CN110404066B - 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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- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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
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。
程序性死亡分子1(programmed death-1,PD-1)是1992年发现的表达在T细胞表面的蛋白受体，参与到细胞的凋亡过程之中。PD-1属于CD28家族，与细胞毒性T淋巴细胞抗原4(cytotoxic T Lymphocyte antigen 4,CTLA-4)具有23％的氨基酸同源性，但其表达却与CTLA-4不同，主要表达在活化的T细胞、B细胞和髓细胞上。PD-1有两个配体，分别为PD-L1和PD-L2。新的研究发现乳腺癌、肺癌、胃癌、肠癌、肾癌、黑色素瘤等人类肿瘤组织中检测到高PD-L1蛋白的表达，且PD-L1的表达水平和患者的临床及预后紧密相关。由于PD-L1起着第二信号通路抑制T细胞增殖的作用，所以阻断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的单克隆抗体能够特异性与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，例如放疗或化疗或除PD-1以外的其他免疫检查点(如CTLA-4等)的抑制剂。
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单抗能够适于临床应用，有必要针对特定的单抗进行制剂的开发研究。同时，还需要根据特定的PD-1单抗制剂研究其与其他治疗剂组合进行联合用药的技术效果。
发明内容
为了追求更佳的临床效果，发明人经过杂交瘤技术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的摸索和研究，发现组氨酸-醋酸缓冲剂对阻止单抗ZMR01聚集、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，单抗ZMR01的等电点高，经过研究发现较为稳定的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。
发明详述
本发明的目的在于提供一种稳定的适用于单抗ZMR01的溶液制剂及其用途。
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的重链可变区和SEQ ID NO:8的轻链可变区氨基酸序列：
SEQ ID NO：7
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIHWVRQAPGQGLEWMGEIDPYDSYTNYNQKFKGRVTMTVDKSTSTVYMELSSLRSEDTAVYYCARPGFTYGGMDFWGQGTLVTVSS
SEQ ID NO：8
DIQMTQSPSSLSASVGDRVTITCKSSQSLFNSGNQKNYLAWYQQKPGKVPKLLIYGASTRDSGVPYRFSGSGSGTDFTLTISSLQPEDVATYYCQNDHYYPYTFGGGTKVEIK
再进一步优选的单抗ZMR01具有SEQ ID NO:9的重链和SEQ ID NO:10的轻链氨基酸序列：
SEQ ID NO：9
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIHWVRQAPGQGLEWMGEIDPYDSYTNYNQKFKGRVTMTVDKSTSTVYMELSSLRSEDTAVYYCARPGFTYGGMDFWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSV MHEALHNHYTQKSLSLSLGK
SEQ ID NO：10
DIQMTQSPSSLSASVGDRVTITCKSSQSLFNSGNQKNYLAWYQQKPGKVPKLLIYGASTRDSGVPYRFSGSGSGTDFTLTISSLQPEDVATYYCQNDHYYPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
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pH5.2。
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、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、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、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。
本发明所述稳定的ZMR01单克隆抗体的溶液制剂的制备方法，特征在于，步骤如下：
(1)配制pH4.5-5.5的组氨酸-醋酸缓冲溶液；
(2)先后向步骤(1)制得的缓冲液中添加蔗糖、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)向步骤(2)制得的溶液中加入单抗ZMR01的溶液，使其浓度达到20-30mg/ml，即得到稳定的ZMR01单克隆抗体的溶液制剂。
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为针对下述靶点的抑制剂，包括：CTLA4，PD-L1，TIGIT，CCR4，CCR8，CSFR1a，B7H3，B7H4，CD96，CD73。
本发明所述联合用药物中额外的治疗剂为针对下述靶点的激动剂，包括：GITR，41BB，OX40，CD40。
本发明所述联合用药物中额外的治疗剂为IDO抑制剂。
本发明所述联合用药物中额外的治疗剂为抗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为针对下述靶点的抑制剂，包括：CTLA4，PD-L1，TIGIT，CCR4，CCR8，CSFR1a，B7H3，B7H4，CD96，CD73。
本发明所述药盒中额外的治疗剂为针对下述靶点的激动剂，包括：GITR，41BB，OX40，CD40。
本发明所述药盒中额外的治疗剂为IDO抑制剂。
本发明所述药盒中额外的治疗剂为抗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或治疗PD-1介导的疾病或者表达PD-L1的癌症中的用途。
所述癌症为肺癌、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。
