGTLVTVSSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>h1764-mu7(SEQ ID NO:36)
EVQLVESGGGLVQPGGSLRLSCAASGNIFKINVMGWYRQAPGKQREWVAAIISGGSTNYADSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAFILTYNDYDLGSDYWGQGTLVTVSSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>h1764-mu8(SEQ ID NO:37)
EVQLVESGGGLVQAGGSLRLSCAASGNIFKINVMGWYRQAPGKGREWVAAIISGGSTNYADSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCAFILTYNDYDLGSDYWGQGTLVTVSSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>h1764-mu9(SEQ ID NO:38)
EVQLVESGGGLVQPGGSLRLSCAASGNIFKINVMGWYRQAPGKGREWVAAIISGGSTNYADSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAFILTYNDYDLGSDYWGQGTLVTVSSEPKSSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
纯化后的IL-6R抗体融合蛋白(含Fc片段,以下也称IL-6R抗体)进行如下一系列的测试。
测试例1:IL-6R抗体的IL-6R阻断实验
阻断IL-6与IL-6R的结合,能够阻止IL-6R/IL-6复合物的形成,从而阻断复合物与细胞膜上gp130的结合,最终阻断下游信号的传导。在体外采用ELISA的方式,测试所有表达纯化后的抗体是否具有阻断IL-6结合IL-6R的能力。检测过程如下:
包被100μL IL-6.Fc 2ng/μl,4℃过夜。2%脱脂乳封闭,37℃1小时。洗平板,加入100μL梯度稀释的待测样品与IL-6R.BP15 1ng/μL。37℃孵育1小时。洗平板,加入1:4000稀释的HRP-链霉亲和素(Jackson,016-030-084)。洗平板后,加入100μL TMB室温显色5min,加入100μL 1M H2SO4终止。读取OD450值。结果如图1A至1C)所示。
测试例2:IL-6R抗体的gp130结合阻断检测
配体IL-6与受体IL-6R结合后的复合体可以与GP130结合,待测抗体通过与IL-6R的结合阻断形成IL-6/IL-6R/gp130复合体,检测IL-6R.BP15上的生物素标签,可以判断抗体是否对形成三聚体有阻断作用。
浓度为1μg/mL(PBS稀释)的gp130 4℃包板过夜,倒掉包被液,用5%脱脂乳的PBS溶液,37℃封闭2-3h。封闭完成后,用洗涤缓冲液PBST(0.1%吐温-20的PBS溶液)洗板3遍。
IL-6.his和IL-6R.BP15的浓度为0.06μg/mL,1%BSA的PBS溶液进行稀释,IL-6R抗体上限浓度为50μg/mL,用稀释液按1:3稀释。稀释液为1%BSA的PBS溶液,用稀释液按1:3稀释。37℃孵育1h。孵育完成后,用洗涤缓冲液PBST(0.1%的吐温-20的PBS溶液)洗板3遍。
二抗HRP链霉亲和素(Jackson,016-030-084)稀释比例为1:2000,37℃孵育1h,用洗涤缓冲液PBST(0.1%的吐温-20的PBS溶液)洗板4遍,TMB显色,读取OD450值。结果如图2A和2B所示。
测试例3:IL-6R抗体的U266B1细胞结合活性
为检测IL-6R抗体与表达IL-6R的细胞的结合能力,利用IL-6R抗体对表达IL-6R的U266B1细胞进行结合活性检测。收集U266B1(TIB-196TM)细胞,400g,4℃离心5分钟;加入含有终浓度10%FBS的预冷的DPBS,400g,4℃离心5分钟,重复两次;将细胞分配至96孔板,10E5/孔;每孔加入50μL样品,孵育45-60分钟,4℃;每孔加入含有终浓度10%FBS的预冷的DPBS 250μL,400g,4℃离心5分钟;重复两次。加入50μL 1:200稀释的二抗Alexa Fluor@488羊抗人IgG(H+L)(Lifetechologies,A11013),4℃避光孵育45分钟;每孔加入含有终浓度10%FBS的预冷的DPBS 250μL,400g,4℃离心5分钟;重复两次;每孔加入100μL预冷的DPBS重悬细胞;上机检测(BD,FACSverse);采用flowjo分析检测结果,结果如图3所示。
测试例4:IL-6R抗体阻断IL-6刺激的TF-1增殖样品测试
IL-6通过与膜型IL-6R结合后可以启动下游信号,诱导TF-1细胞增殖,IL-6R抗体可以阻断IL-6与IL-6R的结合,从而抑制TF-1细胞的增殖。
TF-1细胞培养:TF-1白血病细胞(ATCC,CRL-2003)细胞培养于10%FBS的RPMI1640(2ng/mL rhGM-CSF)(GE,Catalog No.SH30809.01),放置于37℃,5%CO2培养箱中,细胞密度不超过1E6个/mL。
IL-6刺激的TF-1增殖抑制实验步骤:取对数生长期的细胞用PBS洗三遍800rpm离心3分钟,用RPMI1640(FBS 2%,重组人IL-6 5ng/mL)调整细胞密度20000个/孔/180μL,并加入20μL梯度稀释的待测抗体到96孔培养3天后(梯度稀释起始抗体浓度为490nM,10倍梯度稀释至4.9×10-7nM),取100μL细胞悬液与100μL细胞滴度(Promega,Catalog No.G7573)混匀后进行检测。结果如表3所示。
表3.IL-6R抗体对IL-6刺激的TF-1增殖的阻断作用检测
测试例5:IL-6R抗体抑制IL-6诱导的铁调素表达
铁调素的高表达是炎症性贫血的主要发病原因,而IL-6通过与IL-6R结合后激活下游信号通路会上调铁调素的表达水平,因此IL-6R抗体阻断IL-6与IL-6R结合,可以抑制IL-6诱导铁调素表达。实验设计如下:
第一组:空白对照:
第二组:阳性对照,加入IL-6;
第三组:加入h1764-mu3和IL-6;
第四组:加入Tocilizumab和IL-6;
Hep3B细胞(中科院,TCHu106)培养在含10%FBS的EME培养基中(Gibco,11095098),在37℃,5%CO2培养箱中培养,每2~3天传代培养。取对数期生长的Hep3B细胞铺在6孔板中,每孔二十万个细胞,在37℃,5%CO2培养箱中培养。第二天待细胞铺板率达到80%~90%时,第3组、4组每孔分别加入终浓度为5nM的IL-6R抗体h1764-mu3和Tocilizumab。在37℃,5%CO2培养箱中孵育30分钟后,除空白对照外,每孔分别加入终浓度为10ng/ml IL-6蛋白。细胞继续培养24h后,收集细胞,提取总RNA,反转录为cDNA。以cDNA为模板,进行荧光定量PCR检测铁调素的mRNA水平,以微球蛋白mRNA表达水平作为内参,结果如表4和图4所示。
表4.IL-6R抗体抑制IL-6诱导的铁调素表达水平检测
测试例6:抗体BIAcore亲合力(KD)测定
按照人抗捕获试剂盒(Cat.#BR-1008-39,GE)说明书中的方法将人抗捕获抗体共价偶联于Biacore仪器(Biacore T200,GE)的生物传感芯片CM5(Cat.#BR-1000-12,GE)上,从而亲和捕获一定量的待测抗体,然后于芯片表面流经一系列浓度梯度下的抗原(hIL-6R.his和cIL-6R.FH),利用Biacore仪器(Biacore T200,GE)实时检测反应信号从而获得结合和解离曲线。
在每个循环解离完成后,用人抗捕获试剂盒里配置的再生溶液将生物芯片洗净再生。实验中用到的氨基偶联试剂盒购自GE公司(Cat.#BR-1000-50,GE),缓冲液为HBS-EP+10×缓冲溶液(Cat.#BR-1006-69,GE)用D.I.水稀释至1×(pH 7.4)。
实验得到的数据用BIAevaluation 4.1版,GE软件以(1:1)Langmuir模型进行拟合,得出亲和力数值,结果如表5所示。
表5. 1764及各人源化克隆与hIL-6R亲和力BIAcore测定结果
抗体 | ka(1/Ms) | kd(1/s) | KD(M) |
1764-Fc | 1.28E+06 | 1.64E-04 | 1.29E-10 |
h1764-mu1 | 1.23E+06 | 1.28E-04 | 1.05E-10 |
h1764-mu2 | 1.23E+06 | 1.54E-04 | 1.26E-10 |
h1764-mu3 | 1.21E+06 | 1.54E-04 | 1.27E-10 |
h1764-mu4 | 1.20E+06 | 1.50E-04 | 1.25E-10 |
h1764-mu5 | 1.10E+06 | 1.11E-04 | 1.01E-10 |
h1764-mu6 | 1.23E+06 | 2.45E-04 | 2.00E-10 |
h1764-mu7 | 8.97E+05 | 1.17E-04 | 1.31E-10 |
h1764-mu8 | 1.01E+06 | 1.44E-04 | 1.43E-10 |
h1764-mu9 | 8.53E+05 | 1.21E-04 | 1.42E-10 |
测试例7.大鼠药代动力学实验
利用大鼠进行抗体融合蛋白的药代动力学实验测试。大鼠给药方案:
表6.给药方案
SD大鼠12只(西普尔-必凯实验动物有限公司),雌雄各半,每组6只,平均分成2组;静脉注射给药,给药组于给药前及给药后15分钟、8h、1天、2天、4天、7天、10天、14天、21天和28天采集全血0.2mL,不加抗凝剂。取血后在4℃放置30分钟,1000g离心15分钟,取上清(血清)置于EP管中,于-80℃保存。目标物浓度采用ELISA方法测定,采用Winnolin软件计算受试药物的药动学参数。检测结果如表7所示。
表7.药代动力学参数
h1764-mu3 | h1764-mu4 | |
剂量 | 5mg/kg | 5mg/kg |
T<sub>max</sub>(h) | 0.25 | 0.25 |
t<sub>1/2</sub>(h) | 185±17 | 148±9 |
结果显示,h1764-mu3和h1764-mu4的半衰期分别为7.7天和6.2天。
测试例8.加速稳定性测试
为观察抗体的稳定性,对部分抗体进行加速实验。1mg/mL抗体融合蛋白,在40℃放置3天后,观察是否沉淀,并进行SEC检测。检测结果如表8所示。
表8.加速实验结果
抗体 | SEC纯度(%) | 40℃3天 |
1764-Fc | 96.97 | 澄清 |
h1764-mu1 | 98.09 | 澄清 |
h1764-mu2 | 95.84 | 澄清 |
h1764-mu3 | 98.21 | 澄清 |
h1764-mu4 | 94.98 | 澄清 |
制剂制备实施例
示例性的抗IL-6R抗体制剂制备工艺如下:
第一步:取一定量的纯化的抗IL-6R抗体溶液,用不含抗体的缓冲剂进行溶剂置换(优选超滤),经超滤膜至少6倍体积置换,蛋白浓缩到一浓度。加入一定体积的其他辅料母液,并用缓冲液稀释,使抗体及各辅料达到需要的浓度,混匀。产品经过滤后中控取样检测无菌。将原液过0.22μm PVDF滤芯,收集滤液。
