CN115154598A - 一种抗pd-1/vegf双特异性抗体液体制剂 - Google Patents
一种抗pd-1/vegf双特异性抗体液体制剂 Download PDFInfo
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Abstract
本发明涉及生物制药技术领域，具体涉及一种抗PD‑1/VEGF双特异性抗体液体制剂。本发明的抗PD‑1/VEGF双特异性抗体液体制剂包含抗PD‑1/VEGF四价双特异性抗体、缓冲液、表面活性剂及蛋白保护剂。该液体制剂可在2‑8℃至少保存24个月，25℃至少保存6个月，具有优异的长期稳定性，具备广泛的临床应用前景。
Description
技术领域
本发明涉及生物制药技术领域，具体地，涉及一种抗PD-1/VEGF双特异性抗体液体制剂。
背景技术
PD-1(programmed cell death protein 1，程序性死亡受体1)是一种重要的免疫抑制分子，属于免疫球蛋白超家族，是一个长度为268个氨基酸残基的膜蛋白。以PD-1为靶点的免疫调节对抗肿瘤、抗感染、抗自身免疫性疾病及器官移植存活等均有重要的意义。
VEGF(vascular endothelial growth factor，血管内皮生长因子)是肿瘤血管新生过程中起调控作用的重要细胞因子，可促进血管内皮细胞增殖，对肿瘤生存、生长和转移起重要作用。VEGF抑制剂可以抑制肿瘤新生血管的形成，从而抑制肿瘤的生长。
抗PD-1/VEGF双特异性抗体的一级结构较单克隆抗体的一级结构复杂，稳定性较差，更容易产生聚集体和不溶性微粒，因此需要良好的制剂配方来保护。
发明内容
为了解决上述问题，本发明的目的在于提供了一种稳定的抗PD-1/VEGF双特异性抗体液体制剂。本发明的目的还在于提供所述的液体制剂在制备治疗癌症、炎性疾病和自身免疫性疾病的药物中的用途。
为了实现上述发明目的，本发明采用以下技术方案：
本发明的第一个方面提供了一种抗PD-1/VEGF双特异性抗体液体制剂，所述液体制剂包含：
a)10-40mg/ml的抗PD-1/VEGF四价双特异性抗体；
b)20-30mM的缓冲液；
c)0.3-0.5mg/ml的表面活性剂；
d)80-90mg/ml的蛋白保护剂；
所述液体制剂的pH为4.7-6.0；
其中，所述抗PD-1/VEGF四价双特异性抗体包含两条重链和四条共同轻链；其中，所述重链从N末端到C末端包含VH-B-CH1-肽接头-VH-A-CH1-CH2-CH3，所述VH-A为结合VEGF的重链可变区，VH-B为结合PD-1的重链可变区，所述CH1为重链恒定区的第一结构域，所述CH2为重链恒定区的第二结构域，所述CH3为重链恒定区的第三结构域；其中，所述共同轻链从N末端到C末端包含VL-CL，其中，所述VL为轻链可变区，所述CL为轻链恒定区；所述重链的VH-A-CH1和所述VH-B-CH1分别与所述共同轻链的VL-CL配对，所述VH-A和所述VL形成VEGF结合位点，所述VH-B与所述VL形成PD-1结合位点。
在一个优选的实施方案中，所述抗PD-1/VEGF四价双特异性抗体浓度为10-20mg/ml。
在一个优选的实施方案中，所述缓冲液选自由组氨酸缓冲液、醋酸盐缓冲液、磷酸盐缓冲液组成的组中的一种或多种；更优选的，所述组氨酸缓冲液为组氨酸-盐酸组氨酸缓冲液，所述醋酸盐缓冲液为醋酸-醋酸钠缓冲液，所述磷酸盐缓冲液为磷酸二氢钠-磷酸氢二钠缓冲液；进一步更优选的，所述缓冲液为组氨酸-盐酸组氨酸缓冲液。
在一个优选的实施方案中，所述表面活性剂选自由聚山梨酯80、聚山梨酯20、泊洛沙姆188组成的组中的一种或多种；更优选的，所述表面活性剂为聚山梨酯80。
在一个优选的实施方案中，所述蛋白保护剂选自由海藻糖、蔗糖、甘露醇、山梨醇、氯化钠、葡萄糖、果糖、盐酸精氨酸组成的组中的一种或多种；更优选的，所述蛋白保护剂为海藻糖。
在一个优选的实施方案中，所述液体制剂进一步还包含甲硫氨酸；更优选的，所述甲硫氨酸的浓度为10mM。
在一个优选的实施方案中，所述液体制剂的pH为5.0-5.6。
在一个优选的实施方案中，所述液体制剂包含：
a)10-20mg/ml的抗PD-1/VEGF四价双特异性抗体；
b)20-30mM的组氨酸-盐酸组氨酸缓冲液；
c)0.3-0.5mg/ml的聚山梨酯80；
d)80-90mg/ml的海藻糖；
任选地，还包含10mM的甲硫氨酸；
所述液体制剂的pH为5.0-5.6。
在一个优选的实施方案中，所述抗PD-1/VEGF四价双特异性抗体中结合PD-1的重链可变区氨基酸序列如SEQ ID NO：3所示，结合VEGF的重链可变区氨基酸序列如SEQ IDNO：4所示，共同轻链的轻链可变区的氨基酸序列如SEQ ID NO：5所示。
在一个优选的实施方案中，所述抗PD-1/VEGF四价双特异性抗体重链中靠近N末端的CH1结构域和CH1-CH2-CH3来自重链恒定区IgG1、IgG2、IgG3或IgG4，所述靠近N末端的CH1结构域和CH1-CH2-CH3中的CH1可以相同或不同；优选的，所述抗PD-1/VEGF四价双特异性抗体共同轻链中CL为κ轻链恒定区或λ轻链恒定区。
在一个优选的实施方案中，所述抗PD-1/VEGF四价双特异性抗体中肽接头氨基酸序列如SEQ ID NO：6所示。
在一个优选的实施方案中，所述抗PD-1/VEGF四价双特异性抗体重链氨基酸序列如SEQ ID NO：1所示，共同轻链氨基酸序列如SEQ ID NO：2所示。
在一个优选的实施方案中，所述液体制剂为注射剂。
本发明的第二个方面提供了上述的抗PD-1/VEGF双特异性抗体液体制剂在制备治疗癌症、炎性疾病和自身免疫性疾病的药物中的用途。
在一个优选的实施方案中，所述癌症包括但不限于：黑素瘤(例如，转移性恶性黑素瘤)、肾癌(例如，肾透明细胞癌)、前列腺癌(例如，激素难治性前列腺腺癌)、胰腺癌、乳腺癌、结肠癌、肺癌(例如，非小细胞肺癌)、食道癌、头颈鳞状细胞癌、肝癌、卵巢癌、宫颈癌、甲状腺癌、成胶质细胞瘤、神经胶质瘤、白血病、淋巴瘤及其它恶性赘生性疾病。
在一个优选的实施方案中，所述炎性疾病和自身免疫性疾病包括但不限于：眼科疾病、纤维化疾病、哮喘、类风湿性关节炎、系统性红斑狼疮、多发性硬化症、银屑病、特应性皮炎等。
本发明的有益效果在于：本发明的抗PD-1/VEGF双特异性抗体液体制剂可保护抗PD-1/VEGF双特异性抗体，起到了稳定结构相对复杂的双特异性抗体的作用。目的蛋白抗PD1/VEGF双特异性抗体在2-8℃至少保存24个月，25℃至少保存6个月，具有优异的长期稳定性，具备广泛的临床应用前景。
附图说明
图1为本发明的抗PD-1/VEGF四价双特异性抗体的结构示意图。
图2为不同抗体蛋白浓度考察结果分析。
图3为不同缓冲体系考察结果分析。
图4为不同pH考察结果分析。
图5为DOE考察pH、聚山梨酯80结果分析。
图6为不同缓冲液、蛋白保护剂浓度考察结果分析。
具体实施方式
本发明的抗PD-1/VEGF四价双特异性抗体的结构示意图如图1所示。具体地，本发明的抗PD-1/VEGF四价双特异性抗体包含两条重链和四条共同轻链。其中，所述重链从N末端到C末端包含VH-B-CH1-肽接头-VH-A-CH1-CH2-CH3，其中，所述VH-A为结合VEGF的重链可变区，VH-B为结合PD-1的重链可变区，所述CH1为重链恒定区的第一结构域，所述CH2为重链恒定区的第二结构域，所述CH3为重链恒定区的第三结构域。其中，所述共同轻链从N末端到C末端包含VL-CL，其中，所述VL为轻链可变区，所述CL为轻链恒定区，所述重链的VH-A-CH1和所述VH-B-CH1分别与所述共同轻链的VL-CL配对，所述VH-A和所述VL形成VEGF结合位点，所述VH-B与所述VL形成PD-1结合位点。