一种治疗方法，其用于预防或治疗PD-1介导的疾病或病症，所述的疾病优选为癌症；更优选为表达PD-L1的癌症；所述的癌症优选为肺癌、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：
方面1、一种抗人PD-1的单克隆抗体的溶液制剂，其特征在于，包含抗人PD-1的单克隆抗体或其抗原结合片段和缓冲剂，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依次为：HCDR1，SEQ ID 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；所述缓冲剂选自组氨酸-盐酸、醋酸-醋酸钠或组氨酸-醋酸。
方面2、如方面1所述的溶液制剂，其特征在于，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。
方面3、如方面1或2所述的溶液制剂，其特征在于，所述抗人PD-1的单克隆抗体的重链为SEQ ID NO:9所示的序列，轻链为SEQ ID NO:10所示的序列。
方面4、如方面1-3任一所述的溶液制剂，其特征在于，所述的缓冲剂优选为组氨酸-醋酸缓冲剂。
方面5、如方面1-4任一所述的溶液制剂，其特征在于，制剂中还包含稳定剂。
方面6、如方面1-5任一所述的溶液制剂，其特征在于，制剂中还包含稳定剂，所述稳定剂为蔗糖或甘露醇或海藻糖，优选稳定剂为蔗糖。
方面7、如方面1-6任一所述的溶液制剂，其特征在于，制剂中还包含表面活性剂。
方面8、如方面1-7任一所述的溶液制剂，其特征在于，制剂中还包含表面活性剂，所述表面活性剂为聚山梨酯20或聚山梨酯80，优选聚山梨酯20。
方面9、如方面1-8任一所述的溶液制剂，其特征在于，所述溶液制剂的pH为4.5-6.0，优选为4.5-5.5。
方面10、如方面1-9任一所述的溶液制剂，其特征在于，所述制剂包含蔗糖、组氨酸-醋酸缓冲剂、聚山梨酯20中的任意两种或三种。
方面11、如方面1-10任一所述的溶液制剂，其特征在于，所述制剂包含20-30mg/ml的抗人PD-1的单克隆抗体。
方面12、如方面1-11任一所述的溶液制剂，其特征在于，所述制剂包含70-90mg/ml的蔗糖。
方面13、如方面1-12任一所述的溶液制剂，其特征在于，所述制剂包含5-20mM的组氨酸-醋酸缓冲剂。
方面14、如方面1-13任一所述的溶液制剂，其特征在于，所述制剂包含0.1-0.5mg/ml的聚山梨酯20。
方面15、如方面1-14任一所述的溶液制剂，其特征在于，所述制剂包含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。
方面16、如方面1-15所述的溶液制剂，其特征在于，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；
上述制剂的pH范围均为4.5-5.5。
方面17、如方面16所述的溶液制剂，其特征在于，所述抗人PD-1的单克隆抗体的浓度是20-30mg/ml。
方面18、如方面1-17任一所述的抗人PD-1的单克隆抗体的溶液制剂的制备方法，其特征在于，步骤如下：
(1)配制pH4.5-5.5的组氨酸-醋酸缓冲溶液；
(2)依次向步骤(1)制得的缓冲液中添加蔗糖、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)向步骤(2)制得的溶液中加入抗人PD-1的单克隆抗体的溶液，使其浓度达到20-30mg/ml，即得到稳定的抗人PD-1的单克隆抗体的溶液。
方面19、一种联合用药物，其特征在于，包含方面1-17任一所述的溶液制剂和至少一种额外的治疗剂。
方面20、如方面19所述的联合用药物，其特征在于，所述额外的治疗剂为针对下述靶点的抑制剂，包括：CTLA4，PD-L1，TIGIT，CCR4，CCR8，CSFR1a，B7H3，B7H4，CD96，CD73。
方面21、如方面19所述的联合用药物，其特征在于，所述额外的治疗剂为针对下述靶点的激动剂，包括：GITR，41BB，OX40，CD40。
方面22、如方面19所述的联合用药物，其特征在于，所述额外的治疗剂为IDO抑制剂或抗VEGF抗体，所述抗VEGF抗体优选贝伐单抗。
方面23、一种药盒，其特征在于，包含方面1-17任一所述的溶液制剂或方面19-22任一所述的联合用药物。
方面24、如方面23所述的药盒，其特征在于，还包含额外的治疗剂。
方面25、如方面24所述的药盒，其特征在于，所述额外的治疗剂为针对下述靶点的抑制剂，包括：CTLA4，PD-L1，TIGIT，CCR4，CCR8，CSFR1a，B7H3，B7H4，CD96，CD73。
方面26、如方面24所述的药盒，其特征在于，所述额外的治疗剂为针对下述靶点的激动剂，包括：GITR，41BB，OX40，CD40。
方面27、如方面24所述的药盒，其特征在于，所述额外的治疗剂为IDO抑制剂或抗VEGF抗体，所述抗VEGF抗体优选贝伐单抗。
方面28、如方面1-17任一所述的抗人PD-1的单克隆抗体的溶液制剂或方面19-22任一所述的联合用药物或方面23-27任一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的癌症中的用途。
方面29、如方面28所述的用途，其特征在于，所述癌症为肺癌、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。
附图说明
图1ZMR01与PD-1抗原的亲和力测定结合解离图谱
图2Nivolumab与PD-1抗原的亲和力测定结合解离图谱
图3ZMR01和Nivolumab的生物学活性
图4ZMR01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6ZMR01制剂对IFN-γ释放的影响
图7MC38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
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 SEC
，7.8×300mm柱并在Waters e2695-2489HPLC系统上运行。流动相为100mM磷酸钠盐，150mM氯化钠，pH6.8。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Empower3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 PA800plus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。理论上，当抗PD-1单抗、Biotin-PD-1、PD-L1三者同时存在时，Biotin-PD-1优先与抗PD-1单抗结合，剩余的Biotin-PD-1才会与板底的PD-L1结合。通过检测未与抗PD-1单抗结合的剩余Biotin-PD-1的量，从而计算出抗PD-1单抗与PD-L1竞争结合PD-1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。在Jurkat细胞和CHO细胞中稳定表达PD-1和PD-L1，模拟肿瘤细胞的免疫逃避状态。抗PD-1单抗通过抗CD3的激活，逆转了PD-L1/PD-1相互作用对T细胞活化的抑制，展示了抗PD-1单抗在人体内的作用机制。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，SEQ ID NO:1；HCDR2，SEQ IDNO:2；HCDR3，SEQ ID NO:3；轻链可变区的3个CDR依次为：LCDR1，SEQ ID NO:4；LCDR2，SEQID 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SEQID NO:8所示的序列。重链为SEQ ID NO:9所示的序列，轻链为SEQ ID NO:10所示的序列。
实施例2ZMR01对PD-1抗原的亲和力分析
Anti-human Fc antibody蛋白用pH5.0醋酸钠溶液稀释至25μg/mL，用氨基偶联的方式固定化在CM5芯片的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抗原用运行缓冲液稀释至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 T200Evaluation Software做动力学拟合，拟合模型用1：1binding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)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1ZMR01及Nivolumab与PD-1抗原亲和力测定动力学拟合分析结果
实施例3ZMR01的生物学活性分析
取对数生长期的CHO-PD-L1-CD3L细胞，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4ZMR01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，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。本次试验中发现组氨酸-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6ZMR01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，但差别不是非常明显。但是，考虑到组氨酸-盐酸盐的缓冲液对不锈钢制品有溶蚀作用，因此，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。通过以上检测结果也可以看出聚山梨酯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
通过表8的结果显示，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、pH5.2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℃加速1个月(1M)、2个月(2M)、3个月(3M)以及长期3个月稳定性考察，结果如表14所示。
表13ZMR01抗体制剂稳定性结果
| 样品名称 | 结合活性 | SEC(％) | nrCE(％) | rCE(％) |
| 震荡5天 | 97％ | 99.7 | 98.4 | 98.1 |
| 光照5天 | N/A | 99.4 | 98 | 98.3 |
| 高温5天 | N/A | 99.7 | 98.2 | 98.2 |
| 光照10天 | 103％ | 99.1 | 97.9 | 98.2 |
| 高温10天 | 108％ | 99.6 | 98.4 | 97.9 |
| 冻融循环1次 | N/A | 99.7 | 98.6 | 98 |
| 冻融循环2次 | N/A | 99.7 | 98.4 | 98.1 |
| 冻融循环3次 | 113％ | 99.7 | 98.6 | 98.2 |
| 低高温循环1次 | N/A | 99.6 | 98.8 | 98.1 |
| 低高温循环2次 | N/A | 99.6 | 98.2 | 98.1 |
| 低高温循环3次 | 113％ | 99.7 | 98.5 | 98.3 |
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)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)+丙酮酸钠(SP)+1×青霉素链霉素)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，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-2ELISA Ready-SET-Go！试剂盒(invitrogen)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)，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。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，并加入细胞因子GM-CSF(100ng/mL，PEPROTECH)及IL-4(50ng/mL，PEPROTECH)，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)、TNF-α(10ng/mL，PEPROTECH)、IL-6(10ng/mL，PEPROTECH)、PGE2(1μg/mL，Sigma)，37℃、5％CO2细胞培养箱中诱导培养24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，后通过磁珠分选获得CD4+的T淋巴细胞(STEMCELL)。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或者阴性对照抗体hIgG4。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)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组、Nivolumab组(3mg/kg)、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GRAPHPAD PRISM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(1.0mg/kg)和ZMR01(3.0mg/kg)组肿瘤生长抑制率分别为27.5％、60.9％(p<0.02)、67.4％(p<0.02)和76.6％(p<0.001)，ZMR01(0.3mg/kg)、ZMR01(1.0mg/kg)和ZMR01(3.0mg/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、1.0、3.0mg/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<0.02)。
实施例14 ZMR01制剂和抗人VEGF人源化抗体联合用药
将NOG小鼠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、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.)，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.)，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(1.0mg/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抗体的重链序列为：
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
所述QL1101抗体的轻链序列为：
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
序列表
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Claims (10)
1.一种抗人PD-1的单克隆抗体的溶液制剂，其特征在于，所述制剂包含：抗人PD-1的单克隆抗体或其抗原结合片段、缓冲剂、稳定剂和表面活性剂，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依次为：HCDR1，SEQ ID 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；所述缓冲剂选自组氨酸-盐酸或组氨酸-醋酸；所述溶液制剂的pH为4.5-6.0。
2.如权利要求1所述的溶液制剂，其特征在于，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。
3.如权利要求1或2所述的溶液制剂，其特征在于，所述抗人PD-1的单克隆抗体或其抗原结合片段的重链为SEQ ID NO:9所示的序列，轻链为SEQ ID NO:10所示的序列。
4.如权利要求1或2所述的溶液制剂，其特征在于，所述的缓冲剂为组氨酸-醋酸缓冲剂。
5.如权利要求1或2所述的溶液制剂，其特征在于，所述稳定剂为蔗糖或甘露醇或海藻糖。
6.如权利要求5所述的溶液制剂，其特征在于，所述稳定剂为蔗糖。
7.如权利要求1或2所述的溶液制剂，其特征在于，所述表面活性剂为聚山梨酯20或聚山梨酯80。
8.如权利要求7所述的溶液制剂，其特征在于，所述表面活性剂为聚山梨酯20。
9.如权利要求1或2所述的溶液制剂，其特征在于，所述制剂包含抗人PD-1的单克隆抗体、蔗糖、组氨酸-醋酸缓冲剂、聚山梨酯20，溶液的pH为4.5-6.0。
10.如权利要求9所述的溶液制剂，其特征在于，所述制剂包含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。
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| CN113797330A (zh) * | 2020-06-11 | 2021-12-17 | 三生国健药业（上海）股份有限公司 | 一种抗pd-1单克隆抗体液体制剂 |
| BR112022025721A2 (pt) * | 2020-06-19 | 2023-01-03 | Sinocelltech Ltd | Formulação estável para anticorpo monoclonal anti-pd-1 recombinante |
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| WO2022063193A1 (zh) * | 2020-09-24 | 2022-03-31 | 上海齐鲁制药研究中心有限公司 | 同时靶向PD-L1和TGFβ的双功能分子及其医药用途 |
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| CN117337304A (zh) * | 2021-02-18 | 2024-01-02 | 齐鲁普吉湾生物治疗公司 | 抗pd1抗体和抗ctla4抗体的联合 |
| CN113925963B (zh) * | 2021-10-15 | 2023-08-11 | 江苏太平洋美诺克生物药业股份有限公司 | 一种稳定的包含抗cd147单克隆抗体的药物制剂 |
| WO2023160517A1 (zh) * | 2022-02-22 | 2023-08-31 | 齐鲁制药有限公司 | 包含抗ctla4和抗pd1的混合抗体的药物组合物及其治疗用途 |
| CN116688115B (zh) * | 2022-03-18 | 2024-02-06 | 上海齐鲁制药研究中心有限公司 | 一种PD-L1/TGF-β双功能融合蛋白制剂及其用途 |
| CN114984207B (zh) * | 2022-05-09 | 2024-01-26 | 浙江特瑞思药业股份有限公司 | 一种抗pd-1纳米抗体制剂 |
| WO2024002074A1 (zh) * | 2022-06-28 | 2024-01-04 | 齐鲁制药有限公司 | 包含抗ctla4和抗pd1的混合抗体的药物组合物及其治疗用途 |
| WO2024002226A1 (zh) * | 2022-06-30 | 2024-01-04 | 齐鲁制药有限公司 | 包含抗ctla4和抗pd1的混合抗体的药物组合物及其治疗用途 |
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| WO2015112800A1 (en) * | 2014-01-23 | 2015-07-30 | Regeneron Pharmaceuticals, Inc. | Human antibodies to pd-1 |
| CN105622753A (zh) * | 2014-11-04 | 2016-06-01 | 博生吉医药科技(苏州)有限公司 | 一种pd-1单克隆抗体及其应用 |
| TW201711699A (zh) * | 2015-09-28 | 2017-04-01 | 江蘇恆瑞醫藥股份有限公司 | 一種抗ｐｄ－１抗體製劑及其在醫藥上的應用 |
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