CN115569191A - 一种重组人源化抗bcma/cd3双特异性抗体冻干制剂 - Google Patents
一种重组人源化抗bcma/cd3双特异性抗体冻干制剂 Download PDFInfo
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Abstract
本发明属于药物制剂技术领域,具体提供了一种稳定的重组人源化抗BCMA/CD3双特异性抗体冻干制剂,所述冻干制剂使用羟丙基倍他环糊精和桔酸丙酯作为稳定剂,不仅具有稳定性好,复溶迅速,安全性好的特点;而且可以减少赋形剂、增溶剂等的用量,进一步降低了临床用药的安全隐患。本发明提供的冻干制剂的制备工艺简单,适于放大,且质量稳定可控,干燥效果好,产品水分含量低,方便储存和运输。
Description
技术领域
本发明属于药物制剂的技术领域,具体涉及一种重组人源化抗BCMA/CD3双特异性抗体冻干制剂。
背景技术
多发性骨髓瘤是第二常见的血液系统恶性肿瘤,其骨髓中单克隆浆细胞的不受控制的增殖,导致单克隆免疫球蛋白和免疫抑制的过量产生,以及骨溶解和终末器官损伤。目前有两个单克隆抗体已批注临床使用,在过去十年,多发性骨髓瘤治疗方案已经显著提高了患者的存活率。尽管如此,现有的治疗方案仍未满足目前的治疗需求,特别是对于当前疗法具有抗性的复发/难治性患者。
B细胞成熟抗原(BCMA)是一种高度浆细胞特异性抗原,在调节B细胞成熟和分化为浆细胞方面通过参与增殖诱导配体(APRIL)发挥重要作用。BCMA表达限于B细胞谱系并且主要存在于浆细胞和浆母细胞上,并且在一定程度上存在于记忆B细胞上,但在外周和幼稚B细胞上实质上不存在,也未见在其他正常组织细胞中表达。BCMA也在多发性骨髓瘤细胞上表达并参与白血病和淋巴瘤。连同其家族成员TACI(跨膜活化剂和亲环素受体配体相互作用物)和BAFF-R(B细胞活化因子受体),BCMA调节体液免疫、B细胞发育和体内稳态的不同方面。BCMA的表达出现在B-细胞分化作用的较后期并有利于浆母细胞和浆细胞在骨髓中的长期存活。小鼠中BCMA基因的靶向缺失导致骨髓中长寿浆细胞的数量显著减少,指示BCMA对其存活具有重要性。BCMA过表达或通过多发性骨髓瘤细胞中的BCMA刺激APRIL可以直接上调关键免疫检查点分子,这可能有助于免疫抑制骨髓微环境。
在细胞免疫过程中,T淋巴细胞扮演着重要的角色。T细胞所介导的细胞免疫主要是通过T细胞受体(T cell receptor,TCR)特异识别细胞表面由主要组织相容性复合物(MHC)所递呈的抗原肽,进而激活T细胞胞内信号,对该靶细胞进行特异杀伤。这对及时清除体内病变的细胞及预防肿瘤的发生起着至关重要的作用。由于多数癌细胞表面的MHC的表达下调甚至缺失,使得肿瘤细胞能够逃逸免疫杀伤,从而发生肿瘤。
T细胞结合双特异性抗体(T cell-engaging bispecific antibodies,TCBs)代表了一种非常有效的将激活的细胞毒性T细胞重定向到肿瘤的方式。CD3作为T细胞受体的一部分,表达于成熟T细胞,能够转导TCR识别抗原所产生的活化信号。TCBs能够同时结合表面肿瘤抗原和T细胞受体的CD3ε亚基,在T细胞和肿瘤细胞之间提供一个物理连接,从而有效的激活静止的T细胞杀伤肿瘤细胞,达到治疗肿瘤的效果(Smits N C,Sentman C L,Journal of Clinical Oncology,2016:JCO649970.)。因为T细胞双特异性旁路TCR抗原识别和T细胞活化的共刺激要求,它们消除了对肿瘤特异性免疫的需要,并克服了肿瘤微环境中T细胞面临的许多障碍。
近年来,为了解决将两个不同的半抗体进行正确装配问题,科学家们设计开发了多种结构的双特异性抗体。总体归结起来有两大类,一类双特异性抗体不含Fc区,包括BiTE、DART、TrandAbs、bi-Nanobody等。这类结构双抗优点是分子量小,可以在原核细胞中表达,不需要考虑正确装配的问题;缺点是由于没有抗体Fc段,分子量较低,导致其半衰期较短,且这种形式的双抗极易聚合、稳定性差且表达量低,因而临床应用受到一定限制。另一类双特异性抗体保留Fc结构域,例如Triomabs、kih IgG、Cross-mab、orthoFab IgG、DVDIgG、IgG scFv、scFv2-Fc等构型。此类双抗形成IgG样结构,分子结构较大,并且由FcRn介导的细胞内吞和再循环过程,使其具有更长的半衰期;同时保留了Fc介导的部分或全部效应子功能,如抗体依赖细胞介导细胞毒性(ADCC)、补体依赖细胞毒性(CDC)和抗体依赖细胞吞噬(ADCP)。然而这类双抗也不能完全杜绝错配产物的生成,而任何错配分子的残留级分都很难从产物中分离,并且这种方法需要针对两个抗体序列进行大量的突变等基因工程改造,无法达到简单、通用的目的。
因此,研究多集中在开发一种在产品半衰期、稳定性、安全性和可生产性方面具有改善性能的BCMA双特异性分子,比如专利CN111138542A中报道了一种BCMA双特异性抗体分子。但是目前关于BMCA双特异性抗体分子的制剂研究报道较少,合适的制剂产品对于发挥新型的双特性抗体分子的临床应用价值具有重要的影响。
发明内容
本发明的目的在于提供一种稳定的重组人源化抗BCMA/CD3双特异性抗体冻干制剂,所述冻干制剂使用羟丙基倍他环糊精和桔酸丙酯作为稳定剂,通过冷冻干燥制备获得,其具有相对理想的玻璃转化温度,且稳定剂的加入可以有效的防止冷冻干燥过程中各组分的结晶,保证制备的产品在存储、运输或使用中的稳定性。
一方面,本发明提供一种重组人源化抗BCMA/CD3双特异性抗体冻干制剂,所述冻干制剂含有重组人源化抗BCMA/CD3双特异性抗体、羟丙基倍他环糊精和桔酸丙酯及其它药学上可接受的辅料。
优选地,所述冻干制剂冻干前或复溶后的溶液中重组人源化抗BCMA/CD3双特异性抗体的含量为0.1~1.0mg/ml;优选为0.5mg/ml。
优选地,所述冻干制剂中羟丙基倍他环糊精、桔酸丙酯与重组人源化抗BCMA/CD3双特异性抗体的质量比为1~10:1~10:0.1~1。
进一步优选地,所述冻干制剂中羟丙基倍他环糊精、桔酸丙酯与重组人源化抗BCMA/CD3双特异性抗体的质量比为5~10:2~5:0.1~1。
优选地,所述的其它药学上可接受的辅料包括赋形剂、增溶剂和缓冲剂。
进一步优选地,所述的赋形剂选自海藻糖、蔗糖、山梨醇或甘露醇中的一种或几种。
进一步优选地,所述的赋形剂在冻干前或复溶后的溶液中的含量为50~300mM;优选为100~150mM。
进一步优选地,所述的增溶剂为吐温20或吐温80;更加优选为吐温80。
进一步优选地,所述的增溶剂在冻干前或复溶后的溶液中的含量为0.05~0.8mg/ml;优选为0.2~0.5mg/ml。
进一步优选地,所述的缓冲剂为枸橼酸钠/枸橼酸缓冲体系。
进一步优选地,所述的缓冲剂在冻干前或复溶后的溶液中的含量为15-70mM;优选为15-30mM。
进一步优选地,所述的缓冲体系的pH为5.5~6.5。
优选地,所述的一种重组人源化抗BCMA/CD3双特异性抗体冻干制剂,其在冻干前或复溶后的溶液中包含如下组分:
优选地,所述重组人源化抗BCMA/CD3双特异性抗体冻干制剂,其在冻干前或复溶后的溶液中包含如下组分:
另一方面,本发明提供一种所述重组人源化抗BCMA/CD3双特异性抗体的制备方法,具体工艺如下:
称取处方量的枸橼酸钠和枸橼酸用适量注射用水溶解,再准确称取处方量的羟丙基倍他环糊精和桔酸丙酯、赋形剂、增溶剂及重组人源化抗BCMA/CD3双特异性抗体原液加入到枸橼酸钠/枸橼酸缓冲液中,混合均匀即得半成品液,将半成品液用0.22μm滤膜进行无菌过滤,检测内毒素合格后灌装入西林瓶中,冻干即得。
优选地,所述的重组人源化抗BCMA/CD3双特异性抗体冻干制剂的制备方法,包括如下冷冻干燥工艺:
与现有技术相比,本发明具有以下优点:
首先,本发明提供了一种稳定的重组人源化抗BCMA/CD3双特异性抗体冻干制剂,为BCMA/CD3双特异性抗体的临床应用提供了更可靠的用药选择。
其次,本发明提供的重组人源化抗BCMA/CD3双特异性抗体冻干制剂,创造性的使用羟丙基倍他环糊精和桔酸丙酯作为稳定剂,不仅具有稳定性好,复溶迅速,安全性好的特点;而且可以减少赋形剂、增溶剂等的用量,进一步降低了临床用药的安全隐患。
另外,本发明提供的冻干制剂的制备工艺简单,适于放大,且质量稳定可控,干燥效果好,冻干粉水分含量低,方便储存和运输。
具体实施方式
下面通过实施例来进一步说明本发明,应该正确理解的是:本发明的实施例仅仅是用于说明本发明,而不是对本发明的限制,所以,在本发明的方法前提下对本发明的简单改进均属本发明要求保护的范围。
实施例1
(1)处方
(2)制备方法
称取处方量的枸橼酸钠和枸橼酸用适量注射用水溶解,取样检测pH及内毒素合格后,再准确称取处方量的羟丙基倍他环糊精和桔酸丙酯、甘露醇、吐温80及重组人源化抗BCMA/CD3双特异性抗体原液加入到枸橼酸钠/枸橼酸缓冲液中,混合均匀即得半成品液,将半成品液用0.22μm滤膜进行无菌过滤,检测内毒素合格后灌装入西林瓶中,按照如下的冻干曲线冷冻干燥即得。冻干曲线如下:
实施例2
(1)处方
(2)制备方法
称取处方量的枸橼酸钠和枸橼酸用适量注射用水溶解,取样检测pH及内毒素合格后,再准确称取处方量的羟丙基倍他环糊精和桔酸丙酯、蔗糖、吐温80及重组人源化抗BCMA/CD3双特异性抗体原液加入到枸橼酸钠/枸橼酸缓冲液中,混合均匀即得半成品液,将半成品液用0.22μm滤膜进行无菌过滤,检测内毒素合格后灌装入西林瓶中,按照如下的冻干曲线冷冻干燥即得。冻干曲线同实施例1。
实施例3
(1)处方
(2)制备方法
称取处方量的枸橼酸钠和枸橼酸用适量注射用水溶解,取样检测pH及内毒素合格后,再准确称取处方量的羟丙基倍他环糊精和桔酸丙酯、山梨醇、吐温80及重组人源化抗BCMA/CD3双特异性抗体原液加入到枸橼酸钠/枸橼酸缓冲液中,混合均匀即得半成品液,将半成品液用0.22μm滤膜进行无菌过滤,检测内毒素合格后灌装入西林瓶中,按照如下的冻干曲线冷冻干燥即得。冻干曲线如下:
实施例4
(1)处方
(2)制备方法
