CN114632150A - 一种抗pd-l1人源化单克隆抗体的药物组合物 - Google Patents
一种抗pd-l1人源化单克隆抗体的药物组合物 Download PDFInfo
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Abstract
本发明属于抗体制剂领域,具体涉及一种抗PD‑L1人源化单克隆抗体的药物组合物,所述药物组合物包含1‑150mg/ml抗PD‑L1人源化单克隆抗体、3‑50mM缓冲液、2‑150mg/ml等渗调节剂/稳定剂和0.01‑0.8mg/ml表面活性剂,且pH为约4.5‑6.8。该制剂阻止其中抗体的聚合物增长,同时,能长时间较好地维持抗体的生物结合活性。
Description
本申请是申请日为2018年11月02日、中国申请号为201880070081.9、发明名称为“一种抗PD-L1人源化单克隆抗体的药物组合物”的发明申请的分案申请。
技术领域
本发明属于抗体制剂领域,具体而言涉及一种抗PD-L1人源化单克隆抗体的药物组合物。
背景技术
PD-L1(Programmed death-ligand 1)又称为CD247和B7-H1,是程序性死亡分子1(programmed death-1,PD-1)的一个配体。PD-L1在多种肿瘤细胞表面高表达,而且肿瘤的恶性程度以及不良预后与PD-L1的表达水平密切相关。在肿瘤微环境中,癌症细胞表面的PD-L1通过与T细胞表面的PD-1或CD80的结合,抑制T细胞的激活和增殖,促进效应T细胞进入衰竭或无反应状态,诱导T细胞的凋亡,刺激辅助T细胞分化成为调节性T细胞,从而阻止T细胞对肿瘤细胞的杀伤作用。抗PD-L1抗体可以通过阻断PD-L1与PD-1及CD80的相互作用,使得相关的负调控信号不能被启动与传导,从而避免了在肿瘤微环境中的效应T细胞的活性被抑制,使T细胞可以发挥杀伤和抑制肿瘤细胞的功能。由于抗PD-L1抗体能够直接作用于肿瘤组织,因而具有较高的特异性和安全性。目前国际上主要的抗PD-L1单抗药物产品包括罗氏的Atezolizumab和阿斯利康的Durvalumab。
WO2016022630公开了一类新的抗PD-L1抗体,对PD-L1具有较高的亲和力,能够显著抑制细胞表面的PD-L1和PD-1的相互作用,并显著促进T细胞分泌IL-2和IFN-γ。因此,为了提高其成药性,迫切需要开发一种抗PD-L1抗体制剂用于临床治疗。
在抗体制剂领域,因为蛋白质比传统有机和无机药物更复杂,蛋白质的制剂形成了特殊的问题。除水溶性差的化合物外,小分子药物制剂中很少遇到物理不稳定性问题。但由于蛋白质具有集成高度有序结构的能力,很容易发生化学修饰外的大量的结构变化。蛋白质的物理不稳定性比化学不稳定性更难控制,疏水区的外露将促使聚集或自缔结,可能导致物理不稳定性和潜在生物活性的丧失。为了使蛋白质保留生物学活性,制剂必须保持蛋白质氨基酸核心序列的构象完整性完好无损,同时保护蛋白质的多个官能团不受降解并防止蛋白质聚集的产生。
本发明有效控制了抗PD-L1抗体制剂中聚合物的含量以及放置过程中聚合物含量增长、抗体活性改变的问题,从而获得具有高度稳定性的制剂。
发明内容
本发明目的至少在于提供一种高度稳定的药物组合物,其特征在于:所述药物组合物包含抗体,并至少包含缓冲液、等渗调节剂、稳定剂和/或表面活性剂中的一种或几种。特别地,所述药物组合物包含1-150mg/ml抗PD-L1人源化单克隆抗体(单抗)、3-50mM缓冲液、2-150mg/ml等渗调节剂/稳定剂和0.01-0.8mg/ml表面活性剂,且pH为约4.5-6.8。该制剂能阻止其中抗体的聚合物增长,同时,能长时间较好的维持抗体的生物结合活性。
在一些方案中,以w/v计算,抗PD-L1人源化单抗浓度约为5-150mg/ml;优选为约10-60mg/ml;更优选为约10-30mg/ml。在一些具体方案中,抗PD-L1人源化单抗质量体积浓度约10mg/ml、约20mg/ml、约30mg/ml、约40mg/ml、约50mg/ml、约60mg/ml、约70mg/ml、约80mg/ml、约90mg/ml、约100mg/ml、约110mg/ml或约120mg/ml,优选为约10mg/ml、约20mg/ml、约30mg/ml、约40mg/ml、约50mg/ml或约60mg/ml,更优选为约10mg/ml、约20mg/ml或约30mg/ml。在一些实施方案中,抗PD-L1人源化单抗质量体积浓度约10mg/ml。在另一些实施方案中,抗PD-L1人源化单抗质量体积浓度约30mg/ml。在另一些实施方案中,抗PD-L1人源化单抗质量体积浓度约60mg/ml。
在一些方案中,所述缓冲液选自枸橼酸盐缓冲液、醋酸盐缓冲液、组氨酸盐缓冲液或磷酸盐缓冲液;优选枸橼酸盐缓冲液或组氨酸盐缓冲液;更优选组氨酸盐缓冲液。在一些方案中,所述缓冲液浓度约为4.5-50mM,优选约为5-25mM,更优选约为10-20mM,最优选约为10-15mM。
在一些方案中,所述缓冲液为组氨酸盐缓冲液。所述组氨酸盐缓冲液浓度约为5-30mM,优选约为10-25mM,更优选为约为10-20mM,最优选约为10-15mM。在一些具体方案中,所述组氨酸盐缓冲液约5mM、约10mM、约15mM、约20mM、约25mM或约30mM。在一些实施方案中,所述组氨酸盐缓冲液约10mM。在另一些实施方案中,所述组氨酸盐缓冲液约15mM。在另一些实施方案中,所述组氨酸盐缓冲液约20mM。其中,所述组氨酸盐缓冲液包含组氨酸和盐酸。
在一些方案中,所述缓冲液为醋酸盐缓冲液。所述醋酸盐缓冲液浓度约为5-30mM,优选约为10-25mM,更优选约为10-20mM,最优选约为10-15mM。其中,所述醋酸盐缓冲液包含醋酸盐和醋酸。本发明所述的“醋酸盐”包括醋酸的药学上可接受的各种无机酸盐或有机酸盐或其水合物,包括但不限于醋酸钾或其水合物、醋酸钠或其水合物;优选地,所述醋酸盐为醋酸钠或三水合醋酸钠。
在一些方案中,所述缓冲液为枸橼酸盐缓冲液。所述枸橼酸盐缓冲液浓度约为3-30mM,优选约为4.5-30mM,更优选约为5-20mM,最优选约为5-10mM。在一些具体方案中,所述枸橼酸盐缓冲液约5mM、约10mM、约15mM、约20mM或约25mM。在一些实施方案中,所述枸橼酸盐缓冲液约5mM。在另一些实施方案中,所述枸橼酸盐缓冲液约10mM。在另一些实施方案中,所述枸橼酸盐缓冲液约15mM。本发明所述的“枸橼酸”包括枸橼酸本身以及枸橼酸的水合物,例如一水合枸橼酸;所述“枸橼酸盐”包括枸橼酸的药学上可接受的各种无机酸盐或有机酸盐或其水合物,包括但不限于枸橼酸钾或其水合物、枸橼酸钠或其水合物;优选地,所述枸橼酸盐为枸橼酸钠或二水合枸橼酸钠。
在一些方案中,等渗调节剂/稳定剂选自氯化钠、甘露醇、蔗糖、海藻糖、麦芽糖、木糖醇中一种或一种以上;优选氯化钠、甘露醇和蔗糖中的一种或者一种以上;最优选蔗糖。在一些方案中,所述等渗调节剂/稳定剂的含量为约4-150mg/ml,优选为约6-120mg/ml,更优选为约40-100mg/ml,最优选为约60-80mg/ml。
在一些方案中,以w/v计算,所述等渗调节剂/稳定剂为约20-150mg/ml的蔗糖,优选约为40-100mg/ml的蔗糖,更优选约为60-80mg/ml的蔗糖。在一些具体方案中,所述蔗糖的浓度约为40mg/ml、50mg/ml、60mg/ml、70mg/ml、80mg/ml、90mg/ml或100mg/ml。在一些具体实施方案中,所述蔗糖的浓度约60mg/ml。在一些具体实施方案中,所述蔗糖的浓度约70mg/ml。在一些具体实施方案中,所述蔗糖的浓度约80mg/ml。在一些具体实施方案中,所述蔗糖的浓度约90mg/ml。
在一些具体方案中,以w/v计算,所述等渗剂/稳定剂为浓度约5-20mg/ml氯化钠溶液,优选为约5-10mg/ml氯化钠溶液,更优选为约6mg/ml氯化钠溶液。
在一些具体方案中,以w/v计算,所述等渗剂/稳定剂为浓度约10-40mg/ml的甘露醇,优选约为10-30mg/ml的甘露醇,更优选约为20mg/ml的甘露醇。
在一些方案中,所述表面活性剂选自聚山梨酯80、聚山梨酯20、泊洛沙姆188;优选聚山梨酯80或聚山梨酯20;更优选为聚山梨酯80。在一些方案中,以w/v计算,所述表面活性剂的浓度约为0.05-0.6mg/ml,优选约为0.1-0.4mg/ml,更优选约为0.2-0.3mg/ml。
在一些具体方案中,以w/v计算,所述表面活性剂为约0.01-0.8mg/ml的聚山梨酯80或聚山梨酯20。在一些具体方案中,所述表面活性剂为约0.05-0.6mg/ml的聚山梨酯80,优选约为0.1-0.4mg/ml的聚山梨酯80,更优选约为0.2-0.3mg/ml的聚山梨酯80,最优选约为0.2mg/ml的聚山梨酯80。在一些实施方案中,所述药物组合物中聚山梨酯80含量约为0.1mg/ml、0.2mg/ml、0.3mg/ml、0.4mg/ml、0.5mg/ml或0.6mg/ml;优选地,所述药物组合物中聚山梨酯80含量约为0.2mg/ml、0.3mg/ml、0.4mg/ml或0.5mg/ml;更优地,所述药物组合物中聚山梨酯80含量约为0.2mg/ml、0.3mg/ml或0.4mg/ml;最优地,所述药物组合物中聚山梨酯80含量约为0.2mg/ml。在一些实施方案中,所述药物组合物中聚山梨酯80含量约0.1mg/ml。在另一些实施方案中,所述药物组合物中聚山梨酯80含量约0.2mg/ml。在一些实施方案中,所述药物组合物中聚山梨酯80含量约0.3mg/ml。在另一些实施方案中,所述药物组合物中聚山梨酯80含量约0.4mg/ml。在一些实施方案中,所述药物组合物中聚山梨酯80含量约0.5mg/ml。
在一些方案中,所述药物组合物的水溶液pH值选自4.0-6.8;优选为4.5-6.5;更优选为5.5-6.0;最优选5.5。在一些实施方案中,药物组合物水溶液的pH值为约4.5、约4.8、约5.0、约5.2、约5.4、约5.5、约5.6、约5.8或约6.0,优选为约5.0、约5.2、约5.4、约5.5或约5.6,更优选为约5.5。在一些实施方案中,药物组合物水溶液的pH值为约5.0。在一些实施方案中,药物组合物水溶液的pH值为约5.2。在一些实施方案中,药物组合物水溶液的pH值为约5.4。在一些实施方案中,药物组合物水溶液的pH值为约5.5。在一些实施方案中,药物组合物水溶液的pH值为约5.6。在一些实施方案中,药物组合物水溶液的pH值为约5.8。在一些实施方案中,药物组合物水溶液的pH值为约6.0。
优选地,本发明提供的抗PD-L1人源化单抗包含如下氨基酸序列:与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80%(例如81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同源性的重链CDR1区;与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80%(例如81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同源性的重链CDR2区;与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80%(例如81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同源性的重链CDR3区;与SEQ IDNO:7或SEQ ID NO:10所示的氨基酸序列有至少80%(例如81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同源性的轻链CDR1区;与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80%(例如81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同源性的轻链CDR2区;与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80%(例如81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同源性的轻链CDR3区。
在一个具体实施方案中,本发明提供的抗PD-L1人源化单抗包含如下氨基酸序列:选自SEQ IDNO:1或SEQ ID NO:4的重链CDR1区;选自SEQ ID NO:2或SEQ ID NO:5的重链CDR2区;选自SEQ ID NO:3或SEQ ID NO:6的重链CDR3区;选自SEQ ID NO:7或SEQ ID NO:10的轻链CDR1区;选自SEQ ID NO:8或SEQ ID NO:11的轻链CDR2区;选自SEQID NO:9或SEQ IDNO:12的轻链CDR3区。
优选地,本发明提供的抗PD-L1人源化单抗包含如下氨基酸序列:与SEQ ID NO:13或SEQ IDNO:14所示的氨基酸序列有至少80%(例如81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同源性的重链可变区;与SEQ ID NO:15或SEQ ID NO:16所示的氨基酸序列有至少80%(例如81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)同源性的轻链可变区。
在一个具体实施方案中,本发明提供的抗PD-L1人源化单抗包含如下氨基酸序列,如SEQ ID NO:13所示的重链可变区;如SEQ ID NO:15所示的轻链可变区。
在另一个具体实施方案中,本发明提供的抗PD-L1人源化单抗包含如下氨基酸序列,如SEQ ID NO:14所示的重链可变区;如SEQ ID NO:16所示的轻链可变区。
在一个具体实施方案中,本发明提供的抗PD-L1人源化单抗包含如SEQ ID NO.17所示的重链氨基酸序列,和SEQ ID NO.18所示的轻链氨基酸序列。
在另一个具体实施方案中,本发明提供的抗PD-L1人源化单抗包含如SEQ IDNO.19所示的重链氨基酸序列,和SEQ ID NO.20所示的轻链氨基酸序列。
在另一个具体实施方案中,本发明提供的抗PD-L1人源化单抗包含如SEQ IDNO.21所示的重链氨基酸序列,和SEQ ID NO.18所示的轻链氨基酸序列。
本发明提供的抗PD-L1人源化单抗可为IgG1或IgG4抗体,优选地,所述抗PD-L1人源化单抗为IgG1抗体,更优选为糖基化的IgG1抗体。
本发明的一个具体实施方案中,所述药物组合物包含:
(a)质量体积浓度约20mg/mL抗PD-L1人源化单抗,
(b)质量体积浓度约70mg/mL的蔗糖,
(c)质量体积浓度约0.1mg/ml的聚山梨酯80,
(d)摩尔浓度约20mM的组氨酸,
(e)任选盐酸适量,调节组合物的pH值为约5.0。
在本发明的又一个具体实施方案中,所述药物组合物包含:
(a)质量体积浓度约10mg/mL抗PD-L1人源化单抗,
(b)质量体积浓度约6mg/mL的氯化钠,
(c)质量体积浓度约0.1mg/ml的聚山梨酯80,
(d)摩尔浓度约5mM的枸橼酸盐,
并且所述组合物的pH值为约6.0。
在本发明的另一个具体实施方案中,所述药物组合物包含:
(a)质量体积浓度约10mg/mL抗PD-L1人源化单抗,
(b)质量体积浓度约80mg/mL的蔗糖,
(c)质量体积浓度约0.2mg/ml的聚山梨酯80,
(d)摩尔浓度约10mM的组氨酸,
(e)任选盐酸适量,调节组合物的pH值为约5.5。
在本发明的还一个具体实施方案中,所述药物组合物包含:
(a)质量体积浓度约50mg/mL抗PD-L1人源化单抗,
(b)质量体积浓度约80mg/mL的蔗糖,
(c)质量体积浓度约0.3mg/ml的聚山梨酯80,
(d)摩尔浓度约10mM的组氨酸,
(e)任选盐酸适量,调节组合物的pH值为约5.5。
在本发明的又一个更加具体实施方案中,所述药物组合物包含:
(a)质量体积浓度约100mg/mL抗PD-L1人源化单抗,
(b)质量体积浓度约80mg/mL的蔗糖,
(c)质量体积浓度约0.5mg/ml的聚山梨酯80,
(d)摩尔浓度约10mM的组氨酸,
(e)任选盐酸适量,调节组合物的pH值为约5.5。
在本发明的再一个更加具体实施方案中,所述药物组合物包含:
(a)质量体积浓度约5mg/mL抗PD-L1人源化单抗,
(b)质量体积浓度约3mg/mL的氯化钠,
(c)质量体积浓度约20mg/ml的甘露醇,
(d)质量体积浓度约0.1mg/ml的聚山梨酯80,
(e)摩尔浓度约10mM的醋酸盐,
并且所述组合物的pH值为约4.5。
在本发明的还一个具体实施方案中,所述药物组合物包含:
(a)质量体积浓度约30mg/mL抗PD-L1人源化单抗,
(b)质量体积浓度约80mg/mL的蔗糖,
(c)质量体积浓度约0.2mg/ml的聚山梨酯80,
(d)摩尔浓度约10mM的组氨酸,
(e)任选盐酸适量,调节组合物的pH值为约5.5
在本发明的又一个具体实施方案中,所述药物组合物包含:
(a)质量体积浓度约60mg/mL抗PD-L1人源化单抗,
(b)质量体积浓度约80mg/mL的蔗糖,
(c)质量体积浓度约0.2mg/ml的聚山梨酯80,
(d)摩尔浓度约10mM的组氨酸,
(e)任选盐酸适量,调节组合物的pH值为约5.5。
在本发明的再一个具体实施方案中,所述药物组合物包含:
(a)质量体积浓度约10mg/mL抗PD-L1人源化单抗,
(b)质量体积浓度约70mg/mL的蔗糖,
(c)质量体积浓度约0.4mg/ml的聚山梨酯80,
(d)摩尔浓度约20mM的组氨酸,
(e)任选醋酸适量,调节组合物的pH值为约6.5。
在本发明的还一个具体实施方案中,所述药物组合物包含:
(a)质量体积浓度约10mg/mL抗PD-L1人源化单抗,
(b)质量体积浓度约80mg/mL的蔗糖,
(c)质量体积浓度约0.2mg/ml的聚山梨酯80,
(d)摩尔浓度约20mM的组氨酸,
(e)任选盐酸适量,调节组合物的pH值为约5.5。
在本发明的另一个具体实施方案中,所述药物组合物包含:
(a)质量体积浓度约10mg/mL抗PD-L1人源化单抗,
(b)质量体积浓度约6mg/mL的氯化钠,
(c)质量体积浓度约0.2mg/ml的聚山梨酯80,
(d)摩尔浓度约10mM的枸橼酸盐,
并且所述组合物的pH值为约5.0。
在本发明的还一个具体实施方案中,所述药物组合物包含:
(a)质量体积浓度约10mg/mL抗PD-L1人源化单抗,
(b)质量体积浓度约6mg/mL的氯化钠,
(c)质量体积浓度约0.2mg/ml的聚山梨酯80,
(d)摩尔浓度约10mM的磷酸盐,
并且所述组合物的pH值为约5.0。
在一些方案中,药物组合物为水溶性注射液,所述水溶性注射液包括但不限于未经冻干的水溶性制剂或冻干粉重构的水溶性制剂。在另一些方案中,药物组合物为冻干制剂。所述冻干制剂是指水溶液经历冻干过程制备制剂,冻干是一个稳定化过程,其中物质首先被冷冻,然后先通过升华降低溶剂数量(初级干燥过程),然后通过脱附作用降低溶剂数量(二级干燥过程),直到溶剂数量为不再支持生物学活性或化学反应的值。本发明的冻干制剂还可以通过本领域已知的其它方法干燥,如喷雾干燥和鼓泡干燥(bubble drying)。
本发明提供的制剂,其在2~8℃或25℃保存至少6个月的情况下聚合物不超过1.1%,优选地不超过0.9%,更优选为不超过0.5%。
在本发明的另一个方面,本发明还提供制备前述的药物组合物的方法,包括将抗PD-L1人源化单抗与其他试剂相混合,例如与缓冲液、等渗调节剂/稳定剂和/或表面活性剂中的一种或几种相混合。
在本发明的又一个方面,本发明还提供用于治疗受试者中瘤形成病状的方法,包括给所述受试者施用前述的药物组合物。
除特别声明外,本发明中的“约”是指在所给定的具体数值范围±5%范围内波动,优选在±2%范围内波动,更优选在±1%范围内波动。例如pH值为约5.5表示pH为5.5±5%,优选pH为5.5±2%,更优选pH为5.5±1%。
本文中“聚合物”是指抗PD-L1人源化单抗由于肽链上的氨基酸残基相互作用或是分子间因疏水作用或者静电作用等,发生聚集而产生的聚合物。
本文中“降解物”是指抗PD-L1人源化单抗在水溶液中经脱酰胺或肽链断裂等反应产生的比抗PD-L1人源化单抗分子量小的产物。
本发明中高质量的抗PD-L1人源化单抗制剂具有高度的稳定性,解决了产品中聚合物含量过高影响产品安全性的问题,同时也解决了放置过程中聚合物含量增长影响制剂稳定性以及维持抗体活性的问题。
具体实施方式
概括而言,本发明涉及下述各项:
1.高稳定高活性的药物组合物,其特征在于,所述药物组合物包含:
i)抗PD-L1人源化单克隆抗体,和
ii)缓冲液、等渗调节剂和/或表面活性剂中的一种或几种;
可选地,所述药物组合物包含1-150mg/ml抗PD-L1人源化单抗、3-50mM缓冲液、2-150mg/ml等渗调节剂和0.01-0.8mg/ml表面活性剂,且pH为约4.5-6.8。
2.项1所述的药物组合物,所述抗PD-L1人源化单抗浓度为约5-150mg/ml,优选为约10-60mg/ml,更优选为约10-30mg/ml。
3.项1所述的药物组合物,所述抗PD-L1人源化单克隆抗体浓度为约10mg/ml、约20mg/ml、约30mg/ml、约40mg/ml、约50mg/ml、约60mg/ml、约70mg/ml、约80mg/ml、约90mg/ml、约100mg/ml、约110mg/ml或约120mg/ml,优选为约10mg/ml、约20mg/ml、约30mg/ml、约40mg/ml、约50mg/ml或约60mg/ml,更优选为约10mg/ml、约20mg/ml或约30mg/ml。
4.项1-3任一项所述的药物组合物,所述缓冲液选自枸橼酸盐、醋酸盐或组氨酸盐,优选为枸橼酸盐或组氨酸盐,更优选为组氨酸盐。
5.项1-3任一项所述的药物组合物,所述缓冲液的浓度约为4.5-50mM,优选约为5-25mM,更优选约为10-20mM,最优选约为10-15mM。
6.项1-5任一项所述的药物组合物,所述缓冲液为组氨酸盐缓冲液,所述组氨酸盐缓冲液浓度约为5-30mM,优选约为10-25mM,更优选约为10-20mM,最优选为10-15mM。
7.项1-5任一项所述的药物组合物,所述缓冲液为醋酸盐缓冲液,所述醋酸盐缓冲液浓度约为5-30mM,优选约为10-25mM,更优选约为10-20mM,最优选约为10-15mM。
8.项1-5任一项所述的药物组合物,所述缓冲液为枸橼酸盐缓冲液,所述枸橼酸盐缓冲液浓度约为3-30mM,优选约为4.5-30mM,更优选约为5-20mM,最优选约为5-10mM。
9.项1-3任一项所述的药物组合物,所述等渗调节剂选自氯化钠、甘露醇、蔗糖、海藻糖、麦芽糖、木糖醇中一种或一种以上,优选为氯化钠、甘露醇和蔗糖中的一种或者一种以上,最优选蔗糖。
10.项1-3任一项所述的药物组合物,所述等渗调节剂的含量为约4-150mg/ml,优选为约6-120mg/ml,更优选为约40-100mg/ml,最优选为约60-80mg/ml。
11.项1-10任一项所述的药物组合物,所述等渗剂为浓度约20-150mg/ml的蔗糖,优选约为40-100mg/ml的蔗糖,更优选约为60-80mg/ml的蔗糖。
12.项1-10任一项所述的药物组合物,所述等渗剂为浓度约5-20mg/ml氯化钠溶液,优选为约5-10mg/ml氯化钠溶液,更优选为约6mg/ml氯化钠溶液。
13.项1-10任一项所述的药物组合物,所述等渗剂为浓度约10-40mg/ml的甘露醇,优选约为10-30mg/ml的甘露醇,更优选约为20mg/ml的甘露醇。
14.项1-3任一项所述的药物组合物,所述表面活性剂选自聚山梨酯80、聚山梨酯20、泊洛沙姆188;优选聚山梨酯80或聚山梨酯20;更优选为聚山梨酯80。
15.项1-3任一项所述的药物组合物,所述表面活性剂的浓度约为0.05-0.6mg/ml,优选约为0.1-0.4mg/l,更优选约为0.2-0.3mg/ml。
16.项1-3任一项所述的药物组合物,所述表面活性剂为约0.05-0.6mg/ml(w/v)的聚山梨酯80,优选约为0.1-0.4mg/ml的聚山梨酯80,更优选约为0.2-0.3mg/ml的聚山梨酯80,最优选约为0.2mg/ml的聚山梨酯80。
17.项1所述的药物组合物,所述药物组合物的水溶液pH值选自4.0-6.8;优选为4.5-6.5;更优选为5.5-6.0;最优选5.5。
18.项1-17任一项所述的药物组合物,所述药物组合物为水溶液或冻干粉。
19.项1-18任一项所述的药物组合物,所述抗PD-L1人源化单克隆抗体包含如下氨基酸序列:与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80%同源性的重链CDR1区;与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80%同源性的重链CDR2区;与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80%同源性的重链CDR3区;与SEQ IDNO:7或SEQ ID NO:10所示的氨基酸序列有至少80%同源性的轻链CDR1区;与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80%同源性的轻链CDR2区;与SEQ ID NO:9或SEQID NO:12所示的氨基酸序列有至少80%同源性的轻链CDR3区。
20.项19所述的药物组合物,所述抗PD-L1人源化单克隆抗体包含如下氨基酸序列:选自SEQ ID NO:1或SEQ ID NO:4的重链CDR1区;选自SEQ ID NO:2或SEQ ID NO:5的重链CDR2区;选自SEQ ID NO:3或SEQ ID NO:6的重链CDR3区;选自SEQ ID NO:7或SEQ ID NO:10的轻链CDR1区;选自SEQ ID NO:8或SEQ ID NO:11的轻链CDR2区;选自SEQ ID NO:9或SEQID NO:12的轻链CDR3区。
21.项1-18任一项所述的药物组合物,所述抗PD-L1人源化单克隆抗体包含如下氨基酸序列:与SEQ ID NO:13或SEQ ID NO:14所示的氨基酸序列有至少80%同源性的重链可变区;与SEQ ID NO:15或SEQ ID NO:16所示的氨基酸序列有至少80%同源性的轻链可变区。
22.项21所述的药物组合物,所述抗PD-L1人源化单克隆抗体包含如下氨基酸序列,如SEQ ID NO:13所示的重链可变区;如SEQ ID NO:15所示的轻链可变区。
23.项21所述的药物组合物,所述抗PD-L1人源化单克隆抗体包含如下氨基酸序列,如SEQ ID NO:14所示的重链可变区;如SEQ ID NO:16所示的轻链可变区。
24.项1-18任一项所述的药物组合物,所述抗PD-L1人源化单克隆抗体包含如SEQID NO.17所示的重链氨基酸序列,和SEQ ID NO.18所示的轻链氨基酸序列。
25.项1-18任一项所述的药物组组合物,所述抗PD-L1人源化单克隆抗体包含如SEQ ID NO.19所示的重链氨基酸序列,和SEQ ID NO.20的轻链氨基酸序列。
26.项1-18任一项所述的药物组组合物,所述抗PD-L1人源化单克隆抗体包含如SEQ ID NO.21所示的重链氨基酸序列,和SEQ ID NO.18的轻链氨基酸序列。
27.项1所述的药物组合物,所述药物组合物包含:
(a)质量体积浓度约20mg/mL抗PD-L1人源化单克隆抗体,
(b)质量体积浓度约70mg/mL的蔗糖,
(c)质量体积浓度约0.1mg/ml的聚山梨酯80,
(d)摩尔浓度约20mM的组氨酸,
(e)任选盐酸适量,调节组合物的pH值为约5.0。
28.项1所述的药物组合物,所述药物组合物包含:
(a)质量体积浓度约10mg/mL抗PD-L1人源化单克隆抗体,
(b)质量体积浓度约6mg/mL的氯化钠,
(c)质量体积浓度约0.1mg/ml的聚山梨酯80,
(d)摩尔浓度约5mM的枸橼酸盐,
并且所述组合物的pH值为约6.0。
29.项1所述的药物组合物,所述药物组合物包含:
(a)质量体积浓度约10mg/mL抗PD-L1人源化单克隆抗体,
(b)质量体积浓度约80mg/mL的蔗糖,
(c)质量体积浓度约0.2mg/ml的聚山梨酯80,
(d)摩尔浓度约10mM的组氨酸,
(e)任选盐酸适量,调节组合物的pH值为约5.5。
30.项1所述的药物组合物,所述药物组合物包含:
(a)质量体积浓度约50mg/mL抗PD-L1人源化单克隆抗体,
(b)质量体积浓度约80mg/mL的蔗糖,
(c)质量体积浓度约0.3mg/ml的聚山梨酯80,
(d)摩尔浓度约10mM的组氨酸,
(e)任选盐酸适量,调节组合物的pH值为约5.5。
31.项1所述的药物组合物,所述药物组合物包含:
(a)质量体积浓度约100mg/mL抗PD-L1人源化单克隆抗体,