以下实施例中使用的抗PD-1/VEGF四价双特异性抗体来源于中国专利申请CN202010357134.4中的抗PD-1/VEGF双特异性抗体20-Fab-0313-IgG4-V94L，并按照专利申请CN202010357134.4中的方法制备。具体地，其重链20-Fab-0313-IgG4的氨基酸序列如SEQID NO：1所示，其轻链601-LC-V94L氨基酸序列如SEQ ID NO：2所示。将上述序列构建到pcDNA4表达载体中，将20-Fab-0313-IgG4与601-LC-V94L表达载体组合，表达纯化抗体，所得的抗体命名为20-Fab-0313-IgG4-V94L。其中，其结合PD-1的重链可变区氨基酸序列如SEQ ID NO：3所示，其结合VEGF的重链可变区氨基酸序列如SEQ ID NO：4所示，其共同轻链的轻链可变区氨基酸序列均如SEQ ID NO：5所示，其肽接头氨基酸序列如SEQ ID NO：6所示。
SEQ ID NO：1(681个氨基酸)：
EVQLVESGGGLVQPGGSLRLSCAASGFVFSNYDMSWVRQAPGKRLEWVATISGGGGYTYYSDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCASPYGHYGFEYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO：2(214个氨基酸)：
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO：3(118个氨基酸)：
EVQLVESGGGLVQPGGSLRLSCAASGFVFSNYDMSWVRQAPGKRLEWVATISGGGGYTYYSDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCASPYGHYGFEYWGQGTLVTVSS
SEQ ID NO：4(123个氨基酸)：
EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSS
SEQ ID NO：5(107个氨基酸)：
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTLPWTFGQGTKVEIK
SEQ ID NO：6(15个氨基酸)：
GGGGSGGGGSGGGGS
本发明中，术语“双特异性抗体(双抗)”是指能同时特异性结合两种不同抗原(靶点)或两种不同表位的抗体分子。
本发明中，术语“特异性结合”或“结合”是指两分子间的非随机的结合反应，如抗体和其所针对的抗原之间的反应。通常，抗体以小于大约10-7M，例如小于大约10-8M、10-9M、10-10M、10-11M或更小的平衡解离常数(KD)结合该抗原。本发明中，术语“KD”是指特定抗体-抗原相互作用的平衡解离常数，其用于描述抗体与抗原之间的结合亲和力。平衡解离常数越小，抗体-抗原结合越紧密，抗体与抗原之间的亲和力越高。例如，使用表面等离子体共振术(Surface Plasmon Resonance，SPR)在BIACORE仪中测定抗体与抗原的结合亲和力或使用ELISA测定抗体与抗原结合的相对亲和力。
本发明中，术语“价”是指抗体分子中存在指定数量的抗原结合位点。本发明的双特异抗体具有四个抗原结合位点，是四价的。
本发明中，术语“共同轻链”是指包含相同的轻链可变区和轻链恒定区的轻链，其能够与结合第一抗原的第一抗体的重链配对，形成特异性结合第一抗原的结合位点，也能够与结合第二抗原的第二抗体的重链配对，形成特异性结合第二抗原的结合位点。进一步的，共同轻链的轻链可变区与第一抗体的重链可变区形成第一抗原结合位点，共同轻链的轻链可变区与第二抗体的重链可变区形成第二抗原结合位点。
本发明中，术语“肽接头”是指具有氨基酸序列的肽。本发明的肽接头是天然连接子或人工连接子。优选的，本发明的肽接头是人工连接子。本发明的多肽接头可以选自G、GS、SG、GGS、GSG、SGG、GGG、GGGS、SGGG、GGGGS、GGGGSGS、GGGGSGGS、GGGGSGGGGS、GGGGSGGGGSGGGGS(SEQ ID NO：150)、AKTTPKLEEGEFSEAR、AKTTPKLEEGEFSEARV、AKTTPKLGG、SAKTTPKLGG、SAKTTP、RADAAP、RADAAPTVS、RADAAAAGGPGS、SAKTTPKLEEGEFSEARV、ADAAP、ADAAPTVSIFPP、TVAAP、TVAAPSVFIFPP、QPKAAP、QPKAAPSVTLFPP、AKTTPP、AKTTPPSVTPLAP、AKTTAPSVYPLAP、ASTKGP、ASTKGPSVFPLAP、GENKVEYAPALMALS、GPAKELTPLKEAKVS和GHEAAAVMQVQYPAS等。接头还可以是在体内可断裂的肽接头、蛋白酶(如MMP)敏感性接头、可以通过还原而断裂的基于二硫键的接头等，参见先前所描述的(Fusion ProteinTechnologies for Biopharmaceuticals：Applications and Challenges，由StefanR.Schmidt编辑)，或本领域已知的任何可断裂的接头。这些可断裂的接头可以用于在体内释放分子顶部的Fab，以便提高组织渗透和分布，增强与靶标的结合，减少潜在副作用，以及调节2个不同的Fab区的体内功能和半衰期。术语“Fab区”由抗体的重链的VH和CH1以及轻链的VL和CL结构域组成。
以下实施例中使用的检测方法说明如下：
SEC-HPLC纯度、聚体检测方法：
流动相：200mM磷酸盐缓冲液，pH 6.8±0.1。经0.22μm滤膜过滤、超声脱气后使用。色谱柱：TSK G3000SWxl，7.8×300mm 5μm，TOSOH 08541。高效液相色谱仪：WatersAlliance e2695 2489紫外/可见光检测器，Dionex Ultimate 3000VWD-3400(RS)Detector或其他适合配有紫外检测器的HPLC系统。
系统适用性样品：取参考品用流动相稀释浓度至1.0mg/ml，13000rpm离心10min，取上清转移至进样瓶，放入HPLC样品盘。供试品：用流动相稀释供试品浓度至1.0mg/ml，13000rpm离心10min，取上清转移至进样瓶，放入HPLC样品盘。色谱条件：柱温25±2℃；样品温度10±2℃；检测波长UV 280nm；进样体积20μL；流速0.5ml/min。
用色谱软件进行积分，峰面积归一化法计算各个峰的峰面积百分比。系统适用性可接受标准：6针系统适用性样品，聚体与单体的分离度均≥1.5，主峰的保留时间RSD≤1.0％，主峰峰面积RSD≤2.0％，且主峰的不对称性均≤2.0，理论塔板数均≥4000。供试品报告结果：样品的SEC纯度报告为单体主峰的峰面积百分比，聚体含量为聚体峰的峰面积百分比。
IEC-HPLC纯度检测方法：
流动相A：20mM磷酸盐缓冲液，pH 6.5±0.05。经0.22μm滤膜过滤、超声脱气后使用。流动相B：20mM磷酸盐缓冲液+200mM氯化钠，pH 6.5±0.05。经0.22μm滤膜过滤、超声脱气后使用。色谱柱：Propac WCX-10，4×250mm，Thermo Dionex 054993。高效液相色谱仪：Waters Alliance e2695，Dionex Ultimate 3000系列或其他适合配有紫外检测器的HPLC系统。
系统适用性样品：取参考品用流动相稀释浓度至1.0mg/ml，13000rpm离心10min，取上清转移至进样瓶，放入HPLC样品盘。供试品：用流动相稀释供试品浓度至1.0mg/ml，13000rpm离心10min，取上清转移至进样瓶，放入HPLC样品盘。色谱条件：柱温30±2℃；样品温度10±2℃；检测波长UV 214nm；进样体积20μL；流速1.0ml/min。流动相梯度如下表：
纯度分析：用峰面积归一化法计算样品图谱上主峰、酸峰区和碱峰区的峰面积百分比。IEC纯度结果报告为主峰的峰面积百分比。
以下实施例中未注明具体条件的实验方法，通常按照常规条件以及手册中所述的条件，或按照制造厂商所建议的条件实施。实施例中所使用的通用设备、试剂、耗材、辅料等，均可从商业途径获得。
以下实施例中使用的组氨酸缓冲液为组氨酸-盐酸组氨酸缓冲液；使用的醋酸盐缓冲液为醋酸-醋酸钠缓冲液；使用的磷酸盐缓冲液为磷酸二氢钠-磷酸氢二钠缓冲液。
下面结合具体实施例，进一步详细阐述本发明。
实施例1不同抗体蛋白浓度考察
本实施例考察抗体蛋白浓度的影响。按表1配制3组处方，缓冲液为组氨酸缓冲液。处方25℃放置4周，分别于0、3、7、14、21、28天取样检测抗体蛋白SEC-HPLC纯度和IEC-HPLC纯度。考察结果如表2和图2所示。
表1、不同抗体蛋白浓度考察处方
注：1.49mg/ml甲硫氨酸相当于10mM的甲硫氨酸。
表2、不同抗体蛋白浓度考察结果
将表2中结果进行分析，结果如图2所示。由图2结果可知，抗体蛋白的IEC-HPLC纯度和SEC-HPLC纯度随着抗体蛋白浓度升高，下降速度变快，其中抗体蛋白浓度为10mg/ml和20mg/ml的处方的检测结果相近。因此，抗体蛋白浓度优选的范围为10-20mg/ml。
实施例2不同缓冲体系考察
本实施例考察不同缓冲体系对抗体蛋白的影响。配制如表3中所示的6组处方，处方2-1使用醋酸盐缓冲液，处方2-2、2-3和2.4使用组氨酸缓冲液，处方2-5和2-6使用磷酸盐缓冲液。处方25℃放置，分别于0、3、7、14天取样，检测抗体蛋白的SEC-HPLC纯度和IEC-HPLC纯度。考察结果如表4和图3所示。
表3、不同缓冲体系考察处方
注：1.49mg/ml甲硫氨酸相当于10mM的甲硫氨酸。
表4、不同缓冲体系考察结果
由表4和图3结果可知，不同缓冲体系的处方25℃放置0-14天时，抗体蛋白的IEC-HPLC纯度整体没有下降趋势。其中处方2-1至2-5的SEC-HPLC纯度具有相似的趋势，而处方2-6结果稍差，可能是pH较高的原因。以上结果表明在pH4.7-5.8的范围内醋酸盐、组氨酸、磷酸盐缓冲体系没有显著性差异，均可使用。
实施例3不同pH考察
本实施例中考察pH范围及甲硫氨酸对抗体蛋白的影响。按照表5配制4组处方，使用缓冲液为组氨酸缓冲液。处方25℃放置，分别于0、1、2、3周取样，检测抗体蛋白SEC-HPLC纯度和IEC-HPLC纯度。考察结果如表6和图4所示。
表5、不同pH考察处方
注：1.49mg/ml甲硫氨酸相当于10mM的甲硫氨酸。
表6、不同pH考察结果
由表6和图4可知，3-1至3-3组的抗体蛋白SEC-HPLC纯度与IEC-HPLC纯度差异不明显，3-4组结果较其他组差。从而可知pH 5.0-6.0的范围比较适合维持抗体蛋白的稳定性。在这个范围内，甲硫氨酸作用不明显。
实施例4表面活性剂浓度和pH的DOE考察
为进一步对聚山梨酯80浓度及pH值进行优化，本实施例利用JMP软件进行DOE试验设计(如表7所示)。其中抗体蛋白浓度为20mg/ml，使用缓冲液为组氨酸缓冲液(组氨酸浓度20mM)，聚山梨酯80浓度范围为0-1mg/ml，海藻糖浓度为90mg/ml，pH范围为5.0-6.5。考察指标为抗体蛋白SEC-HPLC纯度、IEC-HPLC纯度、及处方中不溶性微粒的含量。考察条件为40℃和25℃分别放置4周。考察结果如表8(40℃)和表9(25℃)所示，分析如图5所示。
表7、聚山梨酯80和pH DOE设计
表8、DOE试验结果(40℃)
表9、DOE试验结果(25℃)
将表8、表9中结果进行回归分析，得出每个处方的降解斜率，然后使用JMP软件对斜率进行DOE模型分析，结果如图5所示。由图5可知，pH较优范围为5.0-5.6，聚山梨酯80浓度范围为0-1.0mg/ml；在pH为5.0-5.6时，更优选的聚山梨酯80浓度范围为0.3-0.5mg/ml。
实施例5不同缓冲液和蛋白保护剂浓度考察
本实施例考察不同缓冲液浓度和蛋白保护剂浓度对制剂影响。配置6组处方，其中抗体蛋白浓度为20mg/ml，聚山梨酯80浓度为0.4mg/ml，组氨酸缓冲液和蛋白保护剂海藻糖浓度如表10所示，pH为5.3。配制后放置40℃，高温考察27天。考察指标为抗体蛋白SEC-HPLC纯度、抗体蛋白IEC-HPLC纯度及处方不溶性微粒。结果如表11和图6所示。
表10、不同缓冲液和蛋白保护剂浓度的考察处方
表11、不同缓冲液和蛋白保护剂浓度考察结果
由表11和图6的结果可知，5-3、5-5、5-6三组不同组氨酸浓度的处方的IEC-HPLC纯度和SEC-HPLC纯度检测结果无显著性差异，但是5-5组处方不溶性微粒超标，且有浑浊现象，因此组氨酸缓冲液中组氨酸的优选含量范围为20-30mM。5-1、5-2、5-3、5-4组结果没有明显差异，考虑到注射液与人体等渗的原则，海藻糖浓度优选为80-90mg/ml。
以上内容是结合具体的实施方式对本发明所作的进一步详细说明，说明是示例性的，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下做出的简单改变或替换，都应当视为属于本发明的保护范围。
序列表
<110> 三生国健药业（上海）股份有限公司
<120> 一种抗PD-1/VEGF双特异性抗体液体制剂
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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 Leu 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
<210> 3
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
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 Phe Val Phe Ser Asn Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Gly Gly Gly Gly Tyr Thr Tyr Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu 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 Ser Pro Tyr Gly His Tyr Gly Phe Glu Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 4
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
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 Asp Phe Thr His 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 Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 5
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
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 Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 6
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Claims (14)
1.一种抗PD-1/VEGF双特异性抗体液体制剂，其特征在于，所述液体制剂包含：
a)10-40mg/ml的抗PD-1/VEGF四价双特异性抗体；
b)20-30mM的缓冲液；
c)0.3-0.5mg/ml的表面活性剂；
d)80-90mg/ml的蛋白保护剂；
所述液体制剂的pH为4.7-6.0；
