CN117897173A - 含有2019新型冠状病毒抗体的药物制剂 - Google Patents
含有2019新型冠状病毒抗体的药物制剂 Download PDFInfo
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Abstract
提供了包含2019新型冠状病毒(2019‑nCoV)抗体和试剂的药物制剂,所述试剂提供了商业上可接受的贮存期限稳定性、使用中稳定性和可接受的患者注射部位体验。此类制剂可以用于减弱、预防和/或治疗2019‑nCoV感染或COVID‑19。
Description
技术领域
本公开内容总体上涉及生物学和医学,并且更具体而言,它涉及具有高中和活性、针对严重急性呼吸综合征冠状病毒2(SARS-CoV-2;下文被称为2019新型冠状病毒或2019-nCoV)的人单克隆抗体(Ab)的组合物,例如药物制剂。该制剂另外包括提供商业上可接受的贮存期限稳定性、使用中稳定性和可接受的患者注射部位体验的试剂。此类制剂可以用于减弱、预防和/或治疗2019-nCoV感染。
背景
由2019-nCoV引起的肺炎2019年底首次正式注意到,在世界各地迅速传播。由2019-CoV引起的疾病已由世界卫生组织(World Health Organization)(WHO)命名为2019冠状病毒病(COVID-19)。这种COVID-19的影响是前所未有的,并且截至2021年3月,全球病例已达到超过1.26亿例,伴随超过280万例死亡,其证实了对于预防和治疗性治疗的持续迫切需要。虽然疫苗仍然是COVID-19预防的主要选项,但中和性单克隆Ab已显示为用于已经感染的那些人的有效治疗选项,并且具有预防已经暴露于2019-nCoV的那些人中的感染的潜力,这可能对某些高风险亚群具有特别益处。
国际专利申请公开号WO 2021/169932描述了称为埃特司韦单抗(etesevimab)、LY-CoV016、JS016或CB6的单克隆2019-nCoV Ab,其可以用于减弱、预防和/或治疗2019-nCoV感染。
由于蛋白质(包括Ab)比传统的有机和无机治疗剂更大且更复杂(例如,除复杂的三维结构之外还具有多重官能团),因此此类蛋白质的配制经常具有困难。例如,为了使蛋白质保持有生物学活性,制剂必须维持其氨基酸的至少一个核心序列的构象完整性,同时保护其多重官能团免于降解。关于蛋白质的降解途径可以涉及化学不稳定性(例如,涉及通过键形成或切割的蛋白质修饰的任何过程,其导致新化学实体)或物理不稳定性(例如,蛋白质的高级结构的变化)。化学不稳定性可以起因于脱酰胺、外消旋、水解、氧化、β消除或二硫化物交换。例如,物理不稳定性可以起因于变性、聚集、沉淀或吸附。三种最常见的蛋白质降解途径是蛋白质聚集、脱酰胺和氧化。参见Cleland等人(1993)Crit.Rev.Ther.DrugCarrier Syst.10:307-377。
鉴于对全球公共卫生的严重威胁,需要包含2019-nCoV Ab的安全有效的制剂,其用作预防剂和治疗剂,尤其是用于减轻、预防和/或治疗2019-nCoV感染。
简述
针对这一需要,本公开内容描述了包含至少一种2019-nCoV Ab(称为埃特司韦单抗)或其药学上可接受的盐的组合物,例如药物制剂。此类制剂可以用于减弱、预防和/或治疗2019-nCoV感染或COVID-19。另外,此类制剂可以包装用于如本文所述的静脉内(IV)或皮下(SQ)施用,且伴随例如产物稳定性和其它期望属性的维持。
特别地,描述了包含2019-nCoV Ab、组氨酸缓冲液、多元醇或张度剂和表面活性剂的制剂。
在一些情况下,2019-nCoV Ab包含重链互补决定区(HCDR)HCDR1、HCDR2和HCDR3,以及轻链互补决定区(LCDR)LCDR1、LCDR2和LCDR3,其中HCDR1具有SEQ ID NO:1的氨基酸序列,HCDR2具有SEQ ID NO:2的氨基酸序列,且HCDR3具有SEQ ID NO:3的氨基酸序列,并且其中LCDR1具有SEQ ID NO:4的氨基酸序列,LCDR2具有SEQ ID NO:5的氨基酸序列,且LCDR3具有SEQ ID NO:6的氨基酸序列。
在其它情况下,2019-nCoV Ab包含重链可变区(HCVR),其中HCVR具有SEQ ID NO:7的氨基酸序列。可替代地,2019-nCoV Ab包含轻链可变区(LCVR),其中LCVR具有SEQ ID NO:8的氨基酸序列。还可替代地,2019-nCoV Ab包含具有SEQ ID NO:7的氨基酸序列的HCVR和具有SEQ ID NO:8的氨基酸序列的LCVR。
在又其它情况下,2019-nCoV Ab包含重链(HC),其中所述HC具有SEQ ID NO:9的氨基酸序列。可替代地,2019-nCoV Ab包含轻链(LC),其中所述LC具有SEQ ID NO:10的氨基酸序列。还可替代地,2019-nCoV Ab包含具有SEQ ID NO:9的氨基酸序列的HC和具有SEQIDNO:10的氨基酸序列的LC。
在上文任何内容中,2019-nCoV Ab可以为约25mg/mL至约150mg/mL的浓度。在一些情况下,2019-nCoV Ab为25mg/mL、30mg/mL、35mg/mL、40mg/mL、45mg/mL或50mg/mL的浓度。在某些情况下,2019-nCoV Ab为30mg/mL至40mg/mL,尤其是35mg/mL的浓度。
在一些情况下,组氨酸缓冲液可以为pH为约5.5至约7.0的L-组氨酸和/或L-组氨酸盐酸盐一水合物。
在上文任何内容中,组氨酸缓冲液可以为约5mM至约40mM的浓度。在某些情况下,组氨酸缓冲液在pH 6.0下为20mM的浓度。
