CN111971062B - 一种抗人pd-1的单克隆抗体制剂、联合用药物及其用途 - Google Patents
一种抗人pd-1的单克隆抗体制剂、联合用药物及其用途 Download PDFInfo
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Abstract
本发明涉及一种稳定的抗人PD‑1抗体的药物制剂、联合用药物及其用途。所述药物制剂含有抗人PD‑1的单克隆抗体、稳定剂、缓冲剂和表面活性剂。本发明的抗人PD‑1抗体的药物制剂可以有效的抑制抗体的聚集和脱酰胺作用,从而阻止抗体蛋白的降解,得到稳定的药物制剂。本发明的联合用药物是将所述抗人PD‑1抗体的药物制剂和其他额外的治疗剂组合使用,以及将所述药物制剂或所述联合用药物用于制备抗肿瘤药物中的用途。
Description
本申请要求于2018年4月28日提交的中国专利申请CN 201810400754.4的优先权。上述申请的全部内容通过引用并入本文。
技术领域
本发明涉及一种稳定的抗人PD-1的单克隆抗体的药物制剂、联合用药物及其用途,属于生物技术领域。
背景技术
肿瘤的免疫逃逸机制与机体对肿瘤的免疫应答之间存在着极为复杂的关系。肿瘤免疫治疗早期,肿瘤特异性的杀伤性T细胞是有其生物活性的,但是,随着肿瘤的不断生长,后期便失去了杀伤的功能。因此,肿瘤免疫治疗是为了最大限度的提高患者自身对肿瘤的免疫系统反应,它不但要在体内激活原有的免疫系统反应,更要维持免疫系统反应的持续时间和反应强度,才是免疫治疗肿瘤的关键。
程序性死亡因子1(programmed death-1,PD-1),也称为CD279,是一种在调节免疫系统的刺激性与抑制性信号之间的平衡和维持外周耐受性中具有至关重要作用的细胞表面受体。其为与CD28具有同源性的免疫球蛋白超家族的抑制性成员。PD-1的结构为单体I型跨膜蛋白,其由一个免疫球蛋白可变区样细胞外结构域以及含有免疫受体酪氨酸抑制基序(ITIM)和免疫受体酪氨酸转换基序(ITSM)的细胞质结构域组成。PD-1主要表达在活化的T细胞、B细胞和髓细胞上。PD-1具有两个已知的配体:PD-L1(B7-H1,CD274)和PD-L2(B7-DC,CD273),它们为B7家族的细胞表面表达的成员。这两个配体已被鉴定为与PD-1特异性相互作用,诱导细胞内信号转导,该细胞内信号转导抑制CD3及CD28介导的T细胞激活,继而削弱T细胞活性,例如,减少细胞增殖、IL-2与IFN-γ分泌,以及其他生长因子及细胞因子分泌。因此,阻断PD-L1/PD-1之间的结合就成为了肿瘤免疫治疗领域备受关注的药物靶点。抗PD-1的抗体能够特异性与PD-1结合并阻断其与受体的相互作用,从而切断肿瘤细胞表面表达的PD-L1与T细胞上PD-1的结合抑制,达到抗癌目的。此外,抗PD-1的抗体与其他治疗方法的联合使用,也在临床实践中获得了突破性的进展。其他治疗方法,包括放疗、化疗或除PD-1以外的其他免疫检查点(如CTLA-4等)的抑制剂等。
虽然现有技术中已经公开了若干PD-1抗体,但追求临床效果更优的新抗体一直是肿瘤免疫领域的热点。抗体药物的主要剂型就是注射剂,CN103429264A、CN106390115A和CN107334728A等专利申请均公开了PD-1抗体的制剂,但是,不同的PD-1抗体的氨基酸序列组成不同,导致其理化性质和高级构象也存在差异,因此,现有技术已有的剂型组成难以适用于所有的PD-1抗体。为了使得特定序列结构的PD-1抗体能够适于临床应用,有必要针对特定的抗体进行制剂的开发研究。同时,还需要根据特定的PD-1抗体制剂研究其与其他治疗剂组合进行联合用药的技术效果。
发明概述
为了追求更佳的临床效果,发明人通过文库筛选获得了一种相较于BMS公司的Nivolumab(商品名Opdivo)技术效果更优的抗人PD-1的单克隆抗体(单抗),命名为ZMR01。在获得单抗ZMR01的基础上,进一步地对ZMR01的制剂处方进行了大量探索性研究,发现组氨酸-醋酸缓冲剂对阻止单抗ZMR01的聚集和降解有明显作用;同时,还发现聚山梨酯20在药物制剂中用作助溶剂,对提高药物溶解度、增强药物的药理作用或减少副作用有明显益处;另外,还意外地发现单抗ZMR01较为稳定的pH范围是4.5-5.5。综上,本发明提供了一种针对特定序列的抗人PD-1的单克隆抗体(如ZMR01)适用的、且能稳定保存所述单抗的溶液制剂,该制剂能够充分防止单抗ZMR01蛋白聚集、降解、氧化或者变性等,从而保持其有效组分的生物学活性,适合于临床使用。进一步地,在得到单抗ZMR01药物制剂的基础上,对该制剂的药物学功能做了深入研究,发现该制剂具备良好的抗肿瘤活性,并且,该制剂与其他治疗剂联用,特别是与抗VEGF单抗联用相较于单独使用该制剂具有更好的抗肿瘤效果。
本发明的一个目的在于提供一种稳定的适用于特定序列的抗人PD-1的单克隆抗体(如ZMR01)的溶液制剂及其用途。本文中以ZMR01为例来描述本发明所用的抗人PD-1单抗。除非是在实施例中或者另外指出,当提到ZMR01时是指本发明所用的具有特定序列的抗人PD-1单克隆抗体。
本发明的稳定的溶液制剂含有单抗ZMR01或其抗原结合片段和缓冲剂。所述溶液制剂还可以含有稳定剂和/或表面活性剂。
本发明所述的溶液制剂中,所述的单抗ZMR01或其抗原结合片段的抗体重链可变区HCDR序列依次为:SEQ ID NO:1,SEQ ID NO:2,SEQ ID NO:3;以及,抗体轻链可变区LCDR序列依次为:SEQ ID NO:4,SEQ ID NO:5,SEQ ID NO:6。所述氨基酸序列如下表所示:
进一步优选的,单抗ZMR01具有SEQ ID NO:7的重链可变区氨基酸序列和SEQ IDNO:8的轻链可变区氨基酸序列。
再进一步优选的,单抗ZMR01具有SEQ ID NO:9的重链氨基酸序列和SEQ ID NO:10的轻链氨基酸序列。
所述单抗ZMR01在制剂中的浓度优选20-30mg/ml,最优选25mg/ml。
本发明所述的缓冲剂选自组氨酸-盐酸缓冲剂、醋酸-醋酸钠缓冲剂、组氨酸-醋酸缓冲剂;进一步优选的药学上可接受的缓冲剂为组氨酸-醋酸缓冲剂;缓冲剂的浓度为5-20mM,最优选10mM。
本发明所述的溶液制剂的pH范围4.5-6.0,优选pH范围是4.5-5.5,最优选pH 5.2。
本发明所述的稳定剂为蔗糖或甘露醇或海藻糖,优选为蔗糖,浓度为70-90mg/ml,最优选90mg/ml。
本发明所述的表面活性剂为聚山梨酯20或聚山梨酯80,浓度为0.1-0.5mg/ml,最优选聚山梨酯20,浓度为0.2mg/ml。
本发明所述的稳定的溶液制剂是一种可注射的药物制剂。
在本发明的一个实施方案中,所述稳定的溶液制剂包含单抗ZMR01或其抗原结合片段、缓冲剂、蔗糖和表面活性剂,任选包括水。
在本发明的一个实施方案中,所述稳定的溶液制剂包含单抗ZMR01或其抗原结合片段、缓冲剂、蔗糖和聚山梨酯20,任选包括水。
在本发明的一个实施方案中,所述稳定的溶液制剂包含单抗ZMR01或其抗原结合片段、组氨酸-醋酸缓冲剂、蔗糖和聚山梨酯20。
在本发明的一个实施方案中,所述稳定的溶液制剂由20-30mg/ml单抗ZMR01或其抗原结合片段、5-20mM组氨酸-醋酸缓冲剂、70-90mg/ml蔗糖、0.1-0.5mg/ml聚山梨酯20组成,pH范围是4.5-5.5。
在本发明的一个实施方案中,所述稳定的溶液制剂包含:
单抗ZMR01和
(1)90mg/ml蔗糖,10mM组氨酸-醋酸缓冲液和0.2mg/ml的聚山梨酯20或者
(2)90mg/ml蔗糖,15mM组氨酸-醋酸缓冲液和0.4mg/ml的聚山梨酯20或者
(3)90mg/ml蔗糖,20mM组氨酸-醋酸缓冲液和0.1mg/ml的聚山梨酯20或者
(4)80mg/ml蔗糖,10mM组氨酸-醋酸缓冲液和0.4mg/ml的聚山梨酯20或者
(5)80mg/ml蔗糖,15mM组氨酸-醋酸缓冲液和0.2mg/ml的聚山梨酯20或者
(6)80mg/ml蔗糖,20mM组氨酸-醋酸缓冲液和0.1mg/ml的聚山梨酯20或者
(7)70mg/ml蔗糖,10mM组氨酸-醋酸缓冲液和0.1mg/ml的聚山梨酯20或者
(8)70mg/ml蔗糖,15mM组氨酸-醋酸缓冲液和0.2mg/ml的聚山梨酯20或者
(9)70mg/ml蔗糖,20mM组氨酸-醋酸缓冲液和0.4mg/ml的聚山梨酯20或者
(10)60mg/ml蔗糖,10mM组氨酸-醋酸缓冲液,0.2mg/ml的聚山梨酯20和50mM的NaCl溶液。
上述(1)-(10)制剂的pH范围均为4.5-5.5。
本发明的溶液制剂可以有效抑制抗体的聚集和脱酰胺作用,从而阻止其中抗体产品的降解,得到稳定性的注射组合物。并且,本发明的溶液制剂对于蛋白氧化降解具有保护作用,还能够与玻璃、不锈钢容器相容,在这些容器中也能够稳定存在。
本发明还提供一种冻干制剂,其由上述溶液制剂经冻干获得,或者所述冻干制剂经复溶以后获得上述的溶液制剂。
本发明还提供制备所述稳定的ZMR01单克隆抗体的溶液制剂的方法,包括如下步骤:
(1)配制pH 4.5-5.5的组氨酸-醋酸缓冲溶液;
(2)向制得的溶液中添加蔗糖和聚山梨酯20,使溶液中蔗糖浓度达70-90mg/ml,聚山梨酯20的浓度达到0.1-0.5mg/ml;
(3)向制得的溶液中加入单抗ZMR01,使其浓度达到20-30mg/ml。
上述步骤(1)、(2)和(3)可以任意顺序进行,只要最终获得稳定的抗体溶液即可。
本发明还提供一种联合用药物,包含ZMR01单克隆抗体的溶液制剂和至少一种额外的治疗剂。
本发明所述的联合用药物,ZMR01单克隆抗体的溶液制剂和至少一种额外的治疗剂既可以混合在一起形成单一的给药单元,也可分别独立成为给药单元,分别使用。
本发明所述联合用药物中额外的治疗剂例如可以选自针对下述靶点的抑制剂:A2AR,CTLA4,PD-L1,TIGIT,CCR4,CCR8,CSF1R1a,B7H3,B7H4,CD47,CD96,CD73,Claudin18.2,VEGF,VEGFR,EGFR,FGFR,Her2,IAP,LAG3,STING,TNF-α,VISTA。
本发明所述联合用药物中额外的治疗剂例如可以选自针对下述靶点的激动剂:GITR,41BB,OX40,CD40,ICOS。
本发明所述联合用药物中额外的治疗剂例如可以选自IDO抑制剂、TDO抑制剂和IAP抑制剂。
本发明所述联合用药物中额外的治疗剂例如可以是抗VEGF抗体,优选贝伐单抗。
本发明还提供一种药盒,包含ZMR01单克隆抗体的溶液制剂或包含ZMR01单克隆抗体的溶液制剂和至少一种额外的治疗剂。
本发明所述药盒中额外的治疗剂例如可以选自针对下述靶点的抑制剂:A2AR,CTLA4,PD-L1,TIGIT,CCR4,CCR8,CSF1R1a,B7H3,B7H4,CD47,CD96,CD73,Claudin18.2,VEGF,VEGFR,EGFR,FGFR,Her2,IAP,LAG3,STING,TNF-α,VISTA。
本发明所述药盒中额外的治疗剂例如可以选自针对下述靶点的激动剂:GITR,41BB,OX40,CD40,ICOS。
本发明所述药盒中额外的治疗剂例如可以选自IDO抑制剂、TDO抑制剂和IAP抑制剂。
本发明所述药盒中额外的治疗剂例如可以是抗VEGF抗体,优选贝伐单抗。
本发明还提供所述溶液制剂或所述联合用药物或所述药盒在制备用于预防和/或治疗PD-1介导的疾病或者表达PD-L1的肿瘤中的用途。
所述肿瘤例如可以选自肺癌、胃癌、黑色素瘤、肾癌、乳腺癌、肠癌、肝癌、卵巢癌、宫颈癌、膀胱癌、食道癌、胰腺癌、头颈肿瘤。
本发明还提供一种治疗方法,其用于受试者中预防或治疗PD-1介导的疾病或病症,所述的疾病优选为肿瘤;更优选为表达PD-L1的肿瘤;所述的肿瘤优选为肺癌、胃癌、黑色素瘤、肾癌、乳腺癌、肠癌、肝癌、卵巢癌、宫颈癌、膀胱癌、食道癌、胰腺癌、头颈肿瘤;最优选为非小细胞肺癌、黑色素瘤和肾癌,所述方法包括给予受试者施用本发明所述的溶液制剂或所述联合用药物或所述药盒。
本发明请求保护如下技术方案:
项目1、一种抗人PD-1的单克隆抗体的溶液制剂,其包含抗人PD-1的单克隆抗体或其抗原结合片段和缓冲剂,其中所述抗人PD-1的单克隆抗体或其抗原结合片段的重链可变区的3个CDR(即HCDR1、HCDR2和HCDR3)的氨基酸序列依次为:SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3;轻链可变区的3个CDR(即LCDR1、LCDR2和LCDR3)的氨基酸序列依次为:SEQ IDNO:4、SEQ ID NO:5和SEQ ID NO:6;所述缓冲剂选自组氨酸-盐酸、醋酸-醋酸盐(如醋酸钠)或组氨酸-醋酸。
项目2、如项目1所述的溶液制剂,其中所述抗人PD-1的单克隆抗体或其抗原结合片段的重链可变区的氨基酸序列为SEQ ID NO:7,轻链可变区的氨基酸序列为SEQ ID NO:8。
项目3、如项目1或2所述的溶液制剂,其中所述抗人PD-1的单克隆抗体的重链的氨基酸序列为SEQ ID NO:9,轻链的氨基酸序列为SEQ ID NO:10。
项目4、如项目1-3任一所述的溶液制剂,其中所述缓冲剂为组氨酸-醋酸缓冲剂。
项目5、如项目1-4任一所述的溶液制剂,其还包含稳定剂。
项目6、如项目1-5任一所述的溶液制剂,其还包含稳定剂,所述稳定剂选自蔗糖、甘露醇和海藻糖,优选地所述稳定剂为蔗糖。
项目7、如项目1-6任一所述的溶液制剂,其还包含表面活性剂。
项目8、如项目1-7任一所述的溶液制剂,其还包含表面活性剂,所述表面活性剂选自聚山梨酯20和聚山梨酯80,优选聚山梨酯20。
项目9、如项目1-8任一所述的溶液制剂,其pH为4.5-6.0,优选为4.5-5.5,例如5.2。
项目10、如项目1-9任一所述的溶液制剂,其包含选自蔗糖、组氨酸-醋酸缓冲剂和聚山梨酯20中的任意两种或三种。
项目11、如项目1-10任一所述的溶液制剂,其包含20-30mg/ml的抗人PD-1的单克隆抗体。
项目12、如项目1-11任一所述的溶液制剂,其包含70-90mg/ml的蔗糖。
项目13、如项目1-12任一所述的溶液制剂,其包含5-20mM的组氨酸-醋酸缓冲剂。
项目14、如项目1-13任一所述的溶液制剂,其包含0.1-0.5mg/ml的聚山梨酯20。
项目15、如项目1-14任一所述的溶液制剂,其包含20-30mg/ml的抗人PD-1的单克隆抗体、70-90mg/ml的蔗糖、5-20mM的组氨酸-醋酸缓冲剂、0.1-0.5mg/ml的聚山梨酯20,溶液的pH为4.5-5.5。
项目16、如项目1-15所述的溶液制剂,其包含抗人PD-1的单克隆抗体和
(1)90mg/ml蔗糖,10mM组氨酸-醋酸缓冲液和0.2mg/ml的聚山梨酯20;或者
(2)90mg/ml蔗糖,15mM组氨酸-醋酸缓冲液和0.4mg/ml的聚山梨酯20;或者
(3)90mg/ml蔗糖,20mM组氨酸-醋酸缓冲液和0.1mg/ml的聚山梨酯20;或者
(4)80mg/ml蔗糖,10mM组氨酸-醋酸缓冲液和0.4mg/ml的聚山梨酯20;或者
(5)80mg/ml蔗糖,15mM组氨酸-醋酸缓冲液和0.2mg/ml的聚山梨酯20;或者
(6)80mg/ml蔗糖,20mM组氨酸-醋酸缓冲液和0.1mg/ml的聚山梨酯20;或者
(7)70mg/ml蔗糖,10mM组氨酸-醋酸缓冲液和0.1mg/ml的聚山梨酯20;或者
(8)70mg/ml蔗糖,15mM组氨酸-醋酸缓冲液和0.2mg/ml的聚山梨酯20;或者
(9)70mg/ml蔗糖,20mM组氨酸-醋酸缓冲液和0.4mg/ml的聚山梨酯20;或者
(10)60mg/ml蔗糖,10mM组氨酸-醋酸缓冲液,0.2mg/ml的聚山梨酯20和50mM的NaCl溶液;以及
所述制剂的pH范围为4.5-5.5。
项目17、如项目16所述的溶液制剂,其中所述抗人PD-1的单克隆抗体的浓度是20-30mg/ml。
项目18、一种冻干制剂,其由项目1至17任一项所述溶液制剂经冻干获得,或者所述冻干制剂经复溶以后获得项目1至17任一项所述溶液制剂。
项目19、制备如项目1-17任一所述的抗人PD-1的单克隆抗体的溶液制剂的方法,其包括:
(1)配制pH 4.5-5.5的组氨酸-醋酸缓冲溶液;
(2)向制得的缓冲液中添加蔗糖和聚山梨酯20,使溶液中蔗糖浓度达到70-90mg/ml,聚山梨酯20的浓度达到0.1-0.5mg/ml;
(3)向制得的溶液中加入单抗ZMR01,使其浓度达到20-30mg/ml;
上述步骤(1)、(2)和(3)可以任意顺序进行,只要最终获得稳定的抗体溶液即可。
项目20、一种联合用药物,其中包含项目1-18任一所述的制剂和至少一种额外的治疗剂。
项目21、如项目20所述的联合用药物,其中所述额外的治疗剂为针对下述靶点的抑制剂,所述靶点选自:A2AR,CTLA4,PD-L1,TIGIT,CCR4,CCR8,CSF1R1a,B7H3,B7H4,CD47,CD96,CD73,Claudin18.2,VEGF,VEGFR,EGFR,FGFR,Her2,IAP,LAG3,STING,TNF-α和VISTA。
项目22、如项目20所述的联合用药物,其中所述额外的治疗剂为针对下述靶点的激动剂,所述靶点选自:GITR,41BB,OX40,CD40和ICOS。
项目23、如项目20所述的联合用药物,其中所述额外的治疗剂选自IDO抑制剂、TDO抑制剂、IAP抑制剂和抗VEGF抗体,例如所述抗VEGF抗体优选是贝伐单抗。
项目24、一种药盒,其中包含项目1-18任一所述的制剂或项目20-23任一所述的联合用药物。
项目25、如项目24所述的药盒,其中还包含额外的治疗剂。
项目26、如项目25所述的药盒,其中所述额外的治疗剂为针对下述靶点的抑制剂,所述靶点选自:A2AR,CTLA4,PD-L1,TIGIT,CCR4,CCR8,CSF1R1a,B7H3,B7H4,CD47,CD96,CD73,Claudin18.2,VEGF,VEGFR,EGFR,FGFR,Her2,IAP,LAG3,STING,TNF-α和VISTA。
项目27、如项目25所述的药盒,其中所述额外的治疗剂为针对下述靶点的激动剂,所述靶点选自:GITR,41BB,OX40,CD40和ICOS。
项目28、如项目25所述的药盒,其中所述额外的治疗剂选自IDO抑制剂、TDO抑制剂、IAP抑制剂和抗VEGF抗体,例如所述抗VEGF抗体是贝伐单抗。
项目29、如项目1-18任一所述的抗人PD-1的单克隆抗体的制剂或项目20-23任一所述的联合用药物或项目24-28任一所述的药盒在制备用于预防和/或治疗PD-1介导的疾病或者表达PD-L1的肿瘤的药物中的用途。
