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Article(id=1198628610430038352, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198628599835227075, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2022-1350, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1670428800000, receivedDateStr=2022-12-08, revisedDate=1680278400000, revisedDateStr=2023-04-01, acceptedDate=null, acceptedDateStr=null, onlineDate=1763704930169, onlineDateStr=2025-11-21, pubDate=1686499200000, pubDateStr=2023-06-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763704930169, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763704930169, creator=13701087609, updateTime=1763704930169, updator=13701087609, issue=Issue{id=1198628599835227075, tenantId=1146029695717560320, journalId=1189982191388893191, year='2023', volume='58', issue='6', pageStart='0', pageEnd='1724', issueExtLink='null', onlineDate='null', pubDate='1686499200000', pubDateStr='2023-06-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1763704927643, creator='13701087609', updateTime=1766137690373, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1208832346359468483, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198628599835227075, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208832346359468484, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198628599835227075, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=1663, endPage=1668, ext={EN=ArticleExt(id=1198628610752999787, articleId=1198628610430038352, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=The PK bioanalysis method study of c-Met antibody-drug conjugate (RC108) in cynomolgus monkey, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Antibody-drug conjugate (ADC) has the characteristics of low toxicity and high efficiency, and plays an important role in cancer treatment. However, due to the complexity of its structure, it brings difficulties in pharmacokinetic (PK) bioanalysis. This study established an analytical method for the detection of ADC (RC108) in cynomolgus monkey plasma by ligand-binding assay (LBA) and liquid chromatography tandem mass spectrometry (LC-MS/MS), which was used to analyze and quantify the total antibody, bound antibody and free drug in cynomolgus monkey plasma. Based on the LBA method, rabbit anti-RC108 Fab and mouse anti-MMAE (monomethyl auristatin E) mAb were pre-coated in 96-well plates as the total antibody and antibody binding reagents, respectively. The samples to be tested were added, and then the detection reagents were added in turn. Goat anti-human IgG (H+L)-HRP, chromogenic solution tetramethylbenzidine (TMB), H2SO4 terminate the reaction, read data at 450 nm/630 nm wavelength of microplate reader; LC-MS/MS analysis method quantifies MMAE concentration, and refer to relevant regulations for methodological validation. The analytical method for quantifying total antibody, bound antibody and free drug of RC108 drug obtained good accuracy and precision, and the selectivity, dilution linearity, hook effect, parallelism and stability were verified. Meet the requirements of biological analysis. Finally, a bioanalytical method for the determination of the concentration of the test substance RC108 (total antibody, conjugated antibody, free MMAE) in cynomolgus monkey plasma with high sensitivity and high throughput was established by LBA and LC-MS/MS method. Subsequent non-clinical research on PK research in cynomolgus monkeys will provide technical support.

, authors=null, authorsList=Hong-yu ZHOU, Shu-juan WANG, Zhi-hao LIU, Ke MA, Ling WANG, Jing JIANG, authorCompany=null, correspAuthors=Jing JIANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2023 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1198628612271337970, articleId=1198628610430038352, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=靶向c-Met抗体偶联药物(RC108)在食蟹猴中PK生物分析方法学研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

抗体偶联药物(antibody-drug conjugate, ADC)有着低毒、高效的药物特点, 在癌症治疗中发挥着重要作用。但是因其结构的复杂性, 带来药代动力学(pharmacokinetic, PK)生物分析的困难。本研究建立一种应用配基结合分析法(ligand-binding assay, LBA)和液相色谱与串联质谱联用法(liquid chromatography-tandem mass spectrometry, LC-MS/MS)检测食蟹猴血浆中ADC (RC108)的分析方法, 用于分析定量食蟹猴血浆中的总抗体、结合抗体和游离药物。基于LBA法, 在96孔板预包被rabbit anti-RC108 Fab和mouse anti-MMAE mAb分别作为总抗体和结合抗体的试剂, 加入待测样品, 随后依次加入检测试剂goat anti-human IgG (H+L)-HRP和显色液四甲基联苯胺(tetramethylbenzidine, TMB), H2SO4终止反应后, 酶标仪450 nm/630 nm波长处读取数据; LC-MS/MS分析方法定量单甲基澳瑞他汀E(MMAE)浓度, 并参考相关法规进行方法学验证。对RC108药物定量总抗体、结合抗体和游离药物的分析方法得到了良好的准确度和精密度, 并对选择性、稀释线性、钩状效应和稳定性等进行了验证, 均符合生物分析的要求。最终通过LBA法和LC-MS/MS法建立了一种兼具高灵敏与高通量的测定食蟹猴血浆中受试物RC108浓度(总抗体、结合抗体、游离MMAE)的生物分析方法, 为后续非临床研究食蟹猴的PK研究提供技术支撑。