在一些情况下,多元醇或张度剂可以为甘露糖醇或蔗糖。在某些情况下,多元醇或张度剂是蔗糖。
在上文任何内容中,多元醇或张度剂可以为约1%(w/v)至约10%(w/v)的浓度。在一些情况下,多元醇或张度剂可以为约4.5%(w/v)至约8.5%(w/v)的浓度。在某些情况下,多元醇或张度剂为约8.0%(w/v)的浓度。在特定情况下,多元醇或张度剂是浓度为8.04%(w/v)的蔗糖。
在一些情况下,表面活性剂可以为聚山梨醇酯。在某些情况下,表面活性剂是聚山梨醇酯80。
在上文任何内容中,表面活性剂可以为约0.01%(w/v)至约0.1%(w/v)的浓度。在某些情况下,表面活性剂为约0.02%(w/v)至约0.05%(w/v)的浓度。在特定情况下,表面活性剂是浓度为0.05%(w/v)的聚山梨醇酯80。
在一种情况下,制剂包含在pH 6.0下浓度为约20mM的L-组氨酸缓冲液、浓度为约8.04%(w/v)的蔗糖和浓度为约0.05%(w/v)的聚山梨醇酯80中具有以下的2019-nCoV Ab:具有SEQ ID NO:1的氨基酸序列的HCDR1、具有SEQ ID NO:2的氨基酸序列的HCDR2、具有SEQID NO:3的氨基酸序列的HCDR3、具有SEQ ID NO:4的氨基酸序列的LCDR1、具有SEQ ID NO:5的氨基酸序列的LCDR2和具有SEQ ID NO:6的氨基酸序列的LCDR3。
在另一种情况下,制剂包含在pH 6.0下浓度为约20mM的L-组氨酸缓冲液、浓度为约8.04%(w/v)的蔗糖和浓度为约0.05%(w/v)的聚山梨醇酯80中具有以下的2019-nCoVAb:具有SEQ ID NO:7的氨基酸序列的HCVR和具有SEQ ID NO:8的氨基酸序列的LCVR。
在又一种情况下,制剂包含在pH 6.0下浓度为约20mM的L-组氨酸缓冲液、浓度为约8.04%(w/v)的蔗糖和浓度为约0.05%(w/v)的聚山梨醇酯80中具有以下的2019-nCoVAb:具有SEQ ID NO:9的氨基酸序列的HC和具有SEQ ID NO:10的氨基酸序列的LC。
在一些情况下,制剂可以包含一种或多种另外的针对2019-nCoV的Ab。
本公开内容还描述了减弱、预防和/或治疗2019-nCoV感染或COVID-19的方法,其中此类方法至少包括向有需要的个体施用有效量/剂量的本文制剂的步骤。在一些情况下,组合物约每周施用一次。在一些情况下,个体具有确诊的2019-nCoV感染。在其它情况下,个体处于暴露于2019-nCoV的风险中。在其它情况下,个体最近暴露于2019-nCoV感染(即,但尚未具有确诊的2019-nCoV感染)。
本公开内容进一步描述了用作药剂的本文组合物。
本公开内容进一步描述了用于治疗2019-nCoV感染的本文组合物。
本公开内容进一步描述了包含本文制剂的制造物品。在一些情况下,制造物品是多用途小瓶。在一些情况下,制造物品是预填充式注射器。在一些情况下,制造物品是自动注射仪器(“自动注射器”;参见例如美国专利号8,734,394)。在一些情况下,制造物品是用于连续灌注的泵,尤其是用于皮下输注的泵。
详述
除非另有定义,否则本文使用的所有技术和科学术语都具有与本公开内容所属领域的技术人员通常理解相同的含义。尽管本文描述了优选的方法和材料,但与本文描述的那些类似或等价的任何方法和材料都可以用于肠降血糖素类似物、药物组合物和方法的实践或测试中。
此外,通过不定冠词“一个”或“一种”提及要素并不排除存在多于一个要素的可能性,除非上下文明确要求存在一个且仅存在一个要素。因此,不定冠词“一个”或“一种”通常意指“至少一个/种”。
定义
如本文使用的,“约”意指在一个或多个值的统计上有意义的范围内,诸如例如陈述的浓度、长度、分子量、pH、序列同一性、时间范围、温度或体积。此类值或范围可以在通常在给定值或范围的20%内,更通常在10%内,且甚至更通常在5%内的数量级内。通过“约”所涵盖的可允许变化将取决于处于研究下的特定系统,并且可以被本领域技术人员容易地了解。
如本文使用的,“亲和力”意指2019-nCoV Ab与2019-nCoV上的表位,诸如例如刺突(S)蛋白(SEQ ID NO:11)的2019-nCoV受体结合结构域(RBD)结合的强度。
如本文使用的,“抗体”或“Ab”等等意指包含具有链间二硫键和链内二硫键的两个HC和两个LC的全长Ab。四条多肽链各自的氨基末端部分包含主要负责抗原识别的可变区。每条HC包含N末端HCVR和HC恒定区(HCCR)。每条轻链包含LC可变区(LCVR)和LC恒定区(LCCR)。此处,Ab是免疫球蛋白G(IgG)型Ab,并且IgG同种型可以进一步分成亚类(例如,IgG1、IgG2、IgG3和IgG4)。HCVR和LCVR区可以进一步细分成称为互补决定区(CDR)的高变区,其间散布有称为构架区(FR)的更保守的区域。每个HCVR和LCVR包含从N末端到C末端按下述次序排列的3个CDR和4个FR:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。在本文中,HC的三个CDR被称为HCDR1、HCDR2和HCDR3,并且LC的三个CDR被称为LCDR1、LCDR2和LCDR3。CDR含有与抗原(例如2019-nCoV RBD)形成特异性相互作用的大部分残基。将残基分配给各种CDR可以通过算法诸如例如Chothia、Kabat或North来完成。North CDR定义基于具有大量晶体结构的亲和力传播聚类(North等人(2011)J.Mol.Bio.406:228-256)。在本文中,CDR最佳地通过序列表中列出的序列来定义,其基于包括North的多重定义的组合。
如本文使用的,“急性呼吸综合征冠状病毒2”、“SARS-CoV-2”、“2019新型冠状病毒”、“2019-nCoV”等等意指引起COVID-19的呼吸道病毒,其通常的特征在于轻度至重度下呼吸道疾病。
如同所有冠状病毒,2019-nCoV具有四种结构蛋白,包括刺突蛋白(S)、包膜蛋白(E)、膜蛋白(M)和核衣壳蛋白(N)。在其中,S蛋白在病毒附着、融合和进入中发挥重要作用,并且它充当用于开发Ab、进入抑制剂和疫苗的靶。S蛋白通过首先经由S1亚基中的RBD与宿主受体结合,然后经由S2亚基融合病毒和宿主膜,来介导病毒进入宿主细胞内。
基于其它冠状病毒,尤其是SARS-CoV和MERS-CoV的研究,与受体结合的重要包膜蛋白是S蛋白。S蛋白可以进一步分为S1和S2。S2的功能是介导膜融合。如本文所述的,C末端结构域(CTD)被鉴定为2019-nCoV RBD,其与ACE2受体结合。因此,靶向RBD的Ab和阻断S与ACE2的结合的Ab可能成为减弱或抑制2019-nCoV感染的中和Ab。
如本文使用的,“结合(bind)”或“结合(binds)”意指蛋白质与另一种蛋白质或分子形成一类化学键或引力的能力,如通过本领域已知的常规方法确定的。结合的特征可以在于约1x10-6M或更少的平衡解离常数(KD)(即,较小的KD表示更紧密的结合)。确定两个分子是否结合的方法是本领域众所周知的,并且包括例如平衡透析、表面等离子共振等等。Ab结合可以如下所述在以单点形式的标准ELISA测定中进行确定,并且结合可以如下所述通过例如分析仪(GE Healthcare Bio-Sciences AB;Uppsala,瑞典)进行表征。虽然本文中的Ab是人的,然而,它们可能显示出与其它物种的交叉反应性。
如本文使用的,关于单克隆Ab的“生物活性”意指Ab结合抗原的能力。它还可以包括与抗原结合并导致可以在体外或体内测量的可测量的生物应答的Ab。此类活性可以为拮抗性的或激动性的。
如本文使用的,“缓冲液”意指通过其酸-碱共轭组分的作用抵抗pH变化的缓冲溶液。一种缓冲液是组氨酸缓冲液,其是包含组氨酸离子的缓冲液。组氨酸缓冲液的实例包括但不限于组氨酸乙酸盐、组氨酸氯化物、组氨酸磷酸盐、组氨酸琥珀酸盐、组氨酸硫酸盐等。
如本文使用的,“化学稳定性”意指治疗剂、物质或产物抵抗产物组成中的潜在变化的能力,所述潜在变化是由于可能发生的化学反应,例如异构化、聚集、氧化、聚合、片段化和水解。
如本文使用的,“2019-nCoV抗体”、“2019-nCoV Ab”等等意指这样的Ab,其与2019-nCoV的RBD结合,从而阻断其与血管紧张素转换酶2(ACE2)受体的结合。示例性的2019-nCovAb是埃特司韦单抗,其是与2019-nCoV RBD结合并阻断2019-nCoV RBD与ACE2受体之间的结合,从而抑制2019-nCoV感染的IgG1 Ab。示例性的2019-nCoV Ab包含三个HCDR-HCDR1、HCDR2和HCDR3-并且包含三个LDCR-LCDR1、LCDR2和LCDR3-其中HCDR1具有SEQ ID NO:1的氨基酸序列,HCDR2具有SEQ ID NO:2的氨基酸序列,HCDR3具有SEQ ID NO:3的氨基酸序列,LCDR1具有SEQ ID NO:4的氨基酸序列,LCDR2具有SEQ ID NO:5的氨基酸序列,并且LCDR3具有SEQ ID NO:6的氨基酸序列。可替代地,2019-nCoV Ab包含具有SEQ ID NO:7的氨基酸序列的HCVR。还可替代地,2019-nCoV Ab包含具有SEQ ID NO:8的氨基酸序列的LCVR。还可替代地,2019-nCoV Ab包含具有氨基酸序列SEQ ID NO:7的HCVR和具有SEQ ID NO:8的氨基酸序列的LCVR。可替代地,2019-nCoV Ab包含具有SEQ ID NO:9的氨基酸序列的HC。还可替代地,2019-nCoV Ab包含具有SEQ ID NO:10的氨基酸序列的LC。还可替代地,2019-nCoV Ab包含具有SEQ ID NO:9的氨基酸序列的HC和具有SEQ ID NO:10的氨基酸序列的LC。具体地,埃特司韦单抗是人IgG1变体(Fc效应子无效)单克隆Ab,其具有2个相同的449个氨基酸的HC多肽(SEQ ID NO:9)和2个相同的216个氨基酸的LC多肽(SEQ ID NO:10),其各自使用中国仓鼠卵巢(CHO)细胞系产生。埃特司韦单抗的翻译后修饰包括HC Asn297上的N连接糖基化和HC C末端Lys的去除。
如本文使用的,“有效量”意指一种或多种活性成分(例如,Ab)或者其药学上可接受的盐的量、浓度或剂量,其在对有此需要的个体的单剂量或多剂量施用后,在处于诊断或治疗下的此类个体中提供了所需效果(即,可以在个体的病况中产生临床上可测量的差异)。可以通过使用已知技术并通过观察在类似情况下获得的结果,通过本领域技术人员容易地确定有效量。在确定用于个体的有效量时,要考虑许多因素,包括但不限于哺乳动物的物种、其大小、年龄和一般健康,所涉及的具体疾病或病症,疾病或病症的涉及程度或严重程度,个体的应答,所施用的具体肠降血糖素类似物,施用模式,所施用制剂的生物利用度特性,选择的剂量方案,伴随用药的使用以及其它相关情况。
如本文使用的,就制剂而言,“冷冻的”意指在低于0℃的温度下。一般地,冷冻制剂并非冷冻干燥的,它也不经受之前或之后的冻干。以此方式,冷冻制剂包含用于贮存(例如,在不锈钢罐中)或冷冻药品(在最终小瓶配置中)的冷冻活性成分(例如,Ab)。
如本文使用的,“有此需要的个体”指患有需要治疗或疗法的病况、疾病、病症或症状,包括例如本文列出的那些的哺乳动物,例如人。特别地,待治疗的优选个体是人,尤其是患有或疑似患有2019-nCoV感染或COVID-19的个体。
如本文使用的,“试剂盒”意指包含用于治疗COVID-19的至少一种试剂(例如,药剂)和包装插页的任何制造品(例如包装或容器),所述包装插页具有用于将试剂施用于患有与COVID-19相关的疾病、病症或病况的个体的说明书。制造品可以作为用于执行本文方法的单元来推广、分发或销售。
如本文使用的,“药剂”意指治疗疾病、病症和/或病况例如COVID-19的活性成分(例如Ab)。
如本文使用的,“微生物稳定性”意指活性成分、物质或产物在暴露于环境或其它微生物时维持其无菌性的能力。
如本文使用的,“药物制剂”或“制剂”意指这样的制剂,其以这样的形式以便允许活性成分(例如Ab)的生物活性是有效的,并不含有对该制剂将施用于其的个体具有不可接受的毒性的另外组分。此类制剂是无菌的。“药学上可接受的”赋形剂(例如添加剂、媒介物等)意指可以合理地施用于个体,以提供所采用的活性成分的有效剂量的那些赋形剂。
如本文使用的,“治疗(treat)”、“治疗(treatment)”或“治疗(treating)”意指管理且护理患有或疑似患有病况的个体,对于所述病况指示了制剂施用,用于对抗或减轻其感染的症状和并发症的目的。治疗包括向此类个体施用包含本文的活性成分(例如Ab)的化合物、组合物或制剂,以预防症状或并发症的发作、减轻症状或并发症、或者消除感染。治疗包括向有此需要的个体施用包含本文的活性成分(例如Ab)的化合物、组合物或制剂,以导致减弱或阻断的2019-nCoV感染。待治疗的个体是动物,尤其是人类。
如本文使用的,“患者”、“受试者”和“个体”在本文中可互换使用,并且意指动物,尤其是人。在某些情况下,个体是人,并且进一步的特征在于具有将受益于施用本文制剂的感染。
如本文使用的,“多元醇”意指具有多重羟基基团的物质,其可以包含在制剂中,并且包括糖(还原糖和非还原糖)、糖醇和糖酸。还原糖的实例包括但不限于果糖、甘露糖、麦芽糖、乳糖、阿拉伯糖、木糖、核糖、鼠李糖、半乳糖和葡萄糖。非还原糖的实例包括但不限于蔗糖、海藻糖、山梨糖、松三糖和棉子糖。糖醇的实例包括但不限于甘露糖醇、木糖醇、赤藓醇、苏糖醇、山梨糖醇和甘油。糖酸的实例包括但不限于L-葡糖酸及其金属性盐。在一些情况下,多元醇是非还原糖或糖醇,尤其是蔗糖或甘露糖醇。
如本文使用的,“防腐剂”意指这样的化合物,其可以包含在制剂中以基本上降低其中的细菌作用,因此促进多用途制剂的生产。防腐剂的实例包括但不限于十八烷基二甲基苄基氯化铵、氯化六甲双铵、苯扎氯铵(其中烷基基团是长链化合物的烷基苄基二甲基氯化铵的混合物)和苄索氯铵。其它防腐剂包括芳香醇如苯酚、丁醇和苯甲醇、对羟基苯甲酸烷基酯如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯、儿茶酚、间苯二酚、环己醇、3-戊醇和间甲酚。
如本文使用的,就制剂而言,“稳定的”意指其中的活性成分(例如,Ab)在贮存时基本上保留其生物活性和/或化学稳定性和/或物理稳定性的制剂。以这种方式,制剂在贮存时基本上保留其化学和物理稳定性,以及保留其生物活性。贮存期一般可以基于制剂的预期贮存期限。
如本文使用的,就制剂而言,“无菌的”意指无菌或者不含或基本上不含所有活的微生物和孢子。
如本文使用的,“表面活性剂”意指表面活性试剂,通常为非离子型表面活性剂。表面活性剂的实例包括但不限于聚山梨醇酯(例如聚山梨醇酯20、40、60和80);泊洛沙姆(例如泊洛沙姆188);Triton;十二烷基硫酸钠(SDS);月桂基硫酸钠;辛基糖苷钠;月桂基-、肉豆蔻基-、亚油基(linoleyl)-或硬脂基-磺基甜菜碱;月桂基-、肉豆蔻基-、亚油基-或硬脂基-肌氨酸;亚油基-、肉豆蔻基-或鲸蜡基-甜菜碱;月桂酰胺丙基-、椰油酰胺丙基-、亚油酰胺丙基-、肉豆蔻酰胺丙基-、棕榈酰胺丙基-或异硬脂酰胺丙基-甜菜碱(例如月桂酰胺丙基);肉豆蔻酰胺丙基-、棕榈酰胺丙基-或异硬脂酰胺丙基-二甲胺;甲基椰油酰基牛磺酸钠或甲基油烯基牛磺酸二钠;和MONAQUATTM系列(Mona Industries,Inc.;Paterson,N.J.);聚乙二醇、聚丙二醇以及乙二醇和丙二醇的共聚物(例如,Pluronics、PF68等);等,尤其是聚山梨醇酯80。
组合物和制剂
本文的组合物是包含2019-nCoV Ab的制剂,所述2019-nCoV Ab具有三个HCDR(即,HCDR1、HCDR2和HCDR3),并且具有三个LDCR(即,LCDR1、LCDR2和LCDR3),其中HCDR1具有SEQID NO:1的氨基酸序列,HCDR2具有SEQ ID NO:2的氨基酸序列,HCDR3具有SEQ ID NO:3的氨基酸序列,LCDR1具有SEQ ID NO:4的氨基酸序列,LCDR2具有SEQ ID NO:5的氨基酸序列,并且LCDR3具有SEQ ID NO:6的氨基酸序列。可替代地,制剂可以包含2019-nCov Ab,其具有含有SEQ ID NO:7的氨基酸序列的HCVR且具有含有SEQ ID NO:8的氨基酸序列的LCVR。可替代地,制剂可以包含2019-nCoV Ab,其具有含有SEQ ID NO:9的氨基酸序列的HC且具有含有SEQ ID NO:10的氨基酸序列的LC。关于2019-nCoV Ab的进一步细节,包括其合成方法,在国际专利申请公开号WO 2021/169932中进行描述。
在一些情况下,2019-nCoV Ab可以包含与SEQ ID NO:7的氨基酸序列具有至少约90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的HCVR序列。在其它情况下,2019-nCoV Ab可以包含与SEQ ID NO:8的氨基酸序列具有至少约90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的LCVR序列。HCVR和/或LCVR可以包含相对于参考序列的取代(例如保守取代)、插入或缺失,但保留与2019-nCoV RBD结合的能力。即,总共1至10个氨基酸可以在SEQ ID NO:7和8中被取代、插入和/或缺失。在一些情况下,取代、插入或缺失在CDR外部的区域中(即,在构架区(FR)中)发生。
2019-CoV Ab可以为约25mg/mL至约150mg/mL的浓度。在一些情况下,2019-nCoVAb为如下的浓度:约30mg/mL至145mg/mL、约35mg/mL至约140mg/mL、约40mg/mL至约135mg/mL、约45mg/mL至约130mg/mL、约50mg/mL至约125mg/mL、约55mg/mL至约120mg/mL、约60mg/mL至约115mg/mL、约65mg/mL至约110mg/mL、约70mg/mL至约105mg/mL、约75mg/mL至约100mg/mL、约80mg/mL至约95mg/mL、或约85mg/mL至约90mg/mL。在一些情况下,2019-nCoVAb可以为如下的浓度:约25mg/mL、约30mg/mL、约35mg/mL、约40mg/mL、约45mg/mL、约50mg/mL、约55mg/mL、约60mg/mL、约65mg/mL、约70mg/mL、约75mg/mL、约80mg/mL、约85mg/mL、约90mg/mL、约95mg/mL、约100mg/mL、约105mg/mL、约110mg/mL、约115mg/mL、约120mg/mL、约125mg/mL、约130mg/mL、约135mg/mL、约140mg/mL、约145mg/mL或约150mg/mL,尤其为约30mg/mL至约40mg/mL。在某些情况下,2019-nCoV Ab为35mg/mL的浓度。
除2019-nCoV Ab之外,制剂还包含缓冲系统以维持适当的pH。示例性的缓冲系统是组氨酸缓冲液,其可以为L-组氨酸和/或L-组氨酸盐酸盐一水合物。
组氨酸缓冲液可以为约5mM至约40mM的浓度。在一些情况下,组氨酸缓冲液可以为约10mM至约35mM、约15mM至约30mM、或约20mM至约25mM的浓度。在一些情况下,组氨酸缓冲液可以为约5mM、约10mM、约15mM、约20mM、约25mM、约30mM、约35mM或约40mM,尤其是约15mM至约25mM的浓度。在某些情况下,组氨酸缓冲液为20mM的浓度。
无论缓冲系统如何,本文制剂的pH可以为约5.5至约7.0。在一些情况下,pH可以为约5.6至约6.9、约5.7至约6.8、约5.8至约6.7、约5.9至约6.6、约6.0至约6.5、约6.1至约6.4、或约6.2至约6.3。在一些情况下,pH可以为约5.5、约5.6、约5.7、约5.8、约5.9、约6.0、约6.1、约6.2、约6.3、约6.4、约6.5、约6.6、约6.7、约6.8、约6.9或约7.0。在某些情况下,pH为6.0。
除上文之外,本文的制剂还包含多元醇或张度剂以成为等渗制剂,其适合于静脉内或皮下施用。示例性的多元醇或张度剂是甘露糖醇或蔗糖。
当多元醇或张度剂是甘露糖醇时,它可以为约3.5%(w/v)至约5.5%(w/v)的浓度。在一些情况下,甘露糖醇可以为如下的浓度:约3.6%(w/v)至约5.4%(w/v)、约3.7%(w/v)至约5.3%(w/v)、约3.8%(w/v)至约5.2%(w/v)、约3.9%(w/v)至约5.1%(w/v)、约4.0%(w/v)至约5.0%(w/v)、约4.1%(w/v)至约4.9%(w/v)、约4.2%(w/v)至约4.8%(w/v)、约4.3%(w/v)至约4.7%(w/v)、约4.4%至约4.6%(w/v)、或约4.5%(w/v)。在一些情况下,甘露糖醇可以为如下的浓度:约3.5%(w/v)、约3.6%(w/v)、约3.7%(w/v)、约3.8%(w/v)、约3.9%(w/v)、约4.0%(w/v)、约4.1%(w/v)、约4.2%(w/v)、约4.3%(w/v)、约4.4%(w/v)、约4.5%(w/v)、约4.6%(w/v)、约4.7%(w/v)、约4.8%(w/v)、约4.9%(w/v)、约5.0%(w/v)、约5.1%(w/v)、约5.2%(w/v)、约5.3%(w/v)、约5.4%(w/v)或约5.5%(w/v)。在某些情况下,甘露糖醇为4.5%(w/v)的浓度。
当多元醇或张度剂是蔗糖时,它可以为约6.5%(w/v)至约8.5%(w/v)的浓度。在一些情况下,蔗糖可以为如下的浓度:约6.6%(w/v)至约8.4%(w/v)、约6.7%(w/v)至约8.3%(w/v)、约6.8%(w/v)至约8.2%(w/v)、约6.9%(w/v)至约8.1%、约7.0%(w/v)至约8.0%(w/v)、约7.1%(w/v)至约7.9%(w/v)、约7.2%(w/v)至约7.8%(w/v)、约7.3%(w/v)至约7.7%(w/v)、约7.4%(w/v)至约7.6%(w/v)、或约7.5%(w/v)。在一些情况下,蔗糖可以为如下的浓度:约6.5%(w/v)、约6.6%(w/v)、约6.7%(w/v)、约6.8%(w/v)、约6.9%(w/v)、约7.0%(w/v)、约7.1%(w/v)、约7.2%(w/v)、约7.3%(w/v)、约7.4%(w/v)、约7.5%(w/v)、约7.6%(w/v)、约7.7%(w/v)、约7.8%(w/v)、约7.9%(w/v)、约8.0%(w/v)、约8.1%(w/v)、约8.2%(w/v)、约8.3%(w/v)、约8.4%(w/v)或约8.5%(w/v)。在一些情况下,蔗糖可以为如下的浓度:约8.00%(w/v)、约8.01%(w/v)、约8.02%(w/v)、约8.03%(w/v)、约8.04%(w/v)、约8.05%(w/v)、约8.06%(w/v)、约8.07%(w/v)、约8.08%(w/v)、约8.09%(w/v)或约8.10%(w/v)。在某些情况下,蔗糖为8.04%(w/v)的浓度。
除上文之外,本文的制剂还包含表面活性剂,以改善制剂的物理和化学特性并改善其功效或生物性能。
在一些情况下,表面活性剂可以为非离子型表面活性剂。示例性的非离子型表面活性剂包括但不限于聚山梨醇酯(例如聚山梨醇酯20、40、60、80等)或泊洛沙姆(例如泊洛沙姆184、188等),尤其是聚山梨醇酯80。
当表面活性剂是聚山梨醇酯80时,它可以为约0.01%(w/v)至约0.1%(w/v)的浓度。在一些情况下,聚山梨醇酯80可以为如下的浓度:约0.02%(w/v)至约0.09%(w/v)、0.03%(w/v)至约0.08%(w/v)、约0.04%(w/v)至约0.07%(w/v)、或约0.05%(w/v)至约0.06%(w/v)。在一些情况下,聚山梨醇酯80可以为如下的浓度:约0.01%(w/v)、0.02%(w/v)、0.03%(w/v)、0.04%(w/v)、0.05%(w/v)、0.06%(w/v)、0.07%(w/v)、0.08%(w/v)、0.09%(w/v)或0.1%(w/v)。在某些情况下,聚山梨醇酯80为0.05%(w/v)的浓度。
本文的制剂在首次生产时是无菌的。因此,制剂任选地可以包含防腐剂,其与组合物的其它组分相容,并且可以以足够的强度添加以满足适用的监管抗微生物防腐剂要求。药学上可接受的防腐剂是本领域技术人员已知的(参见例如,Remington:The Science andPractice of Pharmacy(Troy,编辑,第21版,Lippincott,Williams&Wilkins,2006)。在一些情况下,本文的制剂是不含防腐剂的。
在一种特定情况下,制剂包含在pH 6.0下浓度为约20mM的L-组氨酸缓冲液及浓度为约8.04%(w/v)的蔗糖和浓度为约0.05%(w/v)的聚山梨醇酯80中浓度为约35mg/mL的2019-nCoV Ab,其中所述2019-nCoV Ab包含具有SEQ ID NO:1的氨基酸序列的HCDR1、具有SEQ ID NO:2的氨基酸序列的HCDR2、具有SEQ ID NO:3的氨基酸序列的HCDR3、具有SEQ IDNO:4的氨基酸序列的LCDR1、具有SEQ ID NO:5的氨基酸序列的LCDR2、以及具有SEQ ID NO:6的氨基酸序列的LCDR3。在另一种特定情况下,制剂包含在pH 6.0下浓度为约20mM的L-组氨酸缓冲液及浓度为约8.04%(w/v)的蔗糖和浓度为约0.05%(w/v)的聚山梨醇酯80中浓度为约35mg/mL的2019-nCoV Ab,其中所述2019-nCoV Ab包含具有SEQ ID NO:7的氨基酸序列的HCVR和具有SEQ ID NO:8的氨基酸序列的LCVR。在又一种特定情况下,制剂包含在pH6.0下浓度为约20mM的L-组氨酸缓冲液及浓度为约8.04%(w/v)的蔗糖和浓度为约0.05%(w/v)的聚山梨醇酯80中浓度为约35mg/mL的2019-nCoV Ab,其中所述2019-nCoV Ab包含具有SEQ ID NO:9的氨基酸序列的HC和具有SEQ ID NO:10的氨基酸序列的LC。
本文的组合物可以静脉内(IV)、肌内(IM)或皮下(SQ)施用。可以使用预填充的一次性笔、可重复使用的笔或自动笔式注射器来施用组合物。可替代地,可以使用多用途小瓶或泵装置来施用组合物。在一些情况下,装置是如美国专利号8,734,394中描述的自动注射仪器。
因此,本文的组合物可以存在于预填充式注射器/多用途小瓶中。此类预填充式注射器/多用途小瓶可以用于施用约0.5mL至约1mL的组合物/患者/剂量。组合物的剂量可以使用由临床医生、医师或其它训练有素的医学专业人员确定的给药方案来施用。
可替代地,组合物可以制备用于药液筒,并且因此通过包含防腐剂而不同于上文组合物。
可替代地,组合物可以制备为包含组合物的制造物品的部分,其中所述制造物品可以为多用途小瓶、可重复使用的笔式注射器、预填充的一次性笔、自动注射器或泵。
鉴于上文,本文的组合物与可接受的贮存期限稳定性、使用中稳定性和可接受的注射部位体验相关。
方法
本文的制剂可以用于减弱、预防和/或治疗2019-nCoV感染或COVID-19。例如,本文的制剂可以用于治疗患有活跃2019-nCoV感染的个体。特别地,提供了用于治疗此类受感染个体的方法,其中此类方法至少包括向需要此类治疗的个体施用有效量的本文制剂的步骤。另外,提供了用于预防性预防个体中的感染的方法,其中此类方法至少包括向处于暴露于2019-nCoV的风险中的个体施用有效量的本文制剂的步骤。
在这些方法中,组合物的有效性可以通过例如观察味觉缺失、厌食、咳嗽、腹泻、味觉障碍、发烧、头痛、关节痛、肌肉痛、恶心、呼吸短促、喉咙痛和/或呕吐的显著降低进行评价。
实施例
提供下述非限制性实施例用于说明而非限制的目的。
制剂
实施例1:包含2019-nCoV Ab的制剂
制剂基本上如本文所述的进行制备。此类组合物包含以35、40或125mg/mL的2019-nCoV Ab,例如埃特司韦单抗(例如SEQ ID NO:9的HC和SEQ ID NO:10的LC),以及如表1中所示的另外成分。选择多元醇浓度以成为适合于IV或SQ施用的等渗制剂。
溶液通过以下进行制备:将2019-nCoV Ab加入适当的基质内,混合直至达到溶解成溶液,然后使用适当大小的混合容器使溶液达到最终体积。将每种制剂溶液无菌过滤到0.22-μm PVDF过滤器内,并且以预定的填充体积填充到1型玻璃小瓶内。
表1:示例性制剂。
对于制剂1,2019-nCoV Ab作为400mg/10mL小瓶提供,并且作为预期用于IV施用的无菌冷藏溶液提供。可替代地,2019-nCoV Ab作为700mg/17.5mL小瓶提供,并且作为预期用于IV施用的无菌冷藏溶液提供。
对于制剂2,2019-nCoV Ab作为700mg/20mL小瓶提供,并且作为预期用于IV施用的无菌冷藏溶液提供。
对于制剂3,2019-nCoV Ab作为262.5mg/2.1mL小瓶提供,并且作为预期用于IV施用和/或SC施用的无菌冷藏溶液提供。
对于制剂4,评估了2019-nCoV Ab的稳定性,但并未提供用于临床试验。
对于制剂5,评估了2019-nCoV Ab的稳定性,并且用作原料药制剂。
对于制剂6,评估了2019-nCoV Ab的稳定性,但并未提供用于临床试验。
对于制剂7,评估了2019-nCoV Ab的稳定性,但并未提供用于临床试验。
制剂1和2贮存于2℃-8℃下,而制剂3贮存于不超过-40℃下或可替代地2℃-8℃下,用于如后续实施例中所述的进一步研究。
体外数据(化学和物理稳定性)
实施例2:使用中稳定性研究
选择用于测量制剂的化学和物理稳定性的稳定性指示分析和表征技术包括尺寸排阻层析(SEC)和视觉外观。
表2:制剂1、4和6的冻/融稳定性。
注:1制备为50mL超低密度聚乙烯(ULDP)袋中的30mL填充物;
2制备为125mL聚碳酸酯(PC)瓶中的60mL填充物。
由于蔗糖证实了保护2019-nCoV Ab免受冻/融应激(stress)的能力,因此生成了另一种制剂(即,制剂5),以评估在20mM L-组氨酸缓冲液,pH 6,8.04%(w/v)蔗糖和0.05%(w/v)聚山梨醇酯80的制剂中150mg/mL的较高浓度下的冷冻稳定性(表3)。
表3:制剂5的冻/融稳定性。
注:制备为5mL PC瓶中的2.5mL填充物
稳定性结果显示了,2019-nCoV Ab适合在20mM L-组氨酸缓冲液,pH 6,8.04%(w/v)蔗糖和0.05%(w/v)聚山梨醇酯80中以150mg/mL进行配制。
测试了与在20mM L-组氨酸缓冲液,pH 6.0,4.5%(w/v)甘露糖醇和0.02%(w/v)聚山梨醇酯80中具有40mg/mL 2019-nCoV Ab的制剂(制剂1;表5)相比,在20mM L-组氨酸缓冲液,pH 6,8.5%(w/v)蔗糖和0.05%(w/v)聚山梨醇酯80中具有35mg/mL 2019-nCoV Ab的制剂(即,制剂7;表4)在2℃-8℃下的长期贮存和在25℃下的加速条件的影响。
表4:具有2019-nCoV Ab的制剂的稳定性。
表5:具有2019-nCoV Ab的制剂的稳定性。
含有蔗糖的制剂(表4)的稳定性证实了与含有甘露糖醇的制剂(表5)可比较的稳定性,指示了用蔗糖替换甘露糖醇并不影响2019-nCoV Ab在长期贮存(2℃-8℃)和加速(25℃)条件下的稳定性。为了确保制剂对于IV注射是等渗的,蔗糖的量从8.5%(w/v)降低到8.04%(w/v)。因此,一种制剂含有在20mM L-组氨酸缓冲液,pH 6,8.04%(w/v)蔗糖,0.05%(w/v)聚山梨醇酯80和注射用水中的35mg/mL 2019-nCoV(即,制剂2)。
对制剂1和2执行了另外的研究(表6)。
表6:制剂1和2的可比较性研究。
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还对制剂2进行使用中相容性评价,所述制剂2是纯(未稀释)施用的,或者适当时用0.9%氯化钠注射液进一步稀释,以评估与例如代表临床场所使用的给药装置的接触材料的相容性、以及在剂量制备和施用期间的分子稳定性。所测试的接触材料是聚氯乙烯(PVC)、聚烯烃(聚丙烯和聚乙烯)和聚醚砜(PES)。
同样地,进行了模拟输液研究,以评估与由PVC制成的IV袋和输液器以及由PES制成的内置过滤器(in-line filter)的相容性。该制剂制备为包含大约3.5mg/mL(用0.9%氯化钠注射液稀释的)和35mg/mL(未稀释的)的浓度范围。表7和表8显示了,稀释的或纯制剂在由聚烯烃制成的给药装置中,在室温下贮存长达5小时。
此外,为了提供剂量施用的灵活性,执行了另一项使用中研究,以评估制剂(未稀释的)与由聚丙烯(PP)制成的注射器以及由聚乙烯(PE)制成的输注线的相容性。不使用内置过滤器。表9显示了所制备的给药制剂可以在由聚烯烃制成的给药装置中,在室温下贮存长达4小时。
表7:使用PVC IV袋和具有PES的输注线,关于制剂2的3.5mg/mL输注溶液的模拟使用中结果。
表8:使用PVC IV袋和具有PES的输注线,关于制剂2的35mg/mL输注溶液的模拟使用中结果。
表9:使用PP注射器和PE输注线,关于制剂2的35mg/mL输注溶液的模拟使用中结果。
表10:示例性的药品单位配方。
序列表
下述核酸和/或氨基酸序列在上文的公开内容中被提及,并且在下文提供用于参考。
SEQ ID NO:1-重链决定区1(HCDR1)
SEQ ID NO:2-重链决定区2(HCDR2)
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SEQ ID NO:3-重链决定区3(HCDR3)
SEQ ID NO:4-轻链决定区1(LCDRl)
SEQ ID NO:5-轻链决定区2(LCDR2)
SEQ ID NO:6-轻链决定区3(LCDR3)
SEQ ID NO:7-重链可变区(HCVR)
SEQ ID NO:8-轻链可变区(LCVR)
SEQ ID NO:9-重链(HC)
SEQ ID NO:10-轻链(LC)
SEQ ID NO:11-2019-nCoV刺突(S)蛋白(GenBank登录号:YP_009724390.1)