项目30、如项目29所述的用途,其中所述肿瘤选自肺癌、胃癌、黑色素瘤、肾癌、乳腺癌、肠癌、肝癌、卵巢癌、宫颈癌、膀胱癌、食道癌、胰腺癌和头颈肿瘤;优选地选自非小细胞肺癌、黑色素瘤和肾癌。
项目31、一种用于受试者中预防和/或治疗PD-1介导的疾病或病症的方法,包括给予受试者施用本发明所述的制剂或所述联合用药物或所述药盒。所述的疾病或病症优选为肿瘤;更优选为表达PD-L1的肿瘤;所述的肿瘤优选地选自肺癌、胃癌、黑色素瘤、肾癌、乳腺癌、肠癌、肝癌、卵巢癌、宫颈癌、膀胱癌、食道癌、胰腺癌和头颈肿瘤;最优选地选自非小细胞肺癌、黑色素瘤和肾癌。
附图说明
图1 ZMR01与PD-1抗原的亲和力测定结合解离图谱。
图2 Nivolumab与PD-1抗原的亲和力测定结合解离图谱。
图3 ZMR01和Nivolumab的生物学活性。
图4 ZMR01制剂对SEB活化的PBMC细胞因子IL-2释放的影响。
图5 一次MLR实验中ZMR01制剂对IFN-γ释放的影响。
图6 ZMR01制剂对IFN-γ释放的影响。
图7 MC38肿瘤生长曲线图。
图8 A431肿瘤生长曲线图。
图9 实验终点A431肿瘤体积。
具体实施方式
术语
本说明书中提及的所有公布、专利和专利申请都以引用的方式并入本文,所述引用的程度就如同已特定地和个别地指示将各个别公布、专利或专利申请以引用的方式并入一般。
在下文详细描述本发明前,应理解本发明不限于本文中描述的特定方法学、方案和试剂,因为这些可以变化。还应理解本文中使用的术语仅为了描述具体实施方案,而并不意图限制本发明的范围。除非另外定义,本文中使用的所有技术和科学术语与本发明所属领域中普通技术人员通常的理解具有相同的含义。
本文所公开的某些实施方案包含了数值范围,并且本发明的某些方面可采用范围的方式描述。除非另有说明,应当理解数值范围或者以范围描述的方式仅是出于简洁、便利的目的,并不应当认为是对本发明的范围的严格限定。因此,采用范围方式的描述应当被认为具体地公开了所有可能的子范围以及在该范围内的所有可能的具体数值点,正如这些子范围和数值点在本文中已经明确写出。不论所述数值的宽窄,上述原则均同等适用。当采用范围描述时,该范围包括范围的端点。
当涉及可测量值比如量、暂时持续时间等时,术语“约”是指包括指定值的±20%、或在某些情况下±10%、或在某些情况下±5%、或在某些情况下±1%、或在某些情况下±0.1%的变化。
本文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。
术语“抗人PD-1”的抗体是指能够识别、结合来自于人的PD-1分子的抗体。
本文所用的术语“抗体”,典型是指包含通过共价二硫键和非共价相互作用保持在一起的两条重(H)多肽链和两条轻(L)多肽链的Y型四聚蛋白。天然IgG抗体即具有这样的结构。每条轻链由一个可变结构域(VL)和一个恒定结构域(CL)组成。每条重链包含一个可变结构域(VH)和恒定区。
本领域已知五个主要类别的抗体:IgA,IgD,IgE,IgG和IgM,对应的重链恒定结构域分别被称为α,δ,ε,γ和μ,IgG和IgA可以进一步分为不同的亚类,例如IgG可分为IgG1,IgG2,IgG3,IgG4,IgA可分为IgA1和IgA2。来自任何脊椎动物物种的抗体的轻链基于其恒定结构域的氨基酸序列可以被分配到两种明显相异的类型之一,称为κ和λ。
在IgG、IgA和IgD抗体的情形中,该恒定区包含称为CH1、CH2和CH3的三个结构域(IgM和IgE具有第四结构域CH4)。在IgG、IgA和IgD类别中,CH1和CH2结构域被柔性铰链区分离,该铰链区是可变长度的富含脯氨酸和半胱氨酸的区段。每类抗体进一步包含由配对半胱氨酸残基形成的链间和链内二硫键。
术语“可变区”或“可变结构域”显示出从一种抗体到另一种抗体的氨基酸组成的显著变化,并且主要负责抗原识别和结合。每个轻链/重链对的可变区形成抗体结合位点,使得完整的IgG抗体具有两个结合位点(即它是二价的)。重链的可变区(VH)和轻链的可变区(VL)结构域各包含具有极端变异性的三个区域,被称为高变区(HVR),或更通常地,被称为互补决定区(CDR),VH和VL各有4个骨架区FR,分别用FR1,FR2,FR3,FR4表示。因此,CDR和FR序列通常出现在重链可变结构域(或轻链可变结构域)的以下序列中:FR1-HCDR1(LCDR1)-FR2-HCDR2(LCDR2)-FR3-HCDR3(LCDR3)-FR4。
术语“Fc”用于定义免疫球蛋白重链的C端区域,所述区域包含至少一部分的恒定区。该术语包括天然序列Fc区和变体Fc区。
如在此使用的,广义上的“抗体”的类型可包括如多克隆抗体(polyclonalantibodies)、单克隆抗体、嵌合抗体、人源化抗体及灵长类化抗体、CDR移植抗体(CDR-grafted antibody)、人类抗体(包括重组产生的人类抗体)、重组产生的抗体、胞内抗体、多特异性抗体、双特异性抗体、单价抗体、多价抗体、抗个体基因型抗体、合成抗体(包括突变蛋白及其变体)等等。
术语“单克隆抗体”(或称“单抗”)指由单一细胞克隆产生的基本均质、仅针对某一特定抗原表位的抗体。单克隆抗体可以使用本领域中已知的多种技术制备,包括杂交瘤技术、重组技术、噬菌体展示技术、转基因动物、合成技术或上述技术的组合等。
需说明的是,本发明的单克隆抗体可变区的CDR和FR的划分是根据Kabat定义确定的。而其他命名和编号系统,例如Chothia、IMGT或AHo等,也是本领域技术人员已知的。因此,以本发明的单抗序列为基础,包含任何命名系统衍生的一种或多种CDR的人源化抗体均明确地保持在本发明的范围内。
术语“抗体片段”包含完整抗体的至少一部分。如在此所使用,抗体分子的“片段”包括抗体的“抗原结合片段”,并且术语“抗原结合片段”是指免疫球蛋白或抗体中与所选抗原或其免疫原性决定部分特异性结合或反应的多肽片段,或由此片段进一步衍生的融合蛋白产物,例如单链抗体,嵌合抗原受体中的胞外结合区等。示例性的抗体片段或其抗原结合片段包括但不限于:可变轻链片段、可变重链片段、Fab片段、F(ab’)2片段、Fd片段、Fv片段、单结构域抗体、线性抗体、单链抗体(scFv)及由抗体片段形成的双特异性抗体或多特异性抗体等。
术语“抗原”是指被抗体或抗体结合片段识别并特异性结合的物质,广义上,抗原可以包括所选靶标的任何免疫原性片段或决定簇,包括单表位、多表位、单结构域、多结构域、完整的胞外结构域(ECD)或蛋白质。肽、蛋白质、糖蛋白、多糖和脂质,其部分及其组合均可构成抗原。非限制性示例性抗原包括肿瘤抗原或病原体抗原等。“抗原”也可以指引发免疫反应的分子。任何形式的抗原或含有该抗原的细胞或制剂都可以用于生成对抗原决定簇具有特异性的抗体。抗原可以是分离的全长蛋白质、细胞表面蛋白(例如,用在其表面上表达至少一部分抗原的细胞进行免疫的)、或可溶性蛋白质(例如,仅用该蛋白质的ECD部分进行免疫的)或蛋白质构建体(例如,Fc抗原)。该抗原可以在基因修饰的细胞中产生。前述任何抗原可以单独或与本领域已知的一种或多种免疫原性增强佐剂组合使用。编码该抗原的DNA可以是基因组的或非基因组的(例如,cDNA),并且可以编码足以引起免疫原性应答的至少一部分ECD。可以使用任何载体来转化其中表达抗原的细胞,所述载体包括但不限于腺病毒载体、慢病毒载体、质粒以及非病毒载体如阳离子脂质。
术语“表位”是指抗原上与免疫球蛋白或抗体特异性结合的位点。表位可以由相邻的氨基酸、或通过蛋白质的三级折叠而并列的不相邻的氨基酸形成。由相邻的氨基酸形成的表位通常在暴露于变性溶剂后保持,而通过三级折叠形成的表位通常在变性溶剂处理后丧失。表位通常以独特的空间构象存在并且包括至少3-15个氨基酸。由给定的抗体确定其结合的表位的方法是本领域熟知的,包括免疫印迹和免疫沉淀检测分析等。确定表位的空间构象的方法包括本领域中的技术,例如X射线晶体分析法和二维核磁共振等。
术语“亲和力”或“结合亲和力”指分子(例如抗体)的单一结合位点与其结合配偶体(例如抗原)之间全部非共价相互作用总和的强度。术语“KD”是指特定的抗体-抗原相互作用的解离常数。可以使用本领域已知的各种技术来确定结合亲和力,例如表面等离子体共振、生物层干涉法、双极化干涉法、静态光散射、动态光散射、等温滴定量热法、ELISA、分析超速离心和流式细胞术等。
术语“生物学活性”指抗体结合抗原并导致可测量的生物学反应的能力,所述生物学反应可以在体外或体内进行测量。
术语“药物制剂”或“制剂”或“制剂处方”,表示这样的制品:其存在形式允许活性成分的生物学活性有效,并且不含有对所述制剂要施用的受试者有毒的其他组分。
术语“溶液制剂”表示,在大气压下至少约2℃至约8℃的温度为液体的制剂。
术语“脱酰胺”表示,抗体中的一个或多个天冬酰胺残基已经被衍生成,例如,天冬氨酸或异-天冬氨酸。
术语“聚集”的抗体是这样一种抗体,其已经被发现与其它抗体分子一起聚集,特别是在冷冻和/或搅动之后。