第二步:调节装量至1.15mL,将滤液灌装于2mL西林瓶中,加塞,分别于灌装开始、灌装中间、灌装结束时取样中控检测装量差异。
第三步:开启轧盖机,加铝盖,进行轧盖。
第四步:目检,确认产品无装量不准等缺陷。打印、粘贴西林瓶标签;打印纸盒标签,折叠纸盒,装盒,贴纸盒标签。
制备过程中使用的设备及结果计算方法如下:
SEC分子排阻色谱法:
根据凝胶孔隙的孔径大小与高分子样品分子的线团尺寸间的相对关系而对溶质进行分离的分析的方法。
SEC单体含量百分比=A单体/A总*100%(A单体为样品中主峰单体的峰面积,A总为所有峰面积之和)。
CE毛细管凝胶电泳:
将凝胶移到毛细管中作为支持介质进行的一种电泳,并在一定的电压下根据样品分子量的大小进行分离的方法。
非还原CE(NR-CE)纯度百分比=A主峰/A总*100%(A主峰为样品中主峰的峰面积,A总为所有峰面积之和。
CE测定用仪器:Beckman,型号plus800
iCIEF成像毛细管等点聚焦电泳(简称iCE):
根据蛋白质等电点pI不同进行分离的技术。
iCIEF中性峰含量百分比=中性峰面积/总面积*100%(总面积为酸性峰、中性峰和碱性峰面积之和)。
iCIEF测定所用仪器:simple protein,型号muarice。
粘度测定:采用流变仪(厂家Anton Paar,型号MCR xx2)测定粘度,测定温度25度,样品直接放置于测定平板上测试。
渗透压:冰点法测定渗透压,以冰点下降值与溶液的摩尔浓度成正比例关系为基础,采用高灵敏度感温元件,测定溶液结冰点,通过电量转化为渗透压。仪器厂家罗泽Loser,型号OM815。
实施例1.制剂的缓冲体系筛选
在pH4.5-8.0的一系列缓冲液中,配制抗体浓度为50mg/mL的h1764-mu3制剂,含0.2mg/mL聚山梨醇酯80(PS80)下列制剂样品:
1)10mM醋酸钠盐(AA)pH 4.5;
2)10mM醋酸钠盐(AA)pH 5.0;
3)10mM醋酸钠盐(AA)pH 5.5;
4)10mM枸橼酸钠盐(CA)pH5.0;
5)10mM枸橼酸钠盐(CA)pH5.5
6)10mM琥珀酸钠盐(SA)pH5.0;
7)10mM琥珀酸钠盐(SA)pH5.5;
8)10mM磷酸钠盐(PB)pH 7.0;
9)10mM磷酸钠盐(PB)pH 7.5;
10)10mM组氨酸-盐酸盐(His)pH5.5;
11)10mM组氨酸-盐酸盐(His)pH 6.0;
12)10mM Tris pH 7.5;
13)10mM Tris pH 8.0。
将每种制剂过滤,灌装,加塞,轧盖。然后进行强制降解实验(振摇,25℃,300rpm),以外观、SEC、iCE、NR-CE为评价指标,检测制剂的稳定。结果见下表。
表9.pH和缓冲体系筛选结果
注:外观:用“+”表示乳光及颗粒程度,“+”越多代表乳光越重或颗粒越多。N/A表示,样品由于外观过差,未检测;D7表示第7天;T0表示实验开始时。
外观数据显示,0时CA体系外观有大量细小颗粒,提示抗体在CA缓冲液中不稳定;其余体系0时外观澄清透明。振摇条件下,AA缓冲体系中,pH4.5、5.0和5.5时的外观略优于His缓冲液(pH5.5、6.0)。
SEC数据显示,振摇7天条件下,抗体在SA、AA和His缓冲液中的稳定性优于PB和Tris缓冲液,抗体在PB缓冲液(pH7.5)中的主峰下降超过5%;在相同pH条件下,抗体在His体系中更稳定。而iCE数据显示,0点数据pH5.0和5.5优于4.5。
综上,该抗体在pH5.0~6.0的缓冲液中的稳定性优于其他pH值,在pH 5.5条件下更稳定。
实施例2.制剂缓冲体系的筛选
在10mM组氨酸-醋酸盐(His-AA)、His和AA缓冲液中,制备包含0.4mg/mL PS80和如下成分的h1764-mu3制剂,具体如下:
1)10mM His-AA,pH5.0,20mg/mL抗体;
2)10mM His-AA,pH5.5,20mg/mL抗体;
3)10mM His-AA,pH6.0,20mg/mL抗体。
将每种制剂过滤,灌装,加塞,轧盖。然进行振摇(25℃,300rpm)稳定性考察,以外观、SEC、iCE、NR-CE%为评价指标。
表10.pH和缓冲体系筛选结果
结果表明,抗体在pH5.0-6.0,His-AA缓冲液中外观澄清透明,化学稳定性良好,组间无明显差异。
实施例3.制剂粘度测定
在10mM His-AA pH5.5的缓冲液中制备抗体浓度为100mg/mL,120mg/mL,162mg/mL,200mg/mL,240mg/mL的h1764-mu3制剂,测定不同抗体浓度样品的粘度,结果如下表:
表11.不同蛋白浓度样品粘度
抗体浓度(mg/mL) | 粘度(mPa.s) |
100 | 2.777 |
120 | 5.821 |
162 | 12.090 |
200 | 31.905 |
240 | 49.428 |
结果显示:当抗体浓度大于或等于200mg/mL时,制剂的粘度大于20mPa.s,不利于皮下注射,因此抗体浓度可以为100mg/mL-162mg/mL,优选100mg/mL-120mg/mL。
实施例4.不同抗体浓度的制剂稳定性评价
制备10mM His-AA pH5.5,80mg/mL蔗糖,1.0mg/mL PS80浓度为100mg/mL,120mg/mL的h1764-mu3制剂,振摇7天后,进行稳定性检测,结果见下表。
表12.稳定性检测结果
振摇7天后,上述抗体制剂的SEC/NR-CE/iCE均略有所下降,但均在制剂稳定性变化的可接受范围内,抗体浓度为100mg/mL样品的稳定性结果略优,因此抗体浓度优选100mg/mL。
实施例5.长期稳定性评价
在10mM组氨酸-醋酸(His-AA)pH5.5缓冲液中配制抗体浓度为100mg/mL h1764-mu3,0.4mg/mL聚山梨醇酯80(PS80),80mg/mL蔗糖的制剂,并考察该制剂在4℃及高温25℃条件放置3-9个月的稳定性,结果见表13。
表13.4℃和25℃稳定性数据
结果显示:25℃条件下放置3-6个月后,样品纯度项略有下降,但下降幅度均在稳定制剂变化的可接受范围内;4℃条件下放置9个月,各检测项均无显著变化,说明该处方稳定性较好。
实施例6.表面活性剂筛选
在10mM His-AA pH5.5缓冲液中制备含体100mg/mL抗体,80mg/mL蔗糖和不同表面活性剂的h1764-mu3制剂,具体成分如下:
1)0.4mg/mL PS80;
2)0.6mg/mL PS80;
3)0.8mg/mL PS80;
4)1.0mg/mL PS80;
对样品进行冻融(-35℃-2~8℃)5次和振摇后进行外观及稳定性检测,结果见下表。
表14.吐温浓度筛选实验结果
注:FT5C表示样品在-35℃-2~8℃冻融5个循环。
结果显示,振摇7天和冻融条件下,各组样品外观和稳定性均良好。说明在制剂中加入0.4mg/mL-1.0mg/mL的PS80,可以提高抗体的稳定性。化学稳定性结果显示,0.8mg/mL组与1.0mg/mL组的SEC及NR-CE稳定性最好,iCE%组间无差异;因此优选0.8mg/mL-1.0mg/mL PS80。
实施例7.制剂的长期稳定性评价
在10mM His-AA,pH5.5的缓冲液中配制包含100mg/mL的h1764-mu3抗体,1.0mg/mL聚山梨醇酯80(PS80),75mg/mL蔗糖的制剂,考察制剂的在4℃放置13个月条件的长期稳定性,结果见表15。
表15. 4℃稳定性数据
结果显示:4℃放置13个月后,各检测项均无显著变化,说明该处方稳定性较好。
实施例8.制剂的冻干
在10mM His-AA pH5.5的缓冲液中制备包含100mg/mL抗体,75mg/mL蔗糖,1.0mg/mL PS80的h1764-mu3制剂,将制剂样品进行冻干,冻干程序如下:
表16.冻干程序
冻干后的样品为白色粉饼,外观饱满,无塌陷,说明该冻干程序良好。
将冻干后的样品进行1:1复溶,复溶后的制剂成分为:10mM His-AA,99mg/mL抗体,75mg/mL蔗糖,1.0mg/mL PS80,药物组合物的pH为5.8对复溶液进行稳定性检测,结果见下表:
表17.冻干前后样品稳定性检测
样品 | 外观 | SEC% | NR-CE% | iCE% |
冻干前 | 澄清透明 | 99.0 | 98.4 | 62.9 |
复溶液 | 澄清透明 | 99.1 | 98.6 | 65.4 |
结果显示,该制剂的复溶液稳定性良好。
虽然为了清楚的理解,已经借助于附图和实例详细描述了上述发明,但是描述和实例不应当解释为限制本披露的范围。所有附图中的数值单位与横坐标上标明的单位相同。本文中引用的所有专利和科学文献的公开内容通过引用完整地清楚结合。
序列表
<110> 江苏恒瑞医药股份有限公司、上海恒瑞医药有限公司
<120> 一种抗IL-6R抗体药物组合物及其用途
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Arg Ser Val Gln Leu His Asp Ser Gly Asn Tyr Ser Cys Tyr Arg Ala
65 70 75 80
Gly Arg Pro Ala Gly Thr Val His Leu Leu Val Asp Val Pro Pro Glu
85 90 95
Glu Pro Gln Leu Ser Cys Phe Arg Lys Ser Pro Leu Ser Asn Val Val
100 105 110
Cys Glu Trp Gly Pro Arg Ser Thr Pro Ser Leu Thr Thr Lys Ala Val
115 120 125
Leu Leu Val Arg Lys Phe Gln Asn Ser Pro Ala Glu Asp Phe Gln Glu
130 135 140
Pro Cys Gln Tyr Ser Gln Glu Ser Gln Lys Phe Ser Cys Gln Leu Ala
145 150 155 160
Val Pro Glu Gly Asp Ser Ser Phe Tyr Ile Val Ser Met Cys Val Ala
165 170 175
Ser Ser Val Gly Ser Lys Phe Ser Lys Thr Gln Thr Phe Gln Gly Cys
180 185 190
Gly Ile Leu Gln Pro Asp Pro Pro Ala Asn Ile Thr Val Thr Ala Val
195 200 205
Ala Arg Asn Pro Arg Trp Leu Ser Val Thr Trp Gln Asp Pro His Ser
210 215 220
Trp Asn Ser Ser Phe Tyr Arg Leu Arg Phe Glu Leu Arg Tyr Arg Ala
225 230 235 240
Glu Arg Ser Lys Thr Phe Thr Thr Trp Met Val Lys Asp Leu Gln His
245 250 255
His Cys Val Ile His Asp Ala Trp Ser Gly Leu Arg His Val Val Gln
260 265 270
Leu Arg Ala Gln Glu Glu Phe Gly Gln Gly Glu Trp Ser Glu Trp Ser
275 280 285
Pro Glu Ala Met Gly Thr Pro Trp Thr Glu Ser Arg Ser Pro Pro Ala
290 295 300