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*姜静 , E-mail:
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靶向c-Met抗体偶联药物(RC108)在食蟹猴中PK生物分析方法学研究
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周宏雨 1 , 王淑娟 2 , 刘志浩 2 , 马克 3 , 王凌 2 , 姜静 1, 2, *
药学学报 | 研究论文 2023,58(6): 1663-1668
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药学学报 |研究论文 2023 , 58 (6) : 1663 -1668
靶向c-Met抗体偶联药物(RC108)在食蟹猴中PK生物分析方法学研究
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Binzhou Medical University, Yantai 264003, China
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周宏雨1, 王淑娟2, 刘志浩2, 马克3, 王凌2, 姜静1, 2, *
作者信息
  • 1.滨州医学院, 山东 烟台 264003
  • 2.荣昌生物制药(烟台)股份有限公司, 山东 烟台 265503
  • 3.军科正源(北京)药物研究有限责任公司, 北京 102206
通讯作者:
*姜静 , E-mail:
The PK bioanalysis method study of c-Met antibody-drug conjugate (RC108) in cynomolgus monkey
Hong-yu ZHOU1, Shu-juan WANG2, Zhi-hao LIU2, Ke MA3, Ling WANG2, Jing JIANG1, 2, *
Affiliations
  • 1. Binzhou Medical University, Yantai 264003, China
  • 2. RemeGen Company Ltd., Yantai 265503, China
  • 3. Junke Zhengyuan Pharmaceutical Research Company Ltd., Beijing 102206, China
出版时间: 2023-06-12 doi: 10.16438/j.0513-4870.2022-1350
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摘要
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抗体偶联药物(antibody-drug conjugate, ADC)有着低毒、高效的药物特点, 在癌症治疗中发挥着重要作用。但是因其结构的复杂性, 带来药代动力学(pharmacokinetic, PK)生物分析的困难。本研究建立一种应用配基结合分析法(ligand-binding assay, LBA)和液相色谱与串联质谱联用法(liquid chromatography-tandem mass spectrometry, LC-MS/MS)检测食蟹猴血浆中ADC (RC108)的分析方法, 用于分析定量食蟹猴血浆中的总抗体、结合抗体和游离药物。基于LBA法, 在96孔板预包被rabbit anti-RC108 Fab和mouse anti-MMAE mAb分别作为总抗体和结合抗体的试剂, 加入待测样品, 随后依次加入检测试剂goat anti-human IgG (H+L)-HRP和显色液四甲基联苯胺(tetramethylbenzidine, TMB), H2SO4终止反应后, 酶标仪450 nm/630 nm波长处读取数据; LC-MS/MS分析方法定量单甲基澳瑞他汀E(MMAE)浓度, 并参考相关法规进行方法学验证。对RC108药物定量总抗体、结合抗体和游离药物的分析方法得到了良好的准确度和精密度, 并对选择性、稀释线性、钩状效应和稳定性等进行了验证, 均符合生物分析的要求。最终通过LBA法和LC-MS/MS法建立了一种兼具高灵敏与高通量的测定食蟹猴血浆中受试物RC108浓度(总抗体、结合抗体、游离MMAE)的生物分析方法, 为后续非临床研究食蟹猴的PK研究提供技术支撑。

抗体偶联药物  /  配体结合分析法  /  液相色谱与串联质谱联用法  /  定量分析

Antibody-drug conjugate (ADC) has the characteristics of low toxicity and high efficiency, and plays an important role in cancer treatment. However, due to the complexity of its structure, it brings difficulties in pharmacokinetic (PK) bioanalysis. This study established an analytical method for the detection of ADC (RC108) in cynