CN113456582A - 重组人源化抗pd-1单克隆抗体的液体制剂 - Google Patents

重组人源化抗pd-1单克隆抗体的液体制剂 Download PDF

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CN113456582A
CN113456582A CN202010235536.7A CN202010235536A CN113456582A CN 113456582 A CN113456582 A CN 113456582A CN 202010235536 A CN202010235536 A CN 202010235536A CN 113456582 A CN113456582 A CN 113456582A
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赵丽丽
石曼
刘忠
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Lunan Pharmaceutical Group Corp
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Abstract

本发明与药物制剂领域，具体涉及一种重组人源化抗PD‑1单克隆抗体的液体制剂，包含10mg/ml无糖基化抗PD‑1单克隆抗体，10～20mM缓冲剂，220～270mM稳定剂，0.02～0.06％(w/v)增溶剂，缓冲体系调节pH至5.5～6.5。本发明通过对缓冲液，稳定剂，增溶剂含量进一步的优化，提供一种适用于静脉给药的液体制剂，其在储存期间能保持稳定性，具有较低的具体及其片段化。2～8℃条件下，放置24个月后，制剂的外观、浓度和pH、抗体纯度及电荷异质体均无明显变化。

Description

重组人源化抗PD-1单克隆抗体的液体制剂
技术领域
本发明属于药物制剂领域，具体涉及一种重组人源化抗PD-1单克隆抗体的液体制剂。
背景技术
PD-1是一种免疫抑制性受体，主要在激活的T细胞及B细胞中，作为T细胞抑制受体，与配体PD-L1结合可以抑制T淋巴细胞的活性及相关的体内细胞免疫反应，在肿瘤细胞中可限制T细胞效应子的功能，在肿瘤免疫逃逸中具有重要作用。而抗PD-1单克隆抗体可阻断活化T细胞表面的程序性死亡(PD)-1受体，通过抑制PD-1和PD-1配体(PD-L1)通路可挽救耗竭的T细胞，增强抗肿瘤免疫力，在***方面具有很好的靶向潜能。针对这一优势，国外开发研制抗PD-1单克隆抗体如opdivo，keytruda等单克隆抗体乙腈获批上市，然而这些抗体作为单药应答率低。本发明使用的单克隆抗体其上糖基化修饰被敲除，虽然工艺开发较稳定，均一性较高，且有望获得更好的临床效果，但同时相比较其他抗PD-1单克隆抗体，其由于去除糖基化而对胰蛋白酶等的敏感性显著增加，结构灵活性增强，在低pH情况下更容易有聚体形成的趋势，易聚集沉淀。为了防止蛋白在使用前的储存期间发生变性，聚集作用所致活性或者结构完整性的丧失，针对此无糖基化抗PD-1单克隆抗体的制剂工艺发开很有必要。
专利CN103429264A公开了一种抗-人PD-1抗体或其抗原结合片段的低压冻干的制剂，包含:25mg/ml抗-人PD-1抗体或其抗原结合片段，pH5.0～6.0的10mM组氨酸缓冲液，70mg/ml蔗糖，0.02mg/ml聚山梨酯80。
专利CN107334728A公开了一种抗人PD-1的单克隆抗体的溶液制剂，包含100mg/ml的抗人PD-1单克隆抗体，20mM的组氨酸缓冲剂，250mM的蔗糖，6～8mg/ml的泊洛沙姆188,20～100mg/ml的磺丁醚β环糊精，及2～8mg/ml的苯甲醇。
专利CN107325180A公开了一种适于皮下注射的抗人PD-1的单克隆抗体制剂，包含100mg/ml的抗人PD-1单克隆抗体，10mM的磷酸盐缓冲剂，10mM的柠檬酸盐缓冲剂，250mM的甘露醇，20mM的将氨酸，8mg/ml的吐温20。
专利CN106390115A公开了一种人源化单克隆抗体的稳定制剂，包括25～50mg/ml，pH6.0的10～20mM枸橼酸缓冲液，150mM的甘露醇及50mM氯化钠，0.20％聚山梨酯80。
CN107198773A公开了一种重组抗PD-L1全人单克隆抗体的液体制剂，包含30mg/ml重组抗PD-L1全人单克隆抗体，20mM组氨酸-盐酸组氨酸，150mM甘露醇，55mM氯化钠和0.01wt％聚山梨酯80。
CN105793288A公开了一种PDL1单克隆抗体的含水药物配制剂，包含60mg/ml的抗PDL1单克隆抗体，20mM组氨酸乙酸酯或乙酸钠缓冲液，120mM蔗糖，pH5.8。
以上专利中大多为通过辅料筛选及添加稳定剂或添加剂来提高抗体制剂的稳定性，增加辅料相对会给临床用药带来安全隐患。另外，不同的PD-1抗体结构不同，其表现性质也不相同，因此现有技术的制剂配方并不适用于无糖基化抗PD-1单克隆抗体。
