CN113274494A - 一种抗SARS-CoV-2的重组全人源单克隆抗体的液体制剂 - Google Patents
一种抗SARS-CoV-2的重组全人源单克隆抗体的液体制剂 Download PDFInfo
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Abstract
本发明属于抗体药物制剂领域，具体涉及一种抗SARS‑CoV‑2的重组全人源单克隆抗体(2B11)的液体制剂，其中包括全人源抗新冠病毒单克隆抗体2B11、缓冲液，所述的缓冲液中还包含稳定剂、表面活性剂、以及可选地包含等渗调节剂，所述的液体制剂的溶剂为注射用水，所述的液体制剂的pH为5.5‑6.1。
Description
技术领域
本发明属于抗体药物制剂领域，具体的，涉及一种抗SARS-CoV-2的重组全人源单克隆抗体的液体制剂。
背景技术
SARS-CoV-2是一种新型冠状病毒，自2019年爆发以来已引起全球大流行，严重威胁到全球公共健康。截至目前，虽然已有上市疫苗，但每天全球感染的人数仍在增加，通过接种疫苗产生主动免疫保护，需要数周才能达到保护效力，而针对SARS-CoV-2的抗体则能提供即时的被动免疫，同时对免疫功能低下的人群也能提供有效的保护。
通过前期的研究已经证实，本公司研发的具有独立知识产权的针对SARS-CoV-2的重组全人源单克隆抗体2B11(CN202010567918.X)，能特异性结合SARS-CoV-2表面抗原，从而阻止新冠病毒进一步感染受体细胞，达到保护的作用。对于高风险人群，抗SARS-CoV-2的重组全人源单克隆抗体可以提供短期的即时预防；对于感染后人群，可以通过注射被动免疫的抗体降低重症的风险。。
发明内容
本发明所开发的抗体制剂，包含活性成分“重组全人源抗新冠病毒单克隆抗体”，用于短期预防和治疗SARS-CoV-2感染，为抗体生产、运输和保存过程中的结构和功能稳定性提供保障。
本发明首先涉及一种针对SARS-CoV-2的重组全人源单克隆抗体2B11的液体制剂，所述制剂包括全人源抗新冠病毒单克隆抗体2B11、缓冲液，所述的缓冲液中还包含稳定剂、表面活性剂、以及可选地包含等渗调节剂，所述的液体制剂的溶剂为注射用水，所述的液体制剂的pH为5.5-6.1。
所述的缓冲液为10～50mM组氨酸盐缓冲液，优选20mM组氨酸盐缓冲液，pH为5.5-6.1；
所述的液体制剂中，包括全人源抗新冠病毒单克隆抗体2B11的含量为10～100mg/mL，优选为20mg/ml。
所述的稳定剂为50-150mM的精氨酸，优选125mM的精氨酸。
所述的表面活性剂为0.005％-0.02％的聚山梨酯20，优选0.01％的聚山梨酯20。
所述的等渗调节剂为15-40mM的氯化钠，优选20-30mM的氯化钠，更优选27mM的氯化钠。
本发明还涉及所述的液体制剂在制备检测或抑制SARS-CoV-2病毒的试剂中的应用。
本发明还涉及所述的液体制剂在制备药物中的应用，所述的药物为预防和/或治疗因SARS-CoV-2病毒感染导致的疾病的药物。
优选的，所述的药物为注射剂。
本发明的有益效果在于：
为SARS-CoV-2病毒的检测、鉴定及感染后的治疗提供了新的候选药物。
附图说明
图1、单克隆抗体2B11液体制剂处方开发过程中非还原CE-SDS结果。
图2、单克隆抗体2B11液体制剂处方开发过程中SEC-HPLC结果。
图3、单克隆抗体2B11液体制剂处方开发过程中CEX-HPLC结果。
图4、单克隆抗体2B11液体制剂处方开发过程中亚可见颗粒检测结果。
图5、单克隆抗体2B11液体制剂处方的冻融研究结果。
具体实施方式
若未特别说明，以下实施例中所用的技术手段均为本领域技术人员所熟知的常规手段，所有试剂耗材均为市售商品。
下述实施例中所使用的抗体为全人源化的2B11单抗，该抗体的序列结构参见本公司在先申请CN202010567918.X。
制剂配方如下表所示
| 样品编号 | 主要配方组成 |
| 2B11-01 | 组氨酸，山梨醇，tween20 |
| 2B11-02 | 组氨酸，精氨酸，tween20 |
| 2B11-03 | 组氨酸，精氨酸，泊洛沙姆 |
| 2B11-04 | 组氨酸，甘露醇，tween80 |
| 2B11-05 | 组氨酸，精氨酸，tween80 |
| 2B11-06 | 组氨酸，Gly，tween80 |