Glu Asn Glu Val Ser Thr Pro Met Gln Ala Leu Thr Thr Asn Lys Asp
305 310 315 320
Asp Asp Asn Ile Leu Phe Arg Asp Ser Ala Asn Ala Thr Ser Leu Pro
325 330 335
Val Gln Asp Ser Ser Ser Val Pro Leu Pro Glu Pro Lys Ser Ser Asp
340 345 350
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
355 360 365
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
370 375 380
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
385 390 395 400
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
405 410 415
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
420 425 430
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
435 440 445
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
450 455 460
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
465 470 475 480
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
485 490 495
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
500 505 510
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
515 520 525
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
530 535 540
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
545 550 555 560
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
565 570 575
Gly Lys
<210> 4
<211> 363
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> cIL-6R.FH
<400> 4
Leu Ala Pro Gly Gly Cys Pro Ala Gln Glu Val Ala Arg Gly Val Leu
1 5 10 15
Thr Ser Leu Pro Gly Asp Ser Val Thr Leu Thr Cys Pro Gly Gly Glu
20 25 30
Pro Glu Asp Asn Ala Thr Val His Trp Val Leu Arg Lys Pro Ala Val
35 40 45
Gly Ser His Leu Ser Arg Trp Ala Gly Val Gly Arg Arg Leu Leu Leu
50 55 60
Arg Ser Val Gln Leu His Asp Ser Gly Asn Tyr Ser Cys Tyr Arg Ala
65 70 75 80
Gly Arg Pro Ala Gly Thr Val His Leu Leu Val Asp Val Pro Pro Glu
85 90 95
Glu Pro Gln Leu Ser Cys Phe Arg Lys Ser Pro Leu Ser Asn Val Val
100 105 110
Cys Glu Trp Gly Pro Arg Ser Thr Pro Ser Pro Thr Thr Lys Ala Val
115 120 125
Leu Leu Val Arg Lys Phe Gln Asn Ser Pro Ala Glu Asp Phe Gln Glu
130 135 140
Pro Cys Gln Tyr Ser Gln Glu Ser Gln Lys Phe Ser Cys Gln Leu Ala
145 150 155 160
Val Pro Glu Gly Asp Ser Ser Phe Tyr Ile Val Ser Met Cys Val Ala
165 170 175
Ser Ser Val Gly Ser Lys Leu Ser Lys Thr Gln Thr Phe Gln Gly Cys
180 185 190
Gly Ile Leu Gln Pro Asp Pro Pro Ala Asn Ile Thr Val Thr Ala Val
195 200 205
Ala Arg Asn Pro Arg Trp Leu Ser Val Thr Trp Gln Asp Pro His Ser
210 215 220
Trp Asn Ser Ser Phe Tyr Arg Leu Arg Phe Glu Leu Arg Tyr Arg Ala
225 230 235 240
Glu Arg Ser Lys Thr Phe Thr Thr Trp Met Val Lys Asp Leu Gln His
245 250 255
His Cys Val Ile His Asp Ala Trp Ser Gly Leu Arg His Val Val Gln
260 265 270
Leu Arg Ala Gln Glu Glu Phe Gly Gln Gly Glu Trp Ser Glu Trp Ser
275 280 285
Pro Glu Ala Met Gly Thr Pro Trp Thr Glu Ser Arg Ser Pro Pro Ala
290 295 300
Glu Asn Glu Val Ser Thr Pro Thr Gln Ala Pro Thr Thr Asn Lys Asp
305 310 315 320
Asp Asp Asn Ile Leu Ser Arg Asp Ser Ala Asn Ala Thr Ser Leu Pro
325 330 335
Val Gln Asp Ser Ser Ser Val Pro Leu Pro Gly Ser Ser Asp Tyr Lys
340 345 350
Asp Asp Asp Asp Lys His His His His His His
355 360
<210> 5
<211> 415
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> IL-6.Fc
<400> 5
Val Pro Pro Gly Glu Asp Ser Lys Asp Val Ala Ala Pro His Arg Gln
1 5 10 15
Pro Leu Thr Ser Ser Glu Arg Ile Asp Lys Gln Ile Arg Tyr Ile Leu
20 25 30
Asp Gly Ile Ser Ala Leu Arg Lys Glu Thr Cys Asn Lys Ser Asn Met
35 40 45
Cys Glu Ser Ser Lys Glu Ala Leu Ala Glu Asn Asn Leu Asn Leu Pro
50 55 60
Lys Met Ala Glu Lys Asp Gly Cys Phe Gln Ser Gly Phe Asn Glu Glu
65 70 75 80
Thr Cys Leu Val Lys Ile Ile Thr Gly Leu Leu Glu Phe Glu Val Tyr
85 90 95
Leu Glu Tyr Leu Gln Asn Arg Phe Glu Ser Ser Glu Glu Gln Ala Arg
100 105 110
Ala Val Gln Met Ser Thr Lys Val Leu Ile Gln Phe Leu Gln Lys Lys
115 120 125
Ala Lys Asn Leu Asp Ala Ile Thr Thr Pro Asp Pro Thr Thr Asn Ala
130 135 140
Ser Leu Leu Thr Lys Leu Gln Ala Gln Asn Gln Trp Leu Gln Asp Met
145 150 155 160
Thr Thr His Leu Ile Leu Arg Ser Phe Lys Glu Phe Leu Gln Ser Ser
165 170 175
Leu Arg Ala Leu Arg Gln Met Glu Pro Lys Ser Ser Asp Lys Thr His
180 185 190
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
195 200 205
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
210 215 220
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
225 230 235 240
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
245 250 255
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
260 265 270
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
275 280 285
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
290 295 300
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
305 310 315 320
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
325 330 335
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
340 345 350
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
355 360 365
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
370 375 380
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
385 390 395 400
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
405 410 415
<210> 6
<211> 189
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> IL-6.his
<400> 6
Val Pro Pro Gly Glu Asp Ser Lys Asp Val Ala Ala Pro His Arg Gln
1 5 10 15
Pro Leu Thr Ser Ser Glu Arg Ile Asp Lys Gln Ile Arg Tyr Ile Leu
20 25 30
Asp Gly Ile Ser Ala Leu Arg Lys Glu Thr Cys Asn Lys Ser Asn Met
35 40 45
Cys Glu Ser Ser Lys Glu Ala Leu Ala Glu Asn Asn Leu Asn Leu Pro
50 55 60
Lys Met Ala Glu Lys Asp Gly Cys Phe Gln Ser Gly Phe Asn Glu Glu
65 70 75 80
Thr Cys Leu Val Lys Ile Ile Thr Gly Leu Leu Glu Phe Glu Val Tyr
85 90 95
Leu Glu Tyr Leu Gln Asn Arg Phe Glu Ser Ser Glu Glu Gln Ala Arg
100 105 110
Ala Val Gln Met Ser Thr Lys Val Leu Ile Gln Phe Leu Gln Lys Lys
115 120 125
Ala Lys Asn Leu Asp Ala Ile Thr Thr Pro Asp Pro Thr Thr Asn Ala
130 135 140
Ser Leu Leu Thr Lys Leu Gln Ala Gln Asn Gln Trp Leu Gln Asp Met
145 150 155 160
Thr Thr His Leu Ile Leu Arg Ser Phe Lys Glu Phe Leu Gln Ser Ser
165 170 175
Leu Arg Ala Leu Arg Gln Met His His His His His His
180 185
<210> 7
<211> 829
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> gp130.Fc
<400> 7
Glu Leu Leu Asp Pro Cys Gly Tyr Ile Ser Pro Glu Ser Pro Val Val
1 5 10 15
Gln Leu His Ser Asn Phe Thr Ala Val Cys Val Leu Lys Glu Lys Cys
20 25 30
Met Asp Tyr Phe His Val Asn Ala Asn Tyr Ile Val Trp Lys Thr Asn
35 40 45
His Phe Thr Ile Pro Lys Glu Gln Tyr Thr Ile Ile Asn Arg Thr Ala
50 55 60
Ser Ser Val Thr Phe Thr Asp Ile Ala Ser Leu Asn Ile Gln Leu Thr
65 70 75 80
Cys Asn Ile Leu Thr Phe Gly Gln Leu Glu Gln Asn Val Tyr Gly Ile
85 90 95
Thr Ile Ile Ser Gly Leu Pro Pro Glu Lys Pro Lys Asn Leu Ser Cys
100 105 110
Ile Val Asn Glu Gly Lys Lys Met Arg Cys Glu Trp Asp Gly Gly Arg
115 120 125
Glu Thr His Leu Glu Thr Asn Phe Thr Leu Lys Ser Glu Trp Ala Thr
130 135 140
His Lys Phe Ala Asp Cys Lys Ala Lys Arg Asp Thr Pro Thr Ser Cys
145 150 155 160
Thr Val Asp Tyr Ser Thr Val Tyr Phe Val Asn Ile Glu Val Trp Val
165 170 175
Glu Ala Glu Asn Ala Leu Gly Lys Val Thr Ser Asp His Ile Asn Phe
180 185 190
Asp Pro Val Tyr Lys Val Lys Pro Asn Pro Pro His Asn Leu Ser Val
195 200 205
Ile Asn Ser Glu Glu Leu Ser Ser Ile Leu Lys Leu Thr Trp Thr Asn
210 215 220
Pro Ser Ile Lys Ser Val Ile Ile Leu Lys Tyr Asn Ile Gln Tyr Arg
225 230 235 240
Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile Pro Pro Glu Asp Thr Ala
245 250 255
Ser Thr Arg Ser Ser Phe Thr Val Gln Asp Leu Lys Pro Phe Thr Glu
260 265 270
Tyr Val Phe Arg Ile Arg Cys Met Lys Glu Asp Gly Lys Gly Tyr Trp
275 280 285
Ser Asp Trp Ser Glu Glu Ala Ser Gly Ile Thr Tyr Glu Asp Arg Pro
290 295 300
Ser Lys Ala Pro Ser Phe Trp Tyr Lys Ile Asp Pro Ser His Thr Gln
305 310 315 320
Gly Tyr Arg Thr Val Gln Leu Val Trp Lys Thr Leu Pro Pro Phe Glu
325 330 335
Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val Thr Leu Thr Arg Trp Lys
340 345 350
Ser His Leu Gln Asn Tyr Thr Val Asn Ala Thr Lys Leu Thr Val Asn
355 360 365
Leu Thr Asn Asp Arg Tyr Leu Ala Thr Leu Thr Val Arg Asn Leu Val
370 375 380
Gly Lys Ser Asp Ala Ala Val Leu Thr Ile Pro Ala Cys Asp Phe Gln
385 390 395 400
Ala Thr His Pro Val Met Asp Leu Lys Ala Phe Pro Lys Asp Asn Met
405 410 415
Leu Trp Val Glu Trp Thr Thr Pro Arg Glu Ser Val Lys Lys Tyr Ile
420 425 430
Leu Glu Trp Cys Val Leu Ser Asp Lys Ala Pro Cys Ile Thr Asp Trp
435 440 445
Gln Gln Glu Asp Gly Thr Val His Arg Thr Tyr Leu Arg Gly Asn Leu
450 455 460
Ala Glu Ser Lys Cys Tyr Leu Ile Thr Val Thr Pro Val Tyr Ala Asp
465 470 475 480
Gly Pro Gly Ser Pro Glu Ser Ile Lys Ala Tyr Leu Lys Gln Ala Pro
485 490 495
Pro Ser Lys Gly Pro Thr Val Arg Thr Lys Lys Val Gly Lys Asn Glu
500 505 510
Ala Val Leu Glu Trp Asp Gln Leu Pro Val Asp Val Gln Asn Gly Phe
515 520 525
Ile Arg Asn Tyr Thr Ile Phe Tyr Arg Thr Ile Ile Gly Asn Glu Thr
530 535 540
Ala Val Asn Val Asp Ser Ser His Thr Glu Tyr Thr Leu Ser Ser Leu
545 550 555 560
Thr Ser Asp Thr Leu Tyr Met Val Arg Met Ala Ala Tyr Thr Asp Glu
565 570 575
Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe Thr Thr Pro Lys Phe Ala
580 585 590
Gln Gly Glu Ile Glu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys
595 600 605
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
610 615 620
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
625 630 635 640
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
645 650 655
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
660 665 670
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
675 680 685
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
690 695 700
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
705 710 715 720
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
725 730 735
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
740 745 750
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
755 760 765
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
770 775 780
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
785 790 795 800
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
805 810 815
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
820 825
<210> 8
<211> 449
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> CHAIN