称取处方量的枸橼酸钠和枸橼酸用适量注射用水溶解,取样检测pH及内毒素合格后,再准确称取处方量的羟丙基倍他环糊精和桔酸丙酯、海藻糖、吐温20及重组人源化抗BCMA/CD3双特异性抗体原液加入到枸橼酸钠/枸橼酸缓冲液中,混合均匀即得半成品液,将半成品液用0.22μm滤膜进行无菌过滤,检测内毒素合格后灌装入西林瓶中,按照实施例1的冻干曲线冷冻干燥即得。冻干曲线如下:
实施例5
(1)处方
(2)制备方法
称取处方量的枸橼酸钠和枸橼酸用适量注射用水溶解,取样检测pH及内毒素合格后,再准确称取处方量的羟丙基倍他环糊精和桔酸丙酯、甘露醇、吐温80及重组人源化抗BCMA/CD3双特异性抗体原液加入到枸橼酸钠/枸橼酸缓冲液中,混合均匀即得半成品液,将半成品液用0.22μm滤膜进行无菌过滤,检测内毒素合格后灌装入西林瓶中,按照如下的冻干曲线冷冻干燥即得。冻干曲线同实施例1。
实施例6
(1)处方
(2)制备方法
称取处方量的枸橼酸钠和枸橼酸用适量注射用水溶解,取样检测pH及内毒素合格后,再准确称取处方量的羟丙基倍他环糊精和桔酸丙酯、甘露醇、吐温80及重组人源化抗BCMA/CD3双特异性抗体原液加入到枸橼酸钠/枸橼酸缓冲液中,混合均匀即得半成品液,将半成品液用0.22μm滤膜进行无菌过滤,检测内毒素合格后灌装入西林瓶中,按照实施例1的冻干曲线冷冻干燥即得。冻干曲线同实施例1。
实施例7
(1)处方
(2)制备方法
称取处方量的枸橼酸钠和枸橼酸用适量注射用水溶解,取样检测pH及内毒素合格后,再准确称取处方量的羟丙基倍他环糊精和桔酸丙酯、甘露醇、吐温80及重组人源化抗BCMA/CD3双特异性抗体原液加入到枸橼酸钠/枸橼酸缓冲液中,混合均匀即得半成品液,将半成品液用0.22μm滤膜进行无菌过滤,检测内毒素合格后灌装入西林瓶中,按照实施例1的冻干曲线冷冻干燥即得。冻干曲线同实施例1。
实施例8
(1)处方
(2)制备方法
称取处方量的枸橼酸钠和枸橼酸用适量注射用水溶解,取样检测pH及内毒素合格后,再准确称取处方量的羟丙基倍他环糊精和桔酸丙酯、山梨醇、吐温80及重组人源化抗BCMA/CD3双特异性抗体原液加入到枸橼酸钠/枸橼酸缓冲液中,混合均匀即得半成品液,将半成品液用0.22μm滤膜进行无菌过滤,检测内毒素合格后灌装入西林瓶中,按照如下的冻干曲线冷冻干燥即得。冻干曲线同实施例1。
对比实施例1
(1)处方
(2)制备方法
称取处方量的枸橼酸钠/枸橼酸用适量注射用水溶解,取样检测pH及内毒素合格后,再准确称取处方量的甘露醇、吐温80及重组人源化抗BCMA/CD3双特异性抗体原液加入到醋酸钠/醋酸缓冲液中,混合均匀即得半成品液,将半成品液用0.22μm滤膜进行无菌过滤,检测内毒素合格后灌装入西林瓶中,按照实施例1的冻干曲线冷冻干燥即得。
对比实施例2
(1)处方
(2)制备方法
称取处方量的枸橼酸钠和枸橼酸用适量注射用水溶解,取样检测pH及内毒素合格后,再准确称取处方量的桔酸丙酯、甘露醇、吐温80及重组人源化抗BCMA/CD3双特异性抗体原液加入到枸橼酸钠/枸橼酸缓冲液中,混合均匀即得半成品液,将半成品液用0.22μm滤膜进行无菌过滤,检测内毒素合格后灌装入西林瓶中,按照实施例1的冻干曲线冷冻干燥即得。
对比实施例3
(1)处方
(2)制备方法
称取处方量的枸橼酸钠和枸橼酸用适量注射用水溶解,取样检测pH及内毒素合格后,再准确称取处方量的羟丙基倍他环糊精、甘露醇、吐温80及重组人源化抗BCMA/CD3双特异性抗体原液加入到枸橼酸钠/枸橼酸缓冲液中,混合均匀即得半成品液,将半成品液用0.22μm滤膜进行无菌过滤,检测内毒素合格后灌装入西林瓶中,按照实施例1的冻干曲线冷冻干燥即得。
对比实施例4