| 2B11-07 | 组氨酸，精氨酸，tween80 |
| 2B11-08 | 组氨酸，Gly，tween80 |
| 2B11-09 | 组氨酸，Gly，tween20 |
| 2B11-10 | 组氨酸，山梨醇，tween20 |
| 2B11-11 | 组氨酸，山梨醇，泊洛沙姆 |
| 2B11-12 | 组氨酸，甘露醇，tween80 |
| 2B11-13 | 组氨酸，山梨醇，tween80 |
| 2B11-14 | 组氨酸，甘露醇，tween80 |
| 2B11-15 | 组氨酸，山梨醇，泊洛沙姆 |
| 2B11-16 | 组氨酸，Gly，泊洛沙姆 |
| 2B11-17 | 组氨酸，甘露醇，tween20 |
实施例1、抗体制剂的冻融研究
配方需要在冻融条件下稳定，稳定包括分子排阻凝胶色谱(SEC-HPLC)、非还原毛细管凝胶电泳(非还原CE-SDS)、以及电荷的改变，可通过离子交换色谱(CEX-HPLC)检测。。
(一)分子排阻凝胶色谱(SEC-HPLC)检测抗体降解情况，检测步骤：
(1)流动相溶液的配制(0.1mol/L PB+0.1mol/L Na2SO4+0.05％NaN3)：称取Na2SO414.2g，NaH2PO4·H2O 6.9g，Na2HPO4·12H2O 17.9g，NaN30.5g，加800ml水溶解后，用氢氧化钠溶液调pH至6.7，定容至1L，0.22μm膜过滤待用。
(2)待测样品用去离子水稀释至蛋白浓度为1mg/ml。
(3)洗脱方式：100％流动相等度洗脱。
(4)样品分析：用流动相以1.0ml/min流速平衡高效液相色谱系统至基线平衡后进样分析。
(5)结果处理：采用面积归一化法进行积分。
(二)非还原毛细管凝胶电泳(非还原CE-SDS)检测电荷变异体，检测步骤如下：
(1)样品稀释：将样品用样品缓冲液稀释至1mg/ml。
(2)取95μl稀释样品，加入5μl的烷基化溶液，混匀，6000rpm离心1min；
(3)70℃加热5min，立即冷水浴5min；
(4)6000rpm离心1min，吸取90μl入上样管，采用安捷伦G7100毛细管电泳仪分析。
(5)结果处理：采用面积归一化法进行积分，以IgG主峰的修正峰面积占所有修正峰面积之和的百分比计算主峰的纯度。
(三)离子交换色谱(CEX-HPLC)检测步骤凝聚情况，检测步骤如下：
(1)流动相配制
A液：20mM MES：称取MES 3.9g，加水950ml溶解，用5M NaOH调pH值至7.5±0.05，再用去离子水定容至1L，0.22μm膜过滤备用；
B液：20mM MES+500mM NaCl：称取MES 3.9g，NaCl 29.25g，加去离子水950ml溶解，用5M NaOH调pH值至5.5±0.05，用去离子水定容至1L，0.22μm膜过滤备用。
(2)样品处理：将样品用去离子水稀释至1mg/ml。
(3)色谱过程：用100％A液以1.0ml/min流速平衡高效液相色谱系统至基线平衡。进样后依照梯度洗脱方法进行洗脱，并在30分钟内记录色谱图及数据。
(4)结果处理：按照面积归一化法进行积分，溶剂峰不进行积分。
下表展示了在10-60mg/ml浓度条件下，单抗冻融至少5次(冻融条件：-70℃2天、室温2天)而没有出现降解(非还原CE-SDS)、电荷变异体(CEX-HPLC)和聚集情况(SEC-HPLC)。
下表展示高温-1为高温第5天取样、高温-2为高温第10天取样、高温-3为高温第30天取样的各个制剂的质量检测结果(表中自上而下依次为配方2B11-01～2B11-17)。
下表展示了高温振摇条件下各个制剂的质量检测结果(高温振摇的条件：40℃，200rmp)(表中自上而下依次为配方2B11-01～2B11-17)
实施例2、配方保护剂密度测定
经过实施例1的对比数据，最终确定优选处方配置如下，并进一步测定配方保护剂的密度：
(1)1L保护剂
组氨酸：3.103g；
精氨酸：21.775g；
氯化钠：1.58g；
聚山梨酯20：0.1g；
(2)用900ml注射用水溶解，盐酸调pH5.8，并用容量瓶定容至1L。
(3)称重，根据ρ＝m/V计算保护剂的密度。
结果：保护剂的密度为1.0023g/L。
最后需要说明的是，以上实施例仅用于帮助本领域技术人员理解本发明的实质，不用于限定本发明的保护范围。
Claims (8)
1.一种抗SARS-CoV-2的重组全人源单克隆抗体2B11的液体制剂，其特征在于，
所述制剂包括全人源抗新冠病毒单克隆抗体2B11、缓冲液，
所述的缓冲液中还包含稳定剂、表面活性剂、以及可选地包含等渗调节剂，所述的液体制剂的溶剂为注射用水，所述的液体制剂的pH为5.5-6.1。
2.根据权利要求1所述的液体制剂，其特征在于，所述的缓冲液为10～50mM组氨酸盐缓冲液，优选20mM组氨酸盐缓冲液，pH为5.5-6.1。
3.根据权利要求1所述的液体制剂，其特征在于，所述的液体制剂中，全人源单克隆抗体2B11的含量为10～100mg/mL，优选为20mg/ml。
4.根据权利要求1-3任一所述的液体制剂，其特征在于，所述的稳定剂为50-150mM的精氨酸，优选125mM的精氨酸。
5.根据权利要求1-3任一所述的液体制剂，其特征在于，所述的表面活性剂为0.005％-0.02％的聚山梨酯20，优选0.01％的聚山梨酯20。
6.根据权利要求1-3任一所述的液体制剂，其特征在于，所述的等渗调节剂为15-40mM的氯化钠，优选20-30mM的氯化钠，更优选27mM的氯化钠。
7.权利要求1-6任一所述的液体制剂在制备检测或抑制SARS-CoV-2病毒的试剂中的应用。
8.权利要求1-6任一所述的液体制剂在制备药物中的应用，所述的药物为预防和/或治疗因SARS-CoV-2病毒感染导致的疾病的药物；优选的，所述的药物为注射剂。
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| CN109806392A (zh) * | 2017-11-21 | 2019-05-28 | 沈阳三生制药有限责任公司 | 稳定的抗cd43单克隆抗体的液体制剂 |
| US20200131251A1 (en) * | 2016-12-23 | 2020-04-30 | Serum Institute Of India Private Limited | Improved methods for enhancing antibody productivity in mammalian cell culture and minimizing aggregation during downstream, formulation processes and stable antibody formulations obtained thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20200131251A1 (en) * | 2016-12-23 | 2020-04-30 | Serum Institute Of India Private Limited | Improved methods for enhancing antibody productivity in mammalian cell culture and minimizing aggregation during downstream, formulation processes and stable antibody formulations obtained thereof |
| CN109806392A (zh) * | 2017-11-21 | 2019-05-28 | 沈阳三生制药有限责任公司 | 稳定的抗cd43单克隆抗体的液体制剂 |
| CN109350740A (zh) * | 2017-11-30 | 2019-02-19 | 百奥泰生物科技(广州)有限公司 | 一种治疗il-6相关疾病的人源化抗体的液体制剂 |
| CN111620945A (zh) * | 2020-05-09 | 2020-09-04 | 江苏省疾病预防控制中心(江苏省公共卫生研究院) | 一种抗新型冠状病毒的单克隆抗体或其衍生体 |
| CN112521494A (zh) * | 2020-06-19 | 2021-03-19 | 武汉生物制品研究所有限责任公司 | 一种抗SARS-CoV-2的单克隆抗体2B11 |
Non-Patent Citations (1)
| Title |
|---|
| 许湘等: ""基于新型冠状病毒S蛋白结构及入胞机制的抗体与药物研发"", 《中国生物化学与分子生物学报》 * |
Cited By (1)
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