其中，所述抗PD-1/VEGF四价双特异性抗体包含两条重链和四条共同轻链；其中，所述重链从N末端到C末端包含VH-B-CH1-肽接头-VH-A-CH1-CH2-CH3，所述VH-A为结合VEGF的重链可变区，VH-B为结合PD-1的重链可变区，所述CH1为重链恒定区的第一结构域，所述CH2为重链恒定区的第二结构域，所述CH3为重链恒定区的第三结构域；其中，所述共同轻链从N末端到C末端包含VL-CL，其中，所述VL为轻链可变区，所述CL为轻链恒定区；所述重链的VH-A-CH1和所述VH-B-CH1分别与所述共同轻链的VL-CL配对，所述VH-A和所述VL形成VEGF结合位点，所述VH-B与所述VL形成PD-1结合位点。
2.如权利要求1所述的液体制剂，其特征在于，所述抗PD-1/VEGF四价双特异性抗体浓度为10-20mg/ml。
3.如权利要求1所述的液体制剂，其特征在于，所述缓冲液选自由组氨酸缓冲液、醋酸盐缓冲液、磷酸盐缓冲液组成的组中的一种或多种；优选的，所述组氨酸缓冲液为组氨酸-盐酸组氨酸缓冲液，所述醋酸盐缓冲液为醋酸-醋酸钠缓冲液，所述磷酸盐缓冲液为磷酸二氢钠-磷酸氢二钠缓冲液；更优选的，所述缓冲液为组氨酸-盐酸组氨酸缓冲液。
4.如权利要求1所述的液体制剂，其特征在于，所述表面活性剂选自由聚山梨酯80、聚山梨酯20、泊洛沙姆188组成的组中的一种或多种；优选的，所述表面活性剂为聚山梨酯80。
5.如权利要求1所述的液体制剂，其特征在于，所述蛋白保护剂选自由海藻糖、蔗糖、甘露醇、山梨醇、氯化钠、葡萄糖、果糖、盐酸精氨酸组成的组中的一种或多种；优选的，所述蛋白保护剂为海藻糖。
6.如权利要求1所述的液体制剂，其特征在于，所述液体制剂进一步还包含甲硫氨酸；优选的，所述甲硫氨酸的浓度为10mM。
7.如权利要求1所述的液体制剂，其特征在于，所述液体制剂的pH为5.0-5.6。
8.如权利要求1-7任一项所述的液体制剂，其特征在于，所述液体制剂包含：
a)10-20mg/ml的抗PD-1/VEGF四价双特异性抗体；
b)20-30mM的组氨酸-盐酸组氨酸缓冲液；
c)0.3-0.5mg/ml的聚山梨酯80；
d)80-90mg/ml的海藻糖；
任选地，还包含10mM的甲硫氨酸；
所述液体制剂的pH为5.0-5.6。
9.如权利要求1所述的液体制剂，其特征在于，所述抗PD-1/VEGF四价双特异性抗体中结合PD-1的重链可变区氨基酸序列如SEQ ID NO：3所示，结合VEGF的重链可变区氨基酸序列如SEQ ID NO：4所示，共同轻链的轻链可变区的氨基酸序列如SEQ ID NO：5所示。
10.如权利要求1所述的液体制剂，其特征在于，所述抗PD-1/VEGF四价双特异性抗体重链中靠近N末端的CH1结构域和CH1-CH2-CH3来自重链恒定区IgG1、IgG2、IgG3或IgG4，所述靠近N末端的CH1结构域和CH1-CH2-CH3中的CH1可以相同或不同；优选的，所述抗PD-1/VEGF四价双特异性抗体共同轻链中CL为κ轻链恒定区或λ轻链恒定区。
11.如权利要求1所述的液体制剂，其特征在于，所述抗PD-1/VEGF四价双特异性抗体中肽接头氨基酸序列如SEQ ID NO：6所示。
12.如权利要求9-11任一项所述的液体制剂，其特征在于，所述抗PD-1/VEGF四价双特异性抗体重链氨基酸序列如SEQ ID NO：1所示，共同轻链氨基酸序列如SEQ ID NO：2所示。
13.如权利要求1-12任一项所述的液体制剂在制备治疗癌症、炎性疾病和自身免疫性疾病的药物中的用途。
14.如权利要求13所述的用途，其特征在于，所述癌症选自：黑素瘤、肾癌、前列腺癌、胰腺癌、乳腺癌、结肠癌、肺癌、食道癌、头颈鳞状细胞癌、肝癌、卵巢癌、宫颈癌、甲状腺癌、成胶质细胞瘤、神经胶质瘤、白血病、淋巴瘤及其它恶性赘生性疾病；所述炎性疾病和自身免疫性疾病选自：眼科疾病、纤维化疾病、哮喘、类风湿性关节炎、系统性红斑狼疮、多发性硬化症、银屑病、特应性皮炎。
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