<223> 托珠单抗(Tocilizumab)重链
<400> 8
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 9
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> CHAIN
<223> 托珠单抗(Toci)轻链
<400> 9
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 10
<211> 353
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 20A11-Fc融合蛋白(20A11)
<400> 10
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Val Phe Lys Ile Asn
20 25 30
Val Met Ala Trp Tyr Arg Gln Ala Pro Gly Lys Gly Arg Glu Leu Val
35 40 45
Ala Gly Ile Ile Ser Gly Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Phe Ile Thr Thr Glu Ser Asp Tyr Asp Leu Gly Arg Arg Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Ser Asp Lys
115 120 125
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
130 135 140
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
145 150 155 160
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
165 170 175
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
180 185 190
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
195 200 205
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
210 215 220
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
225 230 235 240
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
245 250 255
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
260 265 270
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
275 280 285
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
290 295 300
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
305 310 315 320
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
325 330 335
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
340 345 350
Lys
<210> 11
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> CHAIN
<223> Sarilumab(Sari)重链
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Arg Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Gly Arg Asp Ser Phe Asp Ile Trp Gly Gln Gly Thr Met Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 12
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> CHAIN
<223> Sarilumab(Sari)轻链
<400> 12
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 13
<211> 363
<212> DNA
<213> Lama pacos
<220>
<221> gene
<223> 1764 VHH编码核酸
<400> 13
gaggtgcagc tggtggagtc tgggggaggg ttggtgcagg ctggggggtc tctgagactc 60
tcctgtgaag cctctggaaa catcttcaag atcaatgtca tgggctggta ccgccaggct 120
ccagggaagc agcgcgagtg ggtcgcagct attattagtg gcggtagcac aaactatgca 180
gactccgtga agggccgatt caccatctcc agagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtctatt actgtaatgc tattctcacc 300
tataacgact atgacctagg gtctgactac tggggccagg ggacccaggt caccgtctcc 360
tca 363
<210> 14
<211> 121
<212> PRT
<213> Lama pacos
<220>
<221> PEPTIDE
<223> 1764 VHH
<400> 14
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 15
<211> 5
<212> PRT
<213> Lama pacos
<220>
<221> DOMAIN
<223> 1764 CDR1
<400> 15
Ile Asn Val Met Gly
1 5
<210> 16
<211> 16
<212> PRT
<213> Lama pacos
<220>
<221> DOMAIN
<223> 1764 CDR2
<400> 16
Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 17
<211> 13
<212> PRT
<213> Lama pacos
<220>
<221> DOMAIN
<223> 1764 CDR3
<400> 17
Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr
1 5 10
<210> 18
<211> 699
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> gene
<223> 人Fc片段
<400> 18
gagcccaaat ctagtgacaa aactcacacg tgcccaccgt gcccagcacc tgaactcctg 60
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 120
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 180
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaagagcag 240
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 300
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 360
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 420
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 480
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 540
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 600
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 660
tacacgcaga agagcctctc cctgtctccg ggtaaatga 699
<210> 19
<211> 232
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 人Fc片段
<400> 19
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 20
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 1764-mu1
<400> 20
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 21
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 1764-mu2
<400> 21
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 22
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 1764-mu3
<400> 22
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 23
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 1764-mu4
<400> 23
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 24
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 1764-mu5
<400> 24
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Phe Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 25
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 1764-mu6
<400> 25
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 26
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 1764-mu7