术语“稳定的”制剂是这样的制剂,其中的蛋白质在保存后基本上保持其物理稳定性和/或化学稳定性和/或生物学活性。优选地,该制剂在保存后基本上保持其物理和化学稳定性,以及其生物学活性。一般基于制剂保质期来选择贮存期。用来测量蛋白质稳定性的各种分析技术是本领域已有的。可以在选定的温度下测量稳定性持续选定的时间。稳定性能够以许多不同的方式进行定性和/或定量地评估,包括评估聚集物形成(例如利用大小排阻层析,通过测量浊度,和/或通过肉眼观察);通过利用阳离子交换层析或毛细管分区电泳评估电荷异质性;氨基末端或羧基末端序列分析;质谱分析;SDS-PAGE分析以比较减小的和完整的抗体;肽图谱分析;评估生物学活性或抗体的抗原结合功能;等等。不稳定性可以包括下列的任一种或多种:聚集,脱酰胺作用(例如Asn脱酰胺作用),氧化作用(例如Met氧化作用),异构化作用(例如Asp异构化作用),剪切/水解/片段化(例如铰链区片段化),琥珀酰亚胺形成,未配对的半胱氨酸,N-末端延伸,C-末端加工,糖基化作用差异,等等。
术语“缓冲剂”或“缓冲液”表示稳定药物制剂pH的药学上可接受的赋形剂。合适的缓冲剂是本领域公知的,且可以在文献中找到的。优选的药学上可接受的缓冲液包括但不限于:组氨酸缓冲液、柠檬酸盐缓冲液、琥珀酸盐缓冲液、醋酸盐缓冲液、精氨酸缓冲液、磷酸盐缓冲液或其混合物等等。缓冲液用本领域已知的酸或碱进行pH调节,可以将pH调至在4.5-6.0范围内的值,特别是调至在4.5-5.5范围内的值,最特别地是调至pH5.2。
术语“稳定剂”表示药学可接受的赋形剂,其在制造,储存和应用过程中保护活性药物成分和/或制剂免受化学和/或物理降解。稳定剂包括但不限于糖,氨基酸,多元醇,环糊精等。
术语“表面活性剂”表示,用于保护蛋白制剂抵抗物理应力(如搅拌和剪切)的药学上可接受的赋形剂。药学上可接受的表面活性剂包括:聚氧乙烯脱水山梨糖醇脂肪酸酯(吐温)、聚氧乙烯烷基醚(例如在商标BrijTM下销售的那些)和聚氧乙烯-聚氧丙烯共聚物(泊洛沙姆,Pluronic)。聚氧乙烯脱水山梨糖醇-脂肪酸酯包括聚山梨酯20(在商标吐温20TM下销售)和聚山梨酯80(在商标吐温80TM下销售)。
术语“联合用药物”指包含各自具有活性成分的两种或两种以上药物制剂的组合,在施用于受试者时需要联合使用。活性成分可以混合在一起形成单一的给药单元,也可分别独立成为给药单元,分别使用。
术语“有效量”指本发明的抗体或片段的药物制剂的剂量,其以单一或多次剂量施用患者后,在治疗的患者中产生预期效果。有效量可以由作为本领域技术人员的主治医师通过考虑以下多种因素来容易地确定:诸如人种差异;体重、年龄和健康状况;涉及的具体疾病;疾病的严重程度;个体患者的应答;施用的具体抗体;施用模式;施用制剂的生物利用率特征;选择的给药方案;和任何伴随疗法的使用。
术语“药盒”包括有效量的一种或多种单位剂型的本发明的药物制剂或联合用药物。在一些实施方案中,药盒可含有治疗或预防性组合物的无菌容器;这样的容器可以是盒、安瓿、瓶、小瓶、管、袋、泡罩包装或本领域已知的其它合适的容器形式。这种容器可以由塑料、玻璃、层压纸、金属箔或其他适合于保持药物的材料制成。此外,药盒还包括将本发明的药物制剂或联合用药物给予个体的说明书。说明书中通常包含使用本发明的药物制剂或联合用药物来治疗或预防疾病的方法。
生产和纯化抗体和抗原结合片段的方法在现有技术中能够熟知和获得,如冷泉港的抗体实验技术指南,5-8章和15章。
本发明工程化的抗体或其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。通过表达与人源抗原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、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。
本文所用的术语“个体”或“受试者”是指任何动物,例如哺乳动物或有袋动物。本发明的个体包括但不限于人类、非人类灵长类动物(例如食蟹猴或恒河猴或其他类型的猕猴)、小鼠、猪、马、驴、牛、绵羊、大鼠和任何种类的家禽。
本文所用的术语“肿瘤”指的是一种以细胞或组织的病理性增生为特征的疾病,及其随后的迁移或侵袭其他组织或器官。肿瘤生长通常是不受控制的和进行性的,不诱导或抑制正常细胞增殖。肿瘤可影响多种细胞、组织或器官,包括但不限于选自膀胱、骨、脑、乳腺、软骨、神经胶质细胞、食管、输卵管、胆囊、心脏、肠、肾、肝、肺、淋巴结、神经组织、卵巢、胰腺、前列腺、骨骼肌、皮肤、脊髓、脾、胃、睾丸、胸腺、甲状腺、气管、尿道、输尿管、尿道、子宫、阴道器官,或组织或相应的细胞。肿瘤包括癌症,如肉瘤,癌,或浆细胞瘤(浆细胞的恶性肿瘤)。本发明所述的肿瘤,可包括,但不限于白血病(如急性白血病、急性淋巴细胞白血病、急性髓细胞性白血病,急性粒细胞白血病,急性早幼粒细胞白血病、急性粒-单核细胞白血病、急性单核细胞白血病、慢性白血病、慢性粒细胞白血病、慢性淋巴细胞白血病、真性红细胞增多症),淋巴瘤(霍奇金病、非霍奇金病)、原发性巨球蛋白血症,重链病,实体瘤如肉瘤和癌症(如纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、内皮肉瘤、淋巴管肉瘤、血管肉瘤、淋巴管内皮肉瘤,间皮瘤,尤文氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、癌、支气管癌、髓样癌、肾细胞癌、肝癌,尼罗河管癌,绒癌、精原细胞瘤、胚胎癌、肾母细胞瘤、宫颈癌、子宫癌、睾丸癌、肺癌、小细胞肺癌、膀胱癌、上皮癌、胶质瘤、星形细胞瘤、髓母细胞瘤,颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤,听神经瘤,少突胶质瘤、神经鞘瘤、脑膜瘤、黑色素瘤、神经母细胞瘤、视网膜母细胞瘤)、食管癌、胆囊癌、肾癌、多发性骨髓瘤。较佳地,所述的“肿瘤”包括但不限于:胰腺癌、肝癌、肺癌、胃癌、食管癌、头颈部鳞状细胞癌、前列腺癌、结肠癌、乳腺癌、淋巴瘤、胆囊癌、肾癌、白血病、多发性骨髓瘤、卵巢癌、宫颈癌和胶质瘤。
本文所用的术语“疾病”或“病症”或“紊乱”等是指任何损害或干扰细胞、组织或器官的正常功能的改变或失调。例如,所述的“疾病”包括但不限于:肿瘤、病原体感染、自身免疫性疾病、T细胞功能障碍性疾病、或免疫耐受能力缺陷(如移植排斥)。
本文所用的术语“治疗”是指在试图改变个人或处理细胞引起的的疾病过程中的临床干预,既可以进行预防也可以在临床病理过程干预。治疗效果包括但不限于,防止疾病的发生或复发、减轻症状、减少任何疾病直接或间接的病理后果、防止转移、减慢疾病的进展速度、改善或缓解病情、缓解或改善预后等。
实施例
通过以下实施例进一步详细说明本发明。在本发明的基础上改变制剂组成成分的浓度或加入其它一些物质,但对提高ZMR01单克隆抗体的蛋白稳定性没有显著作用的改变,仍被视为本发明的一部分。
分子排阻层析(SEC)
使用分子大小排阻层析来量化聚合体、单体和片段。这种测定利用WatersXbridge BEH SEC7.8×300mm柱并在Waters e2695-2489 HPLC系统上运行。流动相为100mM磷酸钠盐,150mM氯化钠,pH 6.8。用流动相稀释样品到1mg/mL,注射体积为25μL。以0.5mL/min的流速将蛋白质等度洗脱30min,于215nm检测洗脱物的吸光度。利用Empower 3软件进行积分处理。
毛细管电泳(CE-SDS)
通过非还原CE-SDS(nrCE)和还原CE-SDS(rCE)分别测定%主峰和%(LC+HC)纯度,将这一测定在BECKMAN COULTER PA800 plus毛细管电泳系统上以50μm I.D.非涂层石英毛细管进行,毛细管有效分离长度20cm,全长30.2cm分离,PDA220nm带宽10nm检测。
竞争ELISA测定结合活性
通过ELISA方法检测抗PD-1单抗与PD-L1竞争结合PD-1的能力。本品可竞争性的阻断PD-L1与PD-1的结合。因此采用竞争ELISA测定本品与PD-L1竞争结合PD-1抗原的能力。首先将人PD-L1包被在96孔板上,然后与梯度稀释的本品竞争结合Biotin-PD-1。本品浓度越高,则与人PD-L1结合的Biotin-PD-1越少。加入底物显色后读取吸光值,计算本品与人PD-L1竞争结合PD-1抗原的能力。试验数据采用SoftMax Pro或其他同类软件进行四参数拟合分析,并按下式自动分析结果:参考品(自制)浓度的对数值为X轴,吸光值为Y轴,软件将给出供试品和参考品的半数有效浓度(EC50),并绘制“S”形曲线。
生物学活性
通过报告基因法检测抗PD-1单抗的生物学活性。该报告基因法包含两种细胞:以CHO-PD-L1-CD3L细胞作为靶细胞,该细胞能稳定表达PD-L1和固定在细胞膜上的anti-CD3-单链抗体片段(scFv);以Jurkat-PD-1-NFAT细胞作为效应细胞,该细胞能稳定表达PD-1和荧光素酶(luciferase),荧光素酶基因受NFAT元件调控。CHO细胞膜上的anti-CD3-scFv与Jurkat细胞表面的CD3结合后,会向Jurkat细胞呈递激活信号,从而表达荧光素酶;CHO细胞表面的PD-L1在与Jurkat细胞表面的PD-1结合后向Jurkat细胞递送抑制信号,抑制荧光素酶的表达;而抗PD-1/抗PD-L1抗体可以阻断PD-1与PD-L1的结合,从而解除抑制信号的递送。因此,可以用该报告基因法测定不同种类的抗PD-1/抗PD-L1抗体的生物学活性。试验数据采用SoftMax Pro或其他同类软件进行四参数拟合分析,并按下式自动分析结果:参考品(自制)浓度的对数值为X轴,吸光值为Y轴,软件将给出供试品和参考品的半数有效浓度(EC50),并绘制“S”形曲线。
差示扫描量热仪(DSC)
通过检测热转变中点温度(Tm)能够直观地说明生物分子的稳定性,Tm值越高,生物分子就越稳定。通过测定可控的加热或者降温过程中蛋白质和其他生物分子吸收或放出的热量,从而对蛋白质的稳定性进行直接的、原位的表征。通过比对不同制剂处方的检测Tm值,得出哪个制剂处方中蛋白更加稳定。测定过程中会出现两个峰(两个Tm),分别代表抗体的不同结构域,主峰是代表抗体的Fab区域,另一个峰是抗体的CH2或者CH3。CH2和CH3是比较保守的,而Fab是可变区,其序列在不同抗体之间是不固定的,因此Fab区域的峰有可能会覆盖CH2或者CH3。另外在处方筛选时,为了保证抗体获得较稳定的制剂处方,筛选范围较宽,会出现一些条件使得抗体构型发生剧烈变化,相应的结构域解折叠,而没有出现相应的Tm值。
以下列举具体实施例来阐明本发明,应理解这些例子仅仅是为了说明本发明,而非限制本发明的范围。
实施例1 抗人PD-1的单克隆抗体ZMR01的筛选以及测序
根据PCT/US2017/060122中记载的筛选方法(参见该文献实施例2)获得抗人PD-1的单克隆抗体ZMR01,经氨基酸序列测定,ZMR01的重链可变区的3个CDR依次为:HCDR1,SEQID NO:1;HCDR2,SEQ ID NO:2;HCDR3,SEQ ID NO:3;轻链可变区的3个CDR依次为:LCDR1,SEQ ID NO:4;LCDR2,SEQ ID NO:5;LCDR3,SEQ ID NO:6。重链可变区为SEQ ID NO:7所示的序列,轻链可变区为SEQ ID NO:8所示的序列。重链为SEQ ID NO:9所示的序列,轻链为SEQID NO:10所示的序列。
实施例2 ZMR01对PD-1抗原的亲和力分析
Anti-human Fc antibody蛋白(GE Healthcare,货号BR-1008-39)用pH5.0醋酸钠溶液(GE Healthcare,货号BR-1003-51)稀释至25μg/mL,用氨基偶联(GE Healthcare,货号BR-1000-50)的方式固定化在CM5芯片(GE Healthcare,货号BR-1005-30)的2个通道(通道1、通道2)上,偶联水平约为8000RU。样品以2μg/mL浓度、30μL/min结合35秒捕获在通道2上,PD-1抗原(Sino Biological,货号10377-H02H)用运行缓冲液(GE Healthcare,货号BR-1006-69)稀释至100nM,之后用同样缓冲液做3倍系列稀释直至1.23nM。空白及各浓度(1.23nM、3.70nM、11.11nM、33.33nM、100nM、33.33nM)样品分别依次流过通道1和2,流速为30μL/min,结合时间3分钟,解离时间20分钟。数据经双重扣减后(即每一个循环中实验通道信号扣减掉对照通道信号,样品信号再扣减掉空白信号)用Biacore T200 EvaluationSoftware做动力学拟合,拟合模型用1∶1 binding模型。
ZMR01与PD-1抗原的亲和力实验分别在全部样品亲和力测定前后时间段进行了2次重复(ZMR01-1和ZMR01-2),亲和力KD分别为1.91nM、1.82nM(平均值1.87nM),2次重复结果亲和力基本一致,说明该实验方法重复性良好,取2次重复的平均值作为该样品与PD-1的最终亲和力,即ZMR01与PD-1抗原的亲和力为1.87nM。Nivolumab(Opdivo,Britol-MyersSquibb,批号AAL9430)与PD-1抗原的亲和力为8.06nM;结果表明,ZMR01对PD-1抗原的亲和力高于Nivolumab。具体数据见表1,传感图及拟合曲线参见图1和图2。
表1 ZMR01及Nivolumab与PD-1抗原亲和力测定动力学拟合分析结果
实施例3 ZMR01的生物学活性分析
取对数生长期的CHO-PD-L1-CD3L细胞(购自中国食品药品检定研究院),调整细胞密度为5×105个/mL,80μL/孔铺板,37℃,5%CO2培养箱中培养,孵育16±2小时;将ZMR01和Nivolumab(Britol-Myers Squibb,批号AAL9430)先用无菌水稀释至1mg/mL,再用测活培养基稀释至80μg/ml,自80μg/mL开始5倍比稀释7次,共8个梯度。调整Jurkat-PD-1-NFAT细胞(购自中国食品药品检定研究院)悬液密度为2×106个/mL;将细胞培养板取出,用多道排枪吸弃各孔上清液,尽量吸净,分别加入40μL/孔稀释好的ZMR01与Nivolumab,再加入40μL/孔的Jurkat-PD-1-NFAT细胞悬液,板中各梯度终浓度分别为40、8、1.6、0.32、0.064、0.0128、0.0026、0.0005μg/mL;37℃,5%CO2培养箱中培养,孵育6小时。作用终点,Luciferase(Promega,货号G7940)染色读板。实验数据采用SoftMax Pro软件进行四参数拟合分析,结果见图3。
表2 检测样品EC50值统计
综上所述,在所检测的ZMR01和Nivolumab生物学活性对比中,ZMR01生物学活性明显高于Nivolumab。
在初步认识了ZMR01的亲和力和生物学活性优于Nivolumab的基础上,接下来将对ZMR01的制剂处方进行研究,以探索出适合ZMR01稳定性存在同时还能保持其良好药物学功能的制剂。
实施例4
选择组氨酸-稀盐酸、组氨酸-醋酸、醋酸-醋酸钠、枸橼酸-枸橼酸钠缓冲剂,通过稳定性考察,筛选出稳定的缓冲体系:
表3 ZMR01抗体的制剂处方
我们对上述溶液进行了SEC、nrCE、rCE、结合活性、DSC分析。
表4 ZMR01抗体制剂的稳定性研究试验结果
注:N.D代表未检出,由于缓冲剂影响了抗体构型,未检测出相应Tm值
在试验中意外地发现枸橼酸-枸橼酸钠缓冲剂中的ZMR01抗体会发生沉淀,因此,此缓冲剂不适合ZMR01抗体。如表4所示的结果,还意外地发现,醋酸-醋酸钠缓冲剂会导致抗体构型的改变,不适用于ZMR01抗体。本次试验中意外地发现,在所测试的缓冲剂系统中,只有组氨酸-盐酸和组氨酸-醋酸缓冲剂对ZMR01抗体效果相近,暂时保留以上两个缓冲剂。
实施例5
ZMR01抗体分别在组氨酸-盐酸和组氨酸-醋酸溶液中分别添加聚山梨酯20、聚山梨酯80,对制剂处方进行稳定性考察,筛选出较为稳定的制剂处方,其成分如下表:
表5 ZMR01抗体的制剂处方
R1 | R2 | R3 | R4 | |
抗体 | 20mg/mL | 20mg/mL | 20mg/mL | 20mg/mL |
蔗糖 | 70mg/mL | 70mg/mL | 70mg/mL | 70mg/mL |
聚山梨酯20 | 0.2mg/mL | / | 0.2mg/mL | / |
聚山梨酯80 | / | 0.2mg/mL | / | 0.2mg/mL |
组氨酸盐酸 | 10mM | 10mM | / | / |
组氨酸醋酸 | / | / | 10mM | 10mM |
pH值 | 5.5 | 5.5 | 5.5 | 5.5 |
我们对上述制剂处方进行了SEC、nrCE、rCE、结合活性、DSC分析。试验结果如表6所示。
表6 ZMR01抗体制剂的稳定性研究试验结果
注:N/A代表未检测本项目
通过以上数据结果可以看出,组氨酸-醋酸的缓冲剂略优于组氨酸-盐酸缓冲剂,尽管差别不是非常明显。而且,组氨酸-盐酸盐的缓冲液对不锈钢制品有溶蚀作用,在制剂制造、流通和储存过程中抗体溶液存在与不锈钢容器相接触的机会。因此,优选地选择组氨酸-醋酸缓冲剂,这样不仅对抗体有保护作用,并且对储存容器也有防护效果。通过以上检测结果还意外地发现,聚山梨酯20相较于聚山梨酯80而言,对ZMR01抗体的稳定性更优。
实施例6
蔗糖作为稳定剂,浓度为70mg/mL,选择聚山梨酯20作为表面活性剂,浓度为0.2mg/mL;组氨酸-醋酸作为缓冲溶液,浓度为10mM。制剂处方如下:
表7 ZMR01抗体不同pH的制剂处方
我们对上述制剂处方进行了SEC、nrCE、rCE、结合活性、DSC分析。试验结果如表8所示。
表8 ZMR01抗体制剂稳定性研究试验结果
注:N.D代表未检出,由于pH变化影响了抗体构型,未检测出相应Tm值
N/A代表未检测本项目
参见表8,发明人意外地发现,ZMR01抗体制剂在pH4.5-6.0的范围是稳定的,最佳的pH范围是4.5-5.5。
实施例7
ZMR01抗体的浓度为25mg/mL,pH为5.2±0.3;其他制剂组成成分及含量如表9所示,同时测定制剂的渗透压。
表9 ZMR01抗体制剂处方
我们对上述制剂处方进行了SEC、nrCE、rCE、结合活性、DSC分析。试验结果如表10所示。
表10 ZMR01抗体制剂处方稳定性研究试验结果
注:N/A代表未检测本项目
通过表10的结果可以看出,ZMR01抗体在10个制剂处方中都是稳定的。另外,人体渗透压范围为280-320mOsmol/kg,而根据表9中渗透压检测的数值来看,R1、R2、R3制剂处方的渗透压略微偏小。因此,综合表9和表10的结果,最优选的制剂组成是:25mg/ml ZMR01抗体、90mg/ml蔗糖、10mM组氨酸-醋酸缓冲剂、0.2mg/ml聚山梨酯20、pH5.2。
实施例8
ZMR01抗体25mg/ml,配制在10mM组氨酸-醋酸缓冲剂、90mg/ml蔗糖、0.2mg/ml聚山梨酯20、pH 5.2中,将制剂分别加入到玻璃瓶、不锈钢和硅胶管中,室温放置24小时。检测SEC、nrCE、rCE、结合活性:
表11 ZMR01抗体不同容器的稳定性结果
样品名称 | 结合活性 | SEC(%) | nrCE(%) | rCE(%) |
玻璃瓶 | 106% | 99.8 | 98.6 | 97.8 |
不锈钢 | 108% | 99.8 | 98.8 | 98.0 |
硅胶管 | 105% | 99.8 | 99.0 | 98.3 |
通过表11数据可以看出,ZMR01抗体制剂在三种容器中都是稳定的。
实施例9
ZMR01抗体25mg/ml,配制在10mM组氨酸-醋酸缓冲剂、90mg/ml的蔗糖、0.2mg/ml的聚山梨酯20、pH5.2中,将制剂分别经过0.22μm的PVDF、PES滤器过滤,检测滤后样品的蛋白含量及聚山梨酯含量。
表12 不同滤器的过滤结果
注:N/A代表未检测本项目
经过以上数据可以看出稳定的ZMR01抗体制剂处方在PVDF、PES滤器过滤后蛋白浓度和聚山梨酯20浓度均没有明显变化。
实施例10
制剂组成:ZMR01抗体25mg/ml、90mg/ml蔗糖、10mM组氨酸-醋酸缓冲剂、0.2mg/ml聚山梨酯20。将该制剂以4ml/瓶灌装至7ml管制瓶中,加塞轧盖。将样品分别置于4500±500Lx强光照射、40±2℃高温、25℃,150rpm震荡5天、低高温(2-8℃和40℃分别放置两天为一个循环)循环3次和反复冻融(-20℃和25℃分别放置两天为一个循环)循环3次,检测SEC、rCE、nrCE、结合活性,结果如表13所示。此外,又进行了ZMR01抗体制剂25℃±2℃加速1个月(1M)、2个月(2M)、3个月(3M)、6个月(6M)以及2-8℃长期3个月(3M)、6个月(6M)、12个月(12M)稳定性考察,检测生物学活性、SEC、nrCE、rCE,结果如表14所示。
表13 ZMR01抗体制剂稳定性结果
注:N/A代表未检测本项目
表14 ZMR01抗体制剂加速及长期稳定性结果
结果证明ZMR01抗体制剂是比较稳定的、经强光、高温或者低温、冻融循环后仍能够符合要求。
在获得了ZMR01制剂组成的基础上,接下来的实施例将使用该制剂来研究单抗的药物学功能,这对于今后的临床应用将具有更强的指导性意义。
实施例11 ZMR01制剂对SEB刺激的人PBMC细胞功能的影响
抽取健康志愿者外周血,利用Ficoll-PaqueTM Plus试剂(GE Healthcare,货号17-1440-02)通过密度梯度离心法分离获得外周血单核细胞(PBMC),用RPMI1640完全培养基(RPMI1640+10%灭活胎牛血清FBS+非必须氨基酸(MEM NEAA,Gibco,货号11140-050)+丙酮酸钠(SP,Gibco,货号11360-070)+1×青霉素链霉素(Gibco,货号15070-063))调整PBMC细胞密度为1×105个/孔,接种96孔透明圆底板,每孔150μL。接种好细胞的96孔板对应孔中分别加入50μL的ZMR01或Nivolumab(Britol-Myers Squibb,批号AAS1144),使其终浓度分别为10、3.33、1.11、0.370、0.123、0.0412、0.0137、0.00457、0.00152μg/mL;然后再加入50μL的SEB,使其终浓度为0.05μg/mL;将96孔板置37℃,5%CO2培养箱中培养4天后,收集细胞上清液,利用Human IL-2 ELISA Ready-SET-Go!试剂盒(invitrogen,货号88-7025-88)检测细胞因子IL-2释放水平。以抗体浓度为横坐标,IL-2为纵坐标,采用GRAPHPAD PRISM软件作图,对ZMR01和Nivolumab进行t-test检验,结果参见图4。
实验结果表明,ZMR01制剂能够有效增强SEB活化的PBMC分泌细胞因子IL-2的能力,并且其效果显著强于Nivolumab(*p<0.05)。
实施例12 混合淋巴细胞反应(MLR)中ZMR01制剂对人T细胞功能的影响
混合淋巴细胞反应实验采用不同志愿者外周血单核细胞(PBMC)来源的树突状细胞(DC)及CD4+T细胞进行共培养。抽取志愿者甲的外周血,利用Ficoll-PaqueTM Plus试剂(GE Healthcare,货号17-1440-02),通过密度梯度离心法分离获得PBMC,后通过磁珠分选获得CD14+的单核细胞(Human Monocyte Isolation Kit,STEMCELL,货号19359)。在含10%胎牛血清、1%非必需氨基酸(Gibco,货号11140-050)、1%丙酮酸钠(Gibco,货号11360-070)的RPMI1640完全培养基,并加入细胞因子GM-CSF(100ng/mL,PEPROTECH,货号300-03-100UG)及IL-4(50ng/mL,PEPROTECH,货号200-04-100UG),37℃,5%CO2细胞培养箱中诱导培养6天(中间进行一次半数换液),从而诱导单核细胞分化成为未成熟树突状细胞(imDC)。imDC进一步在含10%胎牛血清、1%非必需氨基酸、1%丙酮酸钠的RPMI1640完全培养基中,通过加入细胞因子IL-1β(10ng/mL,PEPROTECH,货号200-01B-50UG)、TNF-α(10ng/mL,PEPROTECH,货号300-01A-50UG)、IL-6(10ng/mL,PEPROTECH,货号200-06-50UG)、PGE2(1μg/mL,Sigma,货号P6532-1MG),37℃、5%CO2细胞培养箱中诱导培养24小时或48小时,从而成为成熟树突状细胞(mDC)。
抽取志愿者乙的外周血,利用密度梯度离心法分离获得PBMC,后通过磁珠(EasySepTM Human CD4+T Cell Isolation Kit,STEMCELL,货号17952)分选获得CD4+的T淋巴细胞。将分离获得的T淋巴细胞(接种密度1×105个/孔)与诱导成熟的DC细胞(接种密度2×104个/孔)共同接种于96孔圆底培养板,并加入不同浓度梯度的PD-1单抗ZMR01、Nivolumab(Britol-Myers Squibb,批号AAS1144)或者阴性对照抗体hIgG4(SinoBiological,货号HG4K)。混合细胞培养体系于37℃、5%CO2细胞培养箱中培养5天后收集细胞培养上清液,利用Human IFN-γ ELISA Ready-SET-Go!试剂盒(invitrogen,货号88-7316-88)检测T细胞IFN-γ分泌水平。以加入抗体的浓度为横坐标,IFN-γ含量为纵坐标,采用GRAPHPAD PRISM软件做柱状图,结果见图5。使用四对不同的志愿者的外周血进行4次MLR实验,采用GRAPHPAD PRISM软件做图,进行paired t-test检验,结果见图6。
上述实验结果表明,ZMR01制剂能够有效增强混合淋巴细胞反应体系T细胞的分泌细胞因子IFN-γ功能;当抗体浓度在0.1μg/mL和10μg/mL时,ZMR01制剂增强T细胞分泌IFN-γ的能力优于BMS公司的Nivolumab单抗(*p<0.05)。
实施例13 ZMR01制剂在hPD-1转基因小鼠的MC38结肠癌动物模型中的药效实验
将MC38肿瘤细胞以5×105个/0.1mL浓度,0.1mL/只体积接种于雌性B-hPD-1人源化小鼠(百奥赛图江苏基因生物技术有限公司)的右侧胁肋部皮下,待肿瘤生长到100-150mm3时按肿瘤体积随机分组,每组10只,分别为对照hIgG4(北京义翘神州科技有限公司,批号MA09JL0905)组、Nivolumab组(3mg/kg,Bristol-Myers Squibb,批号AAS1144)、ZMR01(0.3mg/kg)、ZMR01(1.0mg/kg)和ZMR01(3.0mg/kg)组。每周腹腔注射给药2次,共给药6次,在末次给药后第2天结束实验。每周测量并记录肿瘤体积2次,其体积计算公式为:肿瘤体积=0.5×长径×短径2。实验结束时,动物安乐死,计算肿瘤生长抑制率(TGI%),经GRAPHPADPRISM作图对肿瘤体积进行t-test检验。
如图7所示,与hIgG4组相比,Nivolumab组(3mg/kg)、ZMR01(0.3mg/kg)、ZMR01(1mg/kg)和ZMR01(3mg/kg)组肿瘤生长抑制率分别为27.5%、60.9%(p<0.01)、67.4%(p<0.001)和76.6%(p<0.001),ZMR01(0.3mg/kg)、ZMR01(1mg/kg)和ZMR01(3mg/kg)与阴性对照hIgG4组的平均肿瘤体积有显著差异。这一结果表明ZMR01在0.3、1、3mg/kg剂量下对肿瘤生长均都具有显著的抑制作用;在该实验模型中ZMR01具有明显的剂量-效应关系,随给药剂量的增加,抑瘤活性增强,并且ZMR01的抑瘤效果优于BMS公司的Nivolumab单抗(p<0.001)。
实施例14 ZMR01制剂和抗人VEGF人源化抗体联合用药
将NOG小鼠(北京维通利华实验动物技术有限公司)按体重大小随机分组,每组8只,分别为A431细胞+0.9%NaCl注射液组、A431细胞+PBMC+hIgG4+hIgG1组(北京义翘神州科技有限公司,hIgG4批号MA09JL0905,hIgG1批号MB11MA1306)、A431细胞+PBMC+ZMR01(1mg/kg)组、A431细胞+PBMC+抗人VEGF人源化抗体(QL1101,齐鲁制药有限公司,0.5mg/kg)组、A431细胞+PBMC+ZMR01(1mg/kg)+抗人VEGF人源化抗体(0.5mg/kg)联合治疗组。阴性对照组接种A431细胞(6×106个/只,s.c.,购自ATCC),其它实验各组均接种A431细胞(6×106个/只,s.c.)和PBMC(4×106个/只,i.v.,购自Stemexpress,批号1702170123),接种当天记为第0天。第3天开始给药,每周2次,共给药7次,末次给药第2天为试验终点,以安乐法处死动物。每周测量并记录肿瘤体积2次,其体积计算公式为:肿瘤体积=0.5×长径×短径2(图8)。实验结束时,动物安乐死,计算肿瘤生长抑制率(TGI%),经GRAPHPAD PRISM作图对肿瘤体积进行t-test检验。
如图8所示,与hIgG4+hIgG1组相比,ZMR01(1mg/kg)、QL1101(0.5mg/kg)和ZMR01(1mg/kg)+QL1101(0.5mg/kg)组肿瘤生长抑制率分别为34.7%、15.9%和51.0%,并且ZMR01(1mg/kg)和ZMR01(1mg/kg)+抗人VEGF人源化抗体(0.5mg/kg)联合治疗组与hIgG4+hIgG1组的肿瘤体积有显著差异(p值分别<0.01和<0.001),而QL1101(0.5mg/kg)组与hIgG4+hIgG1组的肿瘤体积相比无明显差异(p>0.05)(图9)。这一结果表明ZMR01制剂和抗人VEGF人源化抗体联用治疗对肿瘤生长具有显著的抑制作用,并且联合治疗的效果优于单一的ZMR01组或单一的抗人VEGF人源化抗体组。
其中,所述QL1101抗体的重链序列如SEQ ID NO:11所示,所述QL1101抗体的轻链序列如SEQ ID NO:12所示。
序列表
<120> 一种抗人PD-1的单克隆抗体制剂、联合用药物及其用途
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<170> SIPOSequenceListing 1.0
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Asn Tyr Trp Ile His
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Glu Ile Asp Pro Tyr Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
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<212> PRT
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Pro Gly Phe Thr Tyr Gly Gly Met Asp Phe
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Lys Ser Ser Gln Ser Leu Phe Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 5
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Gly Ala Ser Thr Arg Asp Ser
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Gln Asn Asp His Tyr Tyr Pro Tyr Thr
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
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Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
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Gly Glu Ile Asp Pro Tyr Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe
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Lys Gly Arg Val Thr Met Thr Val Asp Lys Ser Thr Ser Thr Val Tyr
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Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Pro Gly Phe Thr Tyr Gly Gly Met Asp Phe Trp Gly Gln Gly
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Thr Leu Val Thr Val Ser Ser
115
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<213> 人工序列(Artificial Sequence)
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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 Ser Ser Gln Ser Leu Phe Asn Ser
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Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Val Pro Lys Leu Leu Ile Tyr Gly Ala Ser Thr Arg Asp Ser Gly Val
50 55 60
Pro Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn
85 90 95
Asp His Tyr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 9
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
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Gly Glu Ile Asp Pro Tyr Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe
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Lys Gly Arg Val Thr Met Thr Val Asp Lys Ser Thr Ser Thr Val Tyr
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Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Pro Gly Phe Thr Tyr Gly Gly Met Asp Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
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Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
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Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
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Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
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Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
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Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
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Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