CN110354073A公开了一种免疫抑制剂单克隆抗体的液体制剂，包含25mg/ml的无糖基化抗PD-1单克隆抗体，pH6.0的15mM的组氨酸，270mM蔗糖及0.4mg/ml的聚山梨酯20。其在2～8℃放置6个月相对稳定，但是在温度较高环境下的稳定性还待进一步提高。因此还需要提供一种更加稳定的无糖基化抗PD-1单克隆抗体的液体制剂。
发明内容
基于现有技术的不足，本发明的目的在于提供一种稳定的重组人源化抗PD-1单克隆抗体的液体制剂。
本发明的技术方案如下：
一种重组人源化抗PD-1单克隆抗体的液体制剂，包含10mg/ml无糖基化抗PD-1单克隆抗体，10～20mM缓冲剂，220～270mM稳定剂，0.02～0.06％增溶剂，缓冲体系调节pH至5.5～6.5。
优选地，所述缓冲剂为组氨酸盐酸或柠檬酸/柠檬酸钠，进一步优选为组氨酸盐酸。
优选地，所述稳定剂为蔗糖或甘露醇；进一步优选为蔗糖。
优选地，所述增溶剂为聚山梨酯80或聚山梨酯20。
在一种实施方案中，一种重组人源化抗PD-1单克隆抗体的液体制剂，包含10mg/ml无糖基化抗PD-1单克隆抗体，10～20mM组氨酸盐酸缓冲溶液，220～250mM蔗糖，0.02～0.06％(w/v)聚山梨酯80，缓冲体系调节pH至6.0～6.5。
优选地，所述的组氨酸盐酸缓冲溶液的浓度为10mM。
优选地，所述蔗糖浓度为220mM。
优选地，所述聚山梨酯80的含量为0.02％(w/v)。
优选地，所述pH为6.0。
在一个优选的实验方案中，一种重组人源化抗PD-1单克隆抗体的液体制剂包含如下组分：
Figure BDA0002430838180000021
Figure BDA0002430838180000031
本发明还提供一种所述重组人源化抗PD-1单克隆抗体的液体制剂的制备方法，所述方法包括如下步骤：称取处方量的缓冲剂，加入注射用水溶解，调节pH，用上述配制的缓冲体系无糖基化抗PD-1单克隆抗体蛋白原液超滤浓缩，置换无糖基化抗PD-1单克隆抗体蛋白的原始缓冲体系，再加入处方量的蔗糖和聚山梨酯80，搅拌均匀，再用缓冲体系调节蛋白浓度为10mg/ml，经0.22μm滤膜进行无菌过滤后灌装即得。
本发明所述的无糖基化抗PD-1单克隆抗体可参照CN106519034A制备，其无糖基化抗PD-1单克隆抗体的重链和轻链序列如下：
重链区
MEWSWVFLFFLSVTTGVHSEVQLVESGGGLVKPGGSLRLSCAASGFTFSSYGMSWVRQTPEKRLEWVATISGGGRDTYYPDSVKGRFTISRDNAKNNLYLQMSSLRSEDTALYYCARQKDTSWFVHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHNHYTQKSLSLSPGK
轻链区
MSVPTQVLGLLLLWLTDARCEIVLTQSPATLAVSPGERATISCRASESVDDYGISFMNWFQQKPGQPPKLLIYVASNQGSGVPARFSGSGSGTDFTLNIHPMEEDDTAMYFCQQSKEVPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
本发明通过对缓冲液，稳定剂，增溶剂含量进一步的优化，提供一种适用于静脉给药的液体制剂，其在储存期间能保持稳定性，具有较低的聚体及其片段化。2～8℃条件下，放置24个月后，制剂的外观、浓度和pH、抗体纯度及电荷异质体均无明显变化。加速6个月后，制剂的外观、浓度、活性、pH值、纯度(SEC-HPLC)和电荷异质体(CEX-HPLC)的检测结果均无明显变化。
具体实施方式
下面通过实施例的方式进一步说明本发明，所列案例只是制剂筛选试验的部分，并不能因此将本发明限制在所述的是实施例范围之中。下列实施例中未注明的具体条件的试验方法，按照常规方法和条件，或者按照商品说明书选择。实施例中稳定性试验，相关生物学检验按照中国药典的规范进行。实施例中所述的实际均为药用级，市面均有销售。无糖基化抗PD-1单克隆抗体可参照CN106519034A的方法制备。
实施例1
配方：
Figure BDA0002430838180000041
制备方法：
称取处方量的缓冲剂，加入注射用水溶解，调节pH，用上述配制的缓冲体系无糖基化抗PD-1单克隆抗体蛋白原液超滤浓缩，置换无糖基化抗PD-1单克隆抗体蛋白的原始缓冲体系，再加入处方量的蔗糖和聚山梨酯80，搅拌均匀，再用缓冲体系调节蛋白浓度为10mg/ml，经0.22μm滤膜进行无菌过滤后灌装即得。
实施例2
配方：
Figure BDA0002430838180000042
制备方法如实施例1。
实施例3
配方：
Figure BDA0002430838180000043
Figure BDA0002430838180000051
制备方法如实施例1。
实施例4
配方：
Figure BDA0002430838180000052
制备方法如实施例1。
实施例5
配方：
Figure BDA0002430838180000053
制备方法如实施例1。
实施例6
配方：
Figure BDA0002430838180000054
制备方法：