<400> 26
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Phe Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 27
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 1764-mu8
<400> 27
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Phe Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 28
<211> 126
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 1764-mu9
<400> 28
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Phe Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Ser
115 120 125
<210> 29
<211> 353
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 1764-Fc
<400> 29
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser Glu Pro Lys Ser Ser Asp Lys
115 120 125
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
130 135 140
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
145 150 155 160
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
165 170 175
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
180 185 190
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
195 200 205
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
210 215 220
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
225 230 235 240
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
245 250 255
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
260 265 270
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
275 280 285
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
290 295 300
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
305 310 315 320
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
325 330 335
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
340 345 350
Lys
<210> 30
<211> 353
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1764-mu1
<400> 30
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser Glu Pro Lys Ser Ser Asp Lys
115 120 125
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
130 135 140
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
145 150 155 160
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
165 170 175
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
180 185 190
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
195 200 205
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
210 215 220
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
225 230 235 240
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
245 250 255
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
260 265 270
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
275 280 285
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
290 295 300
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
305 310 315 320
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
325 330 335
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
340 345 350
Lys
<210> 31
<211> 353
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1764-mu2
<400> 31
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser Glu Pro Lys Ser Ser Asp Lys
115 120 125
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
130 135 140
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
145 150 155 160
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
165 170 175
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
180 185 190
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
195 200 205
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
210 215 220
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
225 230 235 240
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
245 250 255
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
260 265 270
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
275 280 285
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
290 295 300
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
305 310 315 320
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
325 330 335
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
340 345 350
Lys
<210> 32
<211> 353
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1764-mu3
<400> 32
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Ser Asp Lys
115 120 125
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
130 135 140
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
145 150 155 160
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
165 170 175
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
180 185 190
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
195 200 205
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
210 215 220
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
225 230 235 240
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
245 250 255
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
260 265 270
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
275 280 285
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
290 295 300
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
305 310 315 320
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
325 330 335
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
340 345 350
Lys
<210> 33
<211> 353
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1764-mu4
<400> 33
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Ser Asp Lys
115 120 125
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
130 135 140
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
145 150 155 160
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
165 170 175
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
180 185 190
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
195 200 205
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
210 215 220
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
225 230 235 240
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
245 250 255
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
260 265 270
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
275 280 285
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
290 295 300
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
305 310 315 320
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
325 330 335
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
340 345 350
Lys
<210> 34
<211> 353
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1764-mu5
<400> 34
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Phe Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Ser Asp Lys
115 120 125
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
130 135 140
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
145 150 155 160
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
165 170 175
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
180 185 190
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
195 200 205
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
210 215 220
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
225 230 235 240
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
245 250 255
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
260 265 270
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
275 280 285
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
290 295 300
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
305 310 315 320
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
325 330 335
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
340 345 350
Lys
<210> 35
<211> 353
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1764-mu6
<400> 35
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Ser Asp Lys
115 120 125
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
130 135 140
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
145 150 155 160
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
165 170 175
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
180 185 190
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
195 200 205
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
210 215 220
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
225 230 235 240
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
245 250 255
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
260 265 270
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
275 280 285
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
290 295 300
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
305 310 315 320
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
325 330 335
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
340 345 350
Lys
<210> 36
<211> 353
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1764-mu7
<400> 36
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Phe Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Ser Asp Lys
115 120 125
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
130 135 140
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
145 150 155 160
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
165 170 175
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
180 185 190
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
195 200 205
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
210 215 220
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
225 230 235 240
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
245 250 255
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
260 265 270
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
275 280 285
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
290 295 300
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
305 310 315 320
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
325 330 335
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
340 345 350
Lys
<210> 37
<211> 353
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1764-mu8
<400> 37
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Phe Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Ser Asp Lys
115 120 125
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
130 135 140
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
145 150 155 160