(b)质量体积浓度约80mg/mL的蔗糖,
(c)质量体积浓度约0.5mg/ml的聚山梨酯80,
(d)摩尔浓度约10mM的组氨酸,
(e)任选盐酸适量,调节组合物的pH值为约5.5。
32.项1所述的药物组合物,所述药物组合物包含:
(a)质量体积浓度约5mg/mL抗PD-L1人源化单克隆抗体,
(b)质量体积浓度约3mg/mL的氯化钠,
(c)质量体积浓度约20mg/ml的甘露醇,
(d)质量体积浓度约0.1mg/ml的聚山梨酯80,
(e)摩尔浓度约10mM的醋酸盐,
并且所述组合物的pH值为约4.5。
33.项1所述的药物组合物,所述药物组合物包含:
(a)质量体积浓度约30mg/mL抗PD-L1人源化单克隆抗体,
(b)质量体积浓度约80mg/mL的蔗糖,
(c)质量体积浓度约0.2mg/ml的聚山梨酯80,
(d)摩尔浓度约10mM的组氨酸,
(e)任选盐酸适量,调节组合物的pH值为约5.5。
34.项1所述的药物组合物,所述药物组合物包含:
(a)质量体积浓度约60mg/mL抗PD-L1人源化单克隆抗体,
(b)质量体积浓度约80mg/mL的蔗糖,
(c)质量体积浓度约0.2mg/ml的聚山梨酯80,
(d)摩尔浓度约10mM的组氨酸,
(e)任选盐酸适量,调节组合物的pH值为约5.5。
35.项1所述的药物组合物,所述药物组合物包含:
(a)质量体积浓度约10mg/mL抗PD-L1人源化单克隆抗体,
(b)质量体积浓度约70mg/mL的蔗糖,
(c)质量体积浓度约0.4mg/ml的聚山梨酯80,
(d)摩尔浓度约20mM的组氨酸,
(e)任选醋酸适量,调节组合物的pH值为约6.5。
36.项1所述的药物组合物,所述药物组合物包含:
(a)质量体积浓度约10mg/mL抗PD-L1人源化单克隆抗体,
(b)质量体积浓度约80mg/mL的蔗糖,
(c)质量体积浓度约0.2mg/ml的聚山梨酯80,
(d)摩尔浓度约20mM的组氨酸,
(e)任选盐酸适量,调节组合物的pH值为约5.5。
37.项1所述的药物组合物,所述药物组合物包含:
(a)质量体积浓度约10mg/mL抗PD-L1人源化单克隆抗体,
(b)质量体积浓度约6mg/mL的氯化钠,
(c)质量体积浓度约0.2mg/ml的聚山梨酯80,
(d)摩尔浓度约10mM的枸橼酸盐,
(e)并且所述组合物的pH值为约5.0。
38.项1所述的药物组合物,所述药物组合物包含:
(a)质量体积浓度约10mg/mL抗PD-L1人源化单克隆抗体,
(b)质量体积浓度约6mg/mL的氯化钠,
(c)质量体积浓度约0.2mg/ml的聚山梨酯80,
(d)摩尔浓度约10mM的磷酸盐,
(e)并且所述组合物的pH值为约5.0。
39.制备前述1-38任一项所述的药物组合物的方法,包括将抗PD-L1人源化单克隆抗体与缓冲液、等渗调节剂和/或表面活性剂中的一种或几种相混合。
40.用于治疗受试者中瘤形成病状的方法,包括给所述受试者施用项1-38任一项所述的药物组合物。
下面结合具体实施例对本发明进行进一步的描述,然而,本发明中这些实施例仅用于阐明而不限制本发明的范围。同样,本发明不限于本文描述的任何具体优选的实施方案。本领域技术人员应该理解,对本发明技术特征所作的等同替换,或相应的改进,仍属于本发明的保护范围之内。除特别说明的以外,以下实施例采用的试剂均为市售产品,溶液的配制可以采用本领域常规技术。实施例中抗PD-L1人源化单抗按WO2016022630中所述方法制得,经亲和层析后,按常规的抗体纯化方法得到含有该抗体的洗脱液。
实施例1-12抗PD-L1人源化单抗5G11注射液的制备
按表1制剂配方的制备方法:配制目的缓冲液,用酸碱调节剂调节至所需的pH值。将纯化的抗PD-L1人源化单抗5G11的洗脱液用配制的目的缓冲液进行超滤置换,置换完全后,加入表1中相应的等渗剂/稳定剂和表面活性剂,并控制抗体终浓度至所需的目标浓度,除菌过滤,无菌分装于西林瓶内,加塞扎盖,视检合格,即得。
其中,抗PD-L1人源化单抗5G11包含如SEQ ID NO:13所示的重链可变区序列以及如SEQ ID NO:15所示的轻链可变区序列。实施例中抗PD-L1人源化单抗5G11的重链氨基酸序列如SEQ ID NO.17所示,轻链氨基酸序列如SEQ ID NO.18所示。
表1各实施例的制剂配方
实施例13抗PD-L1人源化单抗5G11注射液的质量研究
按实施例1~12的方法制得抗PD-L1人源化单抗5G11注射液12批。将每批注射液进行全面质量研究,利用分子筛色谱(Size-Exclusion chromatography,SEC)和十二烷基硫酸钠毛细管电泳(CE-SDS)分析蛋白聚体和降解物片段,离子交换色谱(Cation Exchangechromatography,CEX)分析电荷异质性,以及酶联免疫吸附法(ELISA)分析抗体的生物学结合活性。
SEC测定方法:采用TSKgel分子筛色谱柱(厂家:TOSOH;型号:TSKgel G3000 SWXL;规格:5μm,7.8*300),以pH为7.0±0.1含NaCl的Na2HPO4缓冲液为流动相进行洗脱,检测波长为280nm。该色谱条件下出峰先后顺序依次为聚合物峰、主峰、降解物峰。按面积归一化法计算聚合物、主峰和降解物的百分含量。
CEX测定方法:采用BioLCpropacTM色谱柱(厂家:Thermo;型号:ProPac WCX-10BioLC Analytical;规格:4*250mm),以pH为7.0±0.1含NaCl的Na2HPO4缓冲液为流动相进行洗脱,检测波长为280nm。该色谱条件下出峰先后顺序依次为酸区、主峰、碱区。按面积归一化法计算酸区、主峰、碱区的百分含量。
ELISA测定方法:将PD-L1-mFc蛋白包被在微孔板上,清洗封闭,然后将对照品/供试品稀释至特定浓度,与包被蛋白孵育结合,清洗后加入HRP标记羊抗人IgG抗体孵育,洗涤微孔板以除去未结合的反应物,加入底物(TMB)进行显色反应,用终止液终止,在酶标仪上450/650nm测定吸光度值(OD)。OD值读数与包被蛋白结合对照品/供试品浓度正相关。以浓度-溶液吸光度作4参数Logistic曲线拟合,根据拟合曲线计算出对照品/供试品EC50值,并比较供试品和对照品EC50值,得出5G11抗体与PD-L1-mFc蛋白结合活性。
抗PD-L1人源化单抗注射液12批质量研究结果见表2。
表2抗PD-L1人源化单抗5G11注射液的质量研究结果
结果显示,本发明实施例1到实施例12的处方SEC聚合物为0.1-0.3%,主峰为99.6-99.9%,抗体的生物学结合活性均维持在80%以上,符合要求,结果显示本发明的抗PD-L1人源化单抗5G11注射液聚合物很低,质量良好,且具有稳定的活性。
实施例14抗PD-L1人源化单抗5G11注射液2~8℃稳定性研究
按实施例1~12的方法制得抗PD-L1人源化单抗注射液12批。将每批注射液分别置于2~8℃环境中,于0月、1月、2月、3月、6月取样检测。利用分子筛色谱(SEC)和离子交换色谱法(CEX)测定纯度,酶联免疫吸附方法(ELISA)测定单抗的生物学结合活性,考察单抗注射液在2~8℃放置过程中纯度及活性的变化情况,以评价本发明药物组合物的稳定性。涉及指标检测方法同实施例13。抗PD-L1人源化单抗注射液2~8℃纯度及活性稳定性见表3。
表3抗PD-L1人源化单抗5G11注射液2~8℃放置稳定性考察结果
结果显示,实施例1-8以及实施例10-12的制剂处方样品在2~8℃放置6月后聚合物为0.2~0.5%,仅增长0.1~0.2%;主峰仅下降0.1~0.4%;酸区增长0.4~2.9%;碱区略有变化,变化均较小。结果表明,本发明的抗PD-L1人源化单抗5G11注射液2~8℃放置6个月聚合物和降解物基本没有太大变化,酸区和碱区的变化也控制在一定的范围内,生物结合活性均维持在80%以上,说明上述制剂处方高度稳定。
实施例15抗PD-L1人源化单抗5G11注射液25℃稳定性研究
按实施例1~12的方法制得抗PD-L1人源化单抗注射液12批。将每批注射液分别置于25℃环境中,于0月、1月、2月、3月、6月取样检测。利用分子筛色谱(SEC)和离子交换色谱法(CEX)测定纯度,酶联免疫吸附方法(ELISA)测定单抗的生物学结合活性,考察抗PD-L1人源化单抗注射液在25℃放置过程中纯度及活性的变化情况,以评价本发明药物组合物的稳定性。涉及指标检测方法同实施例13。抗PD-L1人源化单抗5G11注射液25℃纯度及活性稳定性见表4。
表4抗PD-L1人源化单抗5G11注射液25℃放置稳定性
结果显示,实施例1-8以及实施例10-12的处方样品在25℃放置6月后聚合物为0.3~0.9%,增长0.4~0.6%;降解物增长0.0~0.5%;主峰下降0.2~0.9%;酸区增长6.1~16.7%,碱区变化较小;抗体的结合活性均高于80%。结果表明,本发明的抗PD-L1人源化单抗5G11注射液25℃放置6个月聚合物、降解物变化较小,活性维持较好。
实施例16抗PD-L1人源化单抗5G11注射液40℃稳定性研究
按实施例1~12的方法制得抗PD-L1人源化单抗注射液12批。将每批注射液分别置于40℃环境中,于0天、2周、4周分别取样检测。利用分子筛色谱(SEC)和离子交换色谱法(CEX)测定纯度,酶联免疫吸附方法(ELISA)测定单抗的生物学结合活性,考察抗PD-L1人源化单抗注射液在40℃高温放置过程中纯度及活性的变化情况,以评价本发明药物组合物的稳定性。涉及指标检测方法同实施例13。抗PD-L1人源化单抗5G11注射液40℃高温纯度及活性稳定性见表5。
表5抗PD-L1人源化单抗5G11注射液40℃高温稳定性考察结果
结果显示,实施例1-8以及实施例10-12的处方样品在40℃高温放置4周后聚合物为0.3~0.9%,增长0.2~0.6%;降解物增长0.0~1.0%;主峰下降0.2~0.9%;抗体的结合活性均维持在80%以上。结果表明,除实施例9的制剂处方外,本发明的抗PD-L1人源化单抗5G11注射液40℃高温放置4周,聚合物、降解物变化较小,活性均维持较好。
实施例17抗PD-L1人源化单抗5G11注射液的振摇稳定性研究
将每批注射液置于25℃恒温环境中振摇,于0周、1周、2周取样检测。利用分子筛色谱(SEC)和离子交换色谱法(CEX)测定纯度,考察抗PD-L1人源化单抗5G11注射液在25℃振摇过程中纯度的变化情况,用酶联免疫吸附方法(ELISA)测定生物学结合活性,以评价本发明药物组合物的稳定性。涉及指标检测方法同实施例13。抗PD-L1人源化单抗5G11注射液25℃振摇纯度及活性稳定性见表6。
表6抗PD-L1人源化单抗5G11注射液的25℃振摇稳定性考察结果
结果显示,实施例1-8以及实施例10-12的处方样品在25℃恒温环境中振摇2周后聚合物为0.1~0.4%,增长0.0~0.1%;降解物增长0.0~0.1%;主峰下降0.1~0.2%;酸区增长0.2~2.4%,碱区没有明显变化;抗体的结合活性均维持在80%以上。结果表明,本发明的抗PD-L1人源化单抗5G11注射液25℃振摇2周各指标变化均较小,各项纯度与活性维持稳定,振摇稳定性良好。
实施例18抗PD-L1人源化单抗5G11注射液的冻融稳定性研究
将每批注射液置于-20℃中冻存2天,再于25℃恒温环境中化冻2天,取样检测,如此循环3次。利用分子筛色谱(SEC)和离子交换色谱法(CEX)测定纯度,酶联免疫吸附(ELISA)方法测定生物学结合活性,考察抗PD-L1人源化单抗5G11注射液在冻融过程中纯度及活性的变化情况,以评价本发明药物组合物的稳定性。涉及指标检测方法同实施例13。冻融纯度及活性稳定性见表7。
表7抗PD-L1人源化单抗5G11注射液的冻融稳定性考察结果
结果显示,实施例1到实施例12的处方在冻融3次后聚合物为0.2~0.4%,仅增长0~0.1%;降解物仅增长0~0.2%;主峰仅下降0~0.3%;酸区和碱区没有明显变化;抗体结合活性均维持在80%以上。结果表明,本发明实施例1到实施例12的处方样品冻融3次后各指标变化范围小,冻融稳定性良好。
根据本发明所公开的内容,虽然根据优选实施方案对本发明的组合物和方法进行了描述,但对本领域技术人员而言,在不背离本发明的概念、精神和范围的情况下,可对在此所述的组合物和/或方法以及所述方法的步骤或步骤的顺序进行改变。
本文所引用的所有文献的公开内容通过引用结合于此,引用程度为,他们提供示例性的、程序上和其他的细节补充本文所述内容。
<110> 正大天晴药业集团股份有限公司
正大天晴药业集团南京顺欣制药有限公司
<120> 一种抗PD-L1人源化单克隆抗体的药物组合物
<130> 2017
<160> 21
<170> PatentIn version 3.3
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Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met Ser
1 5 10 15
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Leu Gly Phe Tyr Ala Met Asp Tyr
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Ser Tyr Gly Met Ser
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Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys Gly
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Gly Tyr Asp Ser Gly Phe Ala Tyr
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Lys Ala Ser Gln Ser Val Ser Asn Asp Val Ala
1 5 10
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Tyr Ala Ala Asn Arg Tyr Thr
1 5
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Gln Gln Asp Tyr Thr Ser Pro Tyr Thr
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Ala Ser Gln Ser Val Ser Thr Ser Ser Ser Ser Phe Met His
1 5 10
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Tyr Ala Ser Asn Leu Glu Ser
1 5
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Gln His Ser Trp Glu Ile Pro Tyr Thr
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<213> 人工序列
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Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Asn Gln Val Val Leu
65 70 75 80
Thr Met Asn Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala
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Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
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Thr Val Ser Ser
115
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Asp Cys Ala
85 90 95
Arg Gly Tyr Asp Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
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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 Lys Ala Ser Gln Ser Val Ser Asn Asp
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Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
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Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
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Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Asp Tyr Thr Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
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Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
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Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser Ser Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
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Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
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Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Asn Gln Val Val Leu
65 70 75 80
Thr Met Asn Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu 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
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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
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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 Ala Val Ser His Glu Asp Pro Glu Val
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Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
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Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
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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
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Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
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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
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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
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Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
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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 Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ala Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Asp Tyr Thr Ser 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
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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
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Arg Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Asp Cys Ala
85 90 95
Arg Gly Tyr Asp Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu 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 Ala 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
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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
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Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser Ser Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
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<213> 人工序列
<400> 21
Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Asn Gln Val Val Leu
65 70 75 80
Thr Met Asn Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440
Claims (15)
1.一种抗PD-L1人源化单克隆抗体药物组合物,其特征在于,所述药物组合物包含:
i)抗PD-L1人源化单克隆抗体,和
ii)缓冲液、等渗调节剂和/或表面活性剂中的一种或几种;
可选地,所述药物组合物包含1-150mg/ml抗PD-L1人源化单克隆抗体、3-50mM缓冲液、2-150mg/ml等渗调节剂和0.01-0.8mg/ml表面活性剂,且pH为约4.5-6.8。
2.根据权利要求1所述的药物组合物,所述抗PD-L1人源化单克隆抗体浓度为约5-150mg/ml,优选为约10-60mg/ml,更优选为约10-30mg/ml。
3.根据权利要求1所述的药物组合物,所述抗PD-L1人源化单克隆抗体浓度为约10mg/ml、约20mg/ml、约30mg/ml、约40mg/ml、约50mg/ml、约60mg/ml、约70mg/ml、约80mg/ml、约90mg/ml、约100mg/ml、约110mg/ml或约120mg/ml,优选为约10mg/ml、约20mg/ml、约30mg/ml、约40mg/ml、约50mg/ml或约60mg/ml,更优选为约10mg/ml、约20mg/ml或约30mg/ml。
4.根据权利要求1-3任一项所述的药物组合物,所述缓冲液选自枸橼酸盐、醋酸盐或组氨酸盐,优选为枸橼酸盐或组氨酸盐,更优选为组氨酸盐。
5.根据权利要求1-3任一项所述的药物组合物,所述缓冲液的浓度约为4.5-50mM,优选约为5-25mM,更优选约为10-20mM,最优选约为10-15mM。
6.根据权利要求1-5任一项所述的药物组合物,所述缓冲液为组氨酸盐缓冲液,所述组氨酸盐缓冲液浓度约为5-30mM,优选约为10-25mM,更优选约为10-20mM,最优选为10-15mM。
7.根据权利要求1-5任一项所述的药物组合物,所述缓冲液为醋酸盐缓冲液,所述醋酸盐缓冲液浓度约为5-30mM,优选约为10-25mM,更优选约为10-20mM,最优选约为10-15mM。
8.根据权利要求1-5任一项所述的药物组合物,所述缓冲液为枸橼酸盐缓冲液,所述枸橼酸盐缓冲液浓度约为3-30mM,优选约为4.5-30mM,更优选约为5-20mM,最优选约为5-10mM。
9.根据权利要求1-3任一项所述的药物组合物,所述等渗调节剂选自氯化钠、甘露醇、蔗糖、海藻糖、麦芽糖、木糖醇中一种或一种以上,优选为氯化钠、甘露醇和蔗糖中的一种或者一种以上,最优选蔗糖。
10.根据权利要求1-3任一项所述的药物组合物,所述等渗调节剂的含量为约4-150mg/ml,优选为约6-120mg/ml,更优选为约40-100mg/ml,最优选为约60-80mg/ml。
11.根据权利要求1-10任一项所述的药物组合物,所述等渗剂为浓度约20-150mg/ml的蔗糖,优选为约40-100mg/ml的蔗糖,更优选为约60-80mg/ml的蔗糖。
12.根据权利要求1-10任一项所述的药物组合物,所述等渗剂为浓度约5-20mg/ml氯化钠溶液,优选为约5-10mg/ml氯化钠溶液,更优选为约6mg/ml氯化钠溶液。
13.根据权利要求1-10任一项所述的药物组合物,所述等渗剂为浓度约10-40mg/ml的甘露醇,优选为约10-30mg/ml的甘露醇,更优选为约20mg/ml的甘露醇。
14.根据权利要求1-3任一项所述的药物组合物,所述表面活性剂选自聚山梨酯80、聚山梨酯20、泊洛沙姆188;优选聚山梨酯80或聚山梨酯20;更优选为聚山梨酯80。
15.根据权利要求1-14任一项所述的药物组合物,所述抗PD-L1人源化单克隆抗体包含如下氨基酸序列:与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80%同源性的重链CDR1区;
与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80%同源性的重链CDR2区;
与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80%同源性的重链CDR3区;
与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80%同源性的轻链CDR1区;
与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80%同源性的轻链CDR2区;
与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80%同源性的轻链CDR3区。
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