称取处方量的缓冲剂，加入注射用水溶解，调节pH，用上述配制的缓冲体系无糖基化抗PD-1单克隆抗体蛋白原液超滤浓缩，置换无糖基化抗PD-1单克隆抗体蛋白的原始缓冲体系，再加入处方量的甘露醇和聚山梨酯80，搅拌均匀，再用缓冲体系调节蛋白浓度为10mg/ml，经0.22μm滤膜进行无菌过滤后灌装即得。
实施例7
配方：
Figure BDA0002430838180000061
制备方法：
称取处方量的缓冲剂，加入注射用水溶解，调节pH，用上述配制的缓冲体系无糖基化抗PD-1单克隆抗体蛋白原液超滤浓缩，置换无糖基化抗PD-1单克隆抗体蛋白的原始缓冲体系，再加入处方量的蔗糖和聚山梨酯80，搅拌均匀，再用缓冲体系调节蛋白浓度为10mg/ml，经0.22μm滤膜进行无菌过滤后灌装即得。
实施例8
配方：
Figure BDA0002430838180000062
制备方法同实施例1。
实施例9
配方：
Figure BDA0002430838180000063
制备方法同实施例1。
验证实施例
分别按照实施例1-9制备样品三批，采用加速稳定性试验和长期试验考察储存稳定性。
长期试验在2～8℃的条件下进行，分别于0个月、3个月、6个月、12个月、24个月末按照稳定性重点考察项目进行检测；加速试验在25℃±2℃条件下进行，时间为6个月，所用设备能控制温度±2℃，并对实际温度进行检测，试验期间第0个月、3个月、6个月末取样一次，按照稳定性重点考察项目检测。结果见表1和表2。
表1 2～8℃长期稳定性试验结果
Figure BDA0002430838180000071
Figure BDA0002430838180000081
表2 25±2℃加速稳定性试验结果
Figure BDA0002430838180000082
Figure BDA0002430838180000091
Figure BDA0002430838180000101
SEQUENCE LISTING
<110> 鲁南制药集团股份有限公司
<120> 重组人源化抗PD-1 单克隆抗体的液体制剂
<130> 2020
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 467
<212> PRT
<213> 人工序列
<400> 1
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Ser Tyr Gly Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu
50 55 60
Glu Trp Val Ala Thr Ile Ser Gly Gly Gly Arg Asp Thr Tyr Tyr Pro
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Asn Leu Tyr Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Leu
100 105 110
Tyr Tyr Cys Ala Arg Gln Lys Asp Thr Ser Trp Phe Val His Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly Lys
465
<210> 2
<211> 238
<212> PRT
<213> 人工序列
<400> 2
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Ala Arg Cys Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ala
20 25 30
Val Ser Pro Gly Glu Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser
35 40 45
Val Asp Asp Tyr Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Val Ala Ser Asn Gln Gly Ser
65 70 75 80
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Asn Ile His Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys
100 105 110
Gln Gln Ser Lys Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
130 135 140
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
165 170 175
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
195 200 205
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
210 215 220
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235