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
165 170 175
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
180 185 190
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
195 200 205
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
210 215 220
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
225 230 235 240
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
245 250 255
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
260 265 270
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
275 280 285
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
290 295 300
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
305 310 315 320
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
325 330 335
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
340 345 350
Lys
<210> 38
<211> 358
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> h1764-mu9
<400> 38
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Ile Phe Lys Ile Asn
20 25 30
Val Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Val
35 40 45
Ala Ala Ile Ile Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Phe Ile Leu Thr Tyr Asn Asp Tyr Asp Leu Gly Ser Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Glu Pro Lys Ser Ser Glu Pro
115 120 125
Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
130 135 140
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
145 150 155 160
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
165 170 175
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
180 185 190
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
195 200 205
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
210 215 220
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
225 230 235 240
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
245 250 255
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
260 265 270
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
275 280 285
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
290 295 300
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
305 310 315 320
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
325 330 335
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
340 345 350
Ser Leu Ser Pro Gly Lys
355
Claims (17)
1.一种药物组合物,其包含抗IL-6R抗体或其抗原结合片段,以及缓冲剂,其中:
所述缓冲剂选自醋酸盐或组氨酸盐缓冲剂,优选为组氨酸-醋酸盐缓冲剂;
所述的抗IL-6R抗体的序列如SEQ ID NO:29、30、31、32、33、34、35、36、37或38所示。
2.根据权利要求1所述的药物组合物,所述缓冲剂的pH为4.5至6.0,优选为5.0至6.0,最优选为约5.5。
3.根据权利要求1或2所述的药物组合物,其中所述缓冲液浓度为5mM至30mM,优选为5mM至15mM,最优选为约10mM。
4.根据权利要求1至3中任一项所述的药物组合物,其中所述抗IL-6R抗体或其抗原结合片段浓度为1mg/mL至180mg/mL,优选为80mg/mL至120mg/mL,最优选为约100mg/mL。
5.根据权利要求1至4中任一项所述的药物组合物,其还包含表面活性剂,所述表面活性剂优选为聚山梨醇酯80或聚山梨醇酯20。
6.根据权利要求5所述的药物组合物,其中所述的表面活性剂的浓度为0.01mg/mL至1.2mg/mL,优选为0.8mg/ml至1.2mg/mL,最优选为约1.0mg/mL。
7.根据权利要求1至6中任一项所述的药物组合物,其还包含稳定剂,所述稳定剂优选为海藻糖或蔗糖。
8.根据权利要求7所述的药物组合物,其中所述稳定剂的浓度为60mg/mL至90mg/mL,优选为70mg/mL至80mg/mL,最优选为约75mg/mL。
9.根据权利要求1至8中任一项所述的药物组合物,其包含:
(a)5mM至15mM的组氨酸盐缓冲剂,pH为4.5至6.0;(b)80mg/mL至120mg/mL的抗IL-6R抗体或其抗原结合片段;(c)0.4mg/mL至1.2mg/mL的聚山梨醇酯80或聚山梨醇酯20;和(d)60mg/mL至90mg/mL的海藻糖或蔗糖;优选地,所述药物组合物包含:
(a)约5mM至16mM的组氨酸-醋酸盐缓冲剂,pH为5.0至6.0;(b)100mg/mL至120mg/mL的抗IL-6R抗体或其抗原结合片段;(c)0.8mg/mL至1.0mg/mL的聚山梨醇酯80;和(d)70mg/mL至80mg/mL的蔗糖。
10.一种稳定的药物组合物,其包含:
(i)约10mM的组氨酸盐缓冲剂,pH为4.5至6.0;0.4mg/mL至1.0mg/mL的聚山梨醇酯80或聚山梨醇酯20;60mg/mL至90mg/mL的蔗糖或海藻糖;和20mg/mL至162mg/mL的序列如SEQ IDNO:32所示的抗IL-6R抗体或其抗原结合片段;
(ii)约10mM的组氨酸盐缓冲剂,pH为5.0至6.0;0.8mg/mL至1.0mg/mL的聚山梨醇酯80或聚山梨醇酯20;70mg/mL至80mg/mL的蔗糖或海藻糖;和100mg/mL至120mg/mL的序列如SEQID NO:32所示的抗IL-6R抗体或其抗原结合片段;
(iii)约10mM组氨酸-醋酸缓盐冲剂,pH为约5.5;0.4mg/mL至1.0mg/mL聚山梨醇酯80;约80mg/mL蔗糖;和100mg/mL至120mg/mL的序列如SEQ ID NO:32所示的抗IL-6R抗体或其抗原结合片段;
(iv)约10mM的组氨酸-醋酸盐缓冲剂,pH为约5.5;约1.0mg/mL的聚山梨醇酯80;约75mg/mL的蔗糖;和约100mg/mL的序列如SEQ ID NO:32所示的抗IL-6R抗体或其抗原结合片段;或
(v)约10mM的组氨酸-醋酸盐缓冲剂,pH为约5.8;约1.0mg/mL的聚山梨醇酯80;约75mg/mL的蔗糖;和约99mg/mL的序列如SEQ ID NO:32所示的抗IL-6R抗体或其抗原结合片段。
11.一种制备权利要求1至10中任一项所述的药物组合物的方法,包括将抗IL-6R抗体或其抗原结合片段原液经缓冲液置换的步骤。
12.一种包含抗IL-6R抗体或其抗原结合片段的冻干制剂,其中所述的冻干制剂通过将权利要求1至10中任一项所述的药物组合物经冷冻干燥获得。
13.一种含有抗IL-6R抗体或其抗原结合片段的复溶溶液,其特征在于所述复溶溶液是通过将权利要求12所述的冻干制剂复溶获得;优选地,所述复溶溶液的pH为4.5至6.3,优选为5.0至6.0,最优选为约5.8。
14.一种制品,其包括容器,该容器中装有如权利要求1至10中任一项所述的药物组合物或权利要求12所述的冻干制剂或权利要求13所述的复溶溶液。
15.一种抗IL-6R抗体,其包含如SEQ ID NO:29、30、31、32、33、34、35、36、37或38所示的序列或与SEQ ID NO:29、30、31、32、33、34、35、36、37或38所示的序列具有至少90%的同源性。
16.根据权利要求1至10中任一项所述的药物组合物,或权利要求12所述的冻干制剂,或权利要求13所述的复溶溶液,或权利要求14所述的抗IL-6R抗体,在制备治疗或预防疾病的药物中的用途;优选地,所述的疾病为与IL-6相关的疾病。
17.根据权利要求16所述的用途,其中所述的疾病选自:脓毒症、多发性骨髓瘤、肾细胞癌、浆细胞白血病、淋巴瘤、B-淋巴组织增生、前列腺癌、骨质疏松症、恶病质、银屑病、肾小球系膜增生性肾小球肾炎、卡波西肉瘤、艾滋病相关的淋巴瘤、类风湿性关节炎、全身发作的青少年特发性关节炎、高丙球蛋白血症、局限性回肠炎、溃疡性大肠炎、系统性红斑狼疮、多发性硬化病、Castleman病、IgMγ-球蛋白病、心脏粘液瘤、哮喘、自体免疫性胰岛素-依赖型糖尿病和炎性贫血。
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WO2024002257A1 (en) * | 2022-06-30 | 2024-01-04 | Suzhou Transcenta Therapeutics Co., Ltd. | Stable pharmaceutical formulation comprising an anti-cldn18.2 antibody |
WO2024083074A1 (en) * | 2022-10-17 | 2024-04-25 | Beigene, Ltd. | Formulations containing anti-tigit antibody and methods of use thereof |
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