(1)处方
(2)制备方法
称取处方量的Tris用适量注射用水溶解,用盐酸调整pH,取样检测pH及内毒素合格后,再准确称取处方量的羟丙基倍他环糊精和桔酸丙酯、甘露醇、吐温80及重组人源化抗BCMA/CD3双特异性抗体原液加入到枸橼酸钠/枸橼酸缓冲液中,混合均匀即得半成品液,将半成品液用0.22μm滤膜进行无菌过滤,检测内毒素合格后灌装入西林瓶中,冻干曲线冷如下所示:
验证实施例
1.差示量热扫描(DSC)
采用MicroCalTM VP-Capillary DSC仪,在仪器程序控制温度下,分别测定实施例1-8和对比实施例1-4的重组人源化抗BCMA/CD3双特异性抗体的半成品溶液的熔化温度Tm值。样品用对应的缓冲溶液稀释至重组人源化抗BCMA/CD3双特异性抗体浓度为1mg/mL后,取350μL样品加入到96孔板的样品孔,相应的缓冲液取350μL加入到buffer孔,扫描温度设置为20~90℃,扫描速率为60℃/hr。数据分析采用MicroCal VP-Capillary DSC自动分析软件,结果见表1。
表1、重组人重组人源化抗BCMA/CD3双特异性抗体的Tm值结果
结果表明,加入羟丙基倍他环糊精和桔酸丙酯后,Tmonset和Tm1明显提高,说明加入羟丙基倍他环糊精和桔酸丙酯能够提高药物的热稳定性。
2.稳定性试验
分别按照实施例1-8及对比实施例1-4制备试制样品,采用加速稳定性试验和长期试验考察贮存稳定性。
加速试验在25℃±2℃的条件下进行,时间为12个月。所用设备能控制温度±2℃,并对实际温度进行监测。在试验期间第0个月、3个月、6个月、12个月末取样一次,按稳定性重点考察项目检测。长期试验在2~8℃的条件下进行,分别于0个月、6个月、12个月、24个月末按稳定性重点考察项目进行检测;(水分含量测定按照《2020版中国药典》第三部通则中规定的库伦法,采用梅特勒-扎利多DL37卡尔费休滴定仪来测定;纯度检查按照通则0514分子排组色谱法和通则0542毛细管电泳法测定;活性按照基于生物发光的报告基因法确定,实验细胞:CHOK1-BCMA-Luc细胞),结果见表2、表3。
表2.2~8℃长期稳定性实验结果
表3.25℃加速稳定性实验结果
Claims (10)
1.一种重组人源化抗BCMA/CD3双特异性抗体冻干制剂,其特征在于,所述冻干制剂含有重组人源化抗BCMA/CD3双特异性抗体、羟丙基倍他环糊精和桔酸丙酯及其它药学上可接受的辅料。
2.如权利要求1所述的冻干制剂,其特征在于,所述冻干制剂中羟丙基倍他环糊精、桔酸丙酯与重组人源化抗BCMA/CD3双特异性抗体的质量比为1~10:1~10:0.1~1。
3.如权利要求1所述的冻干制剂,其特征在于,所述冻干制剂中羟丙基倍他环糊精、桔酸丙酯与重组人源化抗BCMA/CD3双特异性抗体的质量比为5~10:2~5:0.1~1。
4.如权利要求1所述的冻干制剂,其特征在于,所述的其它药学上可接受的辅料包括赋形剂、增溶剂和缓冲剂。
5.如权利要求1所述的冻干制剂,其特征在于,所述的赋形剂选自海藻糖、蔗糖、山梨醇或甘露醇中的一种或几种。
6.如权利要求1所述的冻干制剂,其特征在于,所述的缓冲剂为枸橼酸钠/枸橼酸缓冲体系。
7.如权利要求1所述的冻干制剂,其特征在于,所述的缓冲剂在冻干前或复溶后的溶液中的含量为15-70mM。
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