Claims (10)

1.一种重组人源化抗PD-1单克隆抗体的液体制剂，其特征在于，包含10mg/ml无糖基化抗PD-1单克隆抗体，10～20mM缓冲剂，220～270mM稳定剂，0.02～0.06％增溶剂，缓冲体系调节pH至5.5～6.5。
2.根据权利要求1所述的液体制剂，其特征在于，所述缓冲剂为组氨酸盐酸或柠檬酸/柠檬酸钠。
3.根据权利要求2所述的液体制剂，其特征在于，所述缓冲剂为组氨酸盐酸。
4.根据权利要求1所述的液体制剂，其特征在于，所述稳定剂为蔗糖或甘露醇。
5.根据权利要求4所述的液体制剂，其特征在于，所述稳定剂为蔗糖。
6.根据权利要求1所述的液体制剂，其特征在于，所述增溶剂为聚山梨酯80或聚山梨酯20。
7.根据权利要求1-6任一项所述的液体制剂，其特征在于，包含如下含量的组分：
Figure FDA0002430838170000011
8.根据权利要求1所述的液体制剂，其特征在于，所述无糖基化抗PD-1单克隆抗体其氨基酸序列如下：
重链区
MEWSWVFLFFLSVTTGVHSEVQLVESGGGLVKPGGSLRLSCAASGFTFSSYGMSWVRQTPEKRLEWVATISGGGRDTYYPDSVKGRFTISRDNAKNNLYLQMSSLRSEDTALYYCARQKDTSWFVHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHNHYTQKSLSLSPGK；
轻链区
MSVPTQVLGLLLLWLTDARCEIVLTQSPATLAVSPGERATISCRASESVDDYGISFMNWFQQKPGQPPKLLIYVASNQGSGVPARFSGSGSGTDFTLNIHPMEEDDTAMYFCQQSKEVPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC。
9.一种权利要求7所述的液体制剂的制备方法，其特征在于，包括如下步骤：称取处方量的缓冲剂，加入注射用水溶解，调节pH，用上述配制的缓冲体系无糖基化抗PD-1单克隆抗体蛋白原液超滤浓缩，置换无糖基化抗PD-1单克隆抗体蛋白的原始缓冲体系，再加入处方量的蔗糖和聚山梨酯80，搅拌均匀，再用缓冲体系调节蛋白浓度为10mg/ml，经0.22μm滤膜进行无菌过滤后灌装即得。
10.一种权利要求1-6,8任一项所述的液体制剂的制备方法，其特征在于，包括如下步骤：称取处方量的缓冲剂，加入注射用水溶解，调节pH，用上述配制的缓冲体系无糖基化抗PD-1单克隆抗体蛋白原液超滤浓缩，置换无糖基化抗PD-1单克隆抗体蛋白的原始缓冲体系，再加入处方量的蔗糖和聚山梨酯80，搅拌均匀，再用缓冲体系调节蛋白浓度为10mg/ml，经0.22μm滤膜进行无菌过滤后灌装即得。
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