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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 Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu 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 Leu Gly Lys
435 440 445
<210> 10
<211> 220
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
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 Ser Ser Gln Ser Leu Phe Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Val Pro Lys Leu Leu Ile Tyr Gly Ala Ser Thr Arg Asp Ser Gly Val
50 55 60
Pro Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Asn
85 90 95
Asp His Tyr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
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Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 11
<211> 453
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
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 Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe
50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
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Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Lys
450
<210> 12
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
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 Ser Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile
35 40 45
Tyr Phe Thr Ser Ser Leu His 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 Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp
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
Claims (26)
1.一种抗人PD-1的单克隆抗体的溶液制剂,其包含抗人PD-1的单克隆抗体或其抗原结合片段和缓冲剂;其中所述抗人PD-1的单克隆抗体或其抗原结合片段的重链可变区的3个CDR即HCDR1、HCDR2和HCDR3的氨基酸序列依次为:SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3;轻链可变区的3个CDR即LCDR1、LCDR2和LCDR3的氨基酸序列依次为:SEQ ID NO:4、SEQ IDNO:5和SEQ ID NO:6;所述缓冲剂选自组氨酸-盐酸或组氨酸-醋酸。
2.如权利要求1所述的溶液制剂,其中所述抗人PD-1的单克隆抗体或其抗原结合片段的重链可变区的氨基酸序列为SEQ ID NO:7,轻链可变区的氨基酸序列为SEQ ID NO:8。
3.如权利要求1或2所述的溶液制剂,其中所述抗人PD-1的单克隆抗体或其抗原结合片段的重链的氨基酸序列为SEQ ID NO:9,轻链的氨基酸序列为SEQ ID NO:10。
4.如权利要求1或2所述的溶液制剂,其pH为4.5-6.0。
5.如权利要求1或2所述的溶液制剂,其还包含稳定剂。
6.如权利要求5所述的溶液制剂,所述稳定剂选自蔗糖、甘露醇和海藻糖。
7.如权利要求1或2所述的溶液制剂,其还包含表面活性剂。
8.如权利要求7所述的溶液制剂,所述表面活性剂选自聚山梨酯20和聚山梨酯80。
9.如权利要求3所述的溶液制剂,其包含20-30mg/ml的抗人PD-1的单克隆抗体、70-90mg/ml的蔗糖、5-20mM的组氨酸-醋酸缓冲剂和0.1-0.5mg/ml的聚山梨酯20,溶液的pH为4.5-5.5。
10.如权利要求4所述的溶液制剂,其包含抗人PD-1的单克隆抗体和
(1)90mg/ml蔗糖,10mM组氨酸-醋酸缓冲液和0.2mg/ml的聚山梨酯20;或者
(2)90mg/ml蔗糖,15mM组氨酸-醋酸缓冲液和0.4mg/ml的聚山梨酯20;或者
(3)90mg/ml蔗糖,20mM组氨酸-醋酸缓冲液和0.1mg/ml的聚山梨酯20;或者
(4)80mg/ml蔗糖,10mM组氨酸-醋酸缓冲液和0.4mg/ml的聚山梨酯20;或者
(5)80mg/ml蔗糖,15mM组氨酸-醋酸缓冲液和0.2mg/ml的聚山梨酯20;或者
(6)80mg/ml蔗糖,20mM组氨酸-醋酸缓冲液和0.1mg/ml的聚山梨酯20;或者
(7)70mg/ml蔗糖,10mM组氨酸-醋酸缓冲液和0.1mg/ml的聚山梨酯20;或者
(8)70mg/ml蔗糖,15mM组氨酸-醋酸缓冲液和0.2mg/ml的聚山梨酯20;或者
(9)70mg/ml蔗糖,20mM组氨酸-醋酸缓冲液和0.4mg/ml的聚山梨酯20;或者
(10)60mg/ml蔗糖,10mM组氨酸-醋酸缓冲液,0.2mg/ml的聚山梨酯20和50mM的NaCl溶液;以及
所述制剂的pH范围为4.5-5.5。
11.一种冻干制剂,其由权利要求1至10任一项所述溶液制剂经冻干获得,或者所述冻干制剂经复溶以后获得权利要求1至10任一项所述溶液制剂。
12.如权利要求1-10任一项所述的抗人PD-1的单克隆抗体的溶液制剂的制备方法,其包括:
(1)配制pH 4.5-5.5的组氨酸-醋酸缓冲溶液;
(2)向制得的溶液中添加蔗糖和聚山梨酯20,使溶液中蔗糖浓度达到70-90mg/ml,聚山梨酯20的浓度达到0.1-0.5mg/ml;
(3)向制得的溶液中加入抗人PD-1的单克隆抗体,使其浓度达到20-30mg/ml。
13.一种联合用药物,其包含权利要求1-11任一项所述的制剂和至少一种额外的治疗剂。
14.如权利要求13所述的联合用药物,其中所述额外的治疗剂为针对下述靶点的抑制剂,所述靶点选自:A2AR,CTLA4,PD-L1,TIGIT,CCR4,CCR8,CSF1R1a,B7H3,B7H4,CD47,CD96,CD73,Claudin18.2,VEGF,VEGFR,EGFR,FGFR,Her2,IAP,LAG3,STING,TNF-α和VISTA。
15.如权利要求13所述的联合用药物,其中所述额外的治疗剂为针对下述靶点的激动剂,所述靶点选自:GITR,41BB,OX40,CD40和ICOS。
16.如权利要求13所述的联合用药物,其中所述额外的治疗剂选自IDO抑制剂、TDO抑制剂、IAP抑制剂和抗VEGF抗体。
17.如权利要求16所述的联合用药物,其中所述抗VEGF抗体是贝伐单抗。
18.一种药盒,其包含权利要求1-11任一项所述的制剂或权利要求13-17任一项所述的联合用药物。
19.如权利要求18所述的药盒,其还包含额外的治疗剂。
20.如权利要求19所述的药盒,其中所述额外的治疗剂为针对下述靶点的抑制剂,所述靶点选自:A2AR,CTLA4,PD-L1,TIGIT,CCR4,CCR8,CSF1R1a,B7H3,B7H4,CD47,CD96,CD73,Claudin18.2,VEGF,VEGFR,EGFR,FGFR,Her2,IAP,LAG3,STING,TNF-α和VISTA。
21.如权利要求19所述的药盒,其中所述额外的治疗剂为针对下述靶点的激动剂,所述靶点选自:GITR,41BB,OX40,CD40和ICOS。
22.如权利要求19所述的药盒,其中所述额外的治疗剂选自IDO抑制剂、TDO抑制剂、IAP抑制剂和抗VEGF抗体。
23.如权利要求22所述的药盒,其中所述抗VEGF抗体是贝伐单抗。
24.如权利要求1-11任一项所述的制剂、权利要求13-17任一项所述的联合用药物或权利要求18-23任一项所述的药盒在制备用于预防或治疗PD-1介导的疾病或者表达PD-L1的肿瘤的药物中的用途。
25.如权利要求24所述的用途,其中所述肿瘤选自肺癌、胃癌、黑色素瘤、肾癌、乳腺癌、肠癌、肝癌、卵巢癌、宫颈癌、膀胱癌、食道癌、胰腺癌和头颈肿瘤。
26.如权利要求24或25所述的用途,其中所述肿瘤选自非小细胞肺癌、黑色素瘤和肾癌。
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