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Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
1010 1015 1020
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
1025 1030 1035
Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
1040 1045 1050
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
1055 1060 1065
Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
1070 1075 1080
Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1085 1090 1095
Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
1100 1105 1110
Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
1115 1120 1125
Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro
1130 1135 1140
Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
1145 1150 1155
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn
1160 1165 1170
Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu
1175 1180 1185
Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu
1190 1195 1200
Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu
1205 1210 1215
Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met
1220 1225 1230
Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro
1250 1255 1260
Val Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270
Claims (15)
1.一种药物制剂,其包含:
浓度为约30mg/mL至约150mg/mL的2019新型冠状病毒(2019-nCoV)抗体;
浓度为约5mM至约40mM的组氨酸缓冲液;
浓度为约8.0%(w/v)至约8.5%(w/v)的蔗糖;和
浓度为约0.02%(w/v)至约0.08%(w/v)的聚山梨醇酯80,
其中所述药物组合物具有约5.5至约7.0的pH。
2.权利要求1的药物制剂,其中所述2019-nCoV抗体为约30mg/mL至约40mg/mL的浓度。
3.权利要求1的药物制剂,其中所述2019-nCoV抗体为约35mg/mL的浓度。
4.权利要求1至3中任一项的药物制剂,其中所述组氨酸缓冲液浓度为约20mM。
5.权利要求1至4中任一项的药物制剂,其中所述pH为约6.0。
6.权利要求1至5中任一项的药物制剂,其中蔗糖为约8.05%(w/v)的浓度。
7.权利要求1至6中任一项的药物制剂,其中聚山梨醇酯80为约0.05%(w/v)的浓度。
8.权利要求1至7中任一项的药物制剂,其中所述2019-nCoV抗体包含三个重链重链互补决定区(HCDR)和三个轻链互补决定区(LCDR),并且其中HCDR1包含SEQ ID NO:1,HCDR2包含SEQ ID NO:2,HCDR3包含SEQ ID NO:3,LCDR1包含SEQ ID NO:4,LCDR2包含SEQ ID NO:5且LCDR3包含SEQ ID NO:6。
9.权利要求8的药物制剂,其中所述2019-nCoV抗体包含含有SEQ ID NO:7的重链可变区(HCVR)。
10.权利要求8或9的药物制剂,其中所述2019-nCoV抗体包含含有SEQ ID NO:8的轻链可变区。
11.权利要求8的药物制剂,其中所述2019-nCoV抗体包含含有SEQ ID NO:9的重链。
12.权利要求8或11的药物制剂,其中所述2019-nCoV抗体包含含有SEQ ID NO:10的轻链。
13.权利要求1至12中任一项的药物制剂,其进一步包含一种或多种另外的2019-nCoV抗体。
14.一种治疗2019新型冠状病毒(2019-nCoV)感染或COVID-19的方法,其包括以下步骤:
向患有2019-nCoV感染的个体施用有效量的权利要求1至13中任一项的药物制剂。
15.一种预防个体中的2019新型冠状病毒(2019-nCoV)感染或COVID-19的方法,其包括以下步骤:
向处于暴露风险中或暴露于2019-nCoV的个体施用有效量的权利要求1至13中任一项的药物制剂。
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WO2021169932A1 (zh) | 2020-02-24 | 2021-09-02 | 中国科学院微生物研究所 | 新型冠状病毒的人源单克隆抗体及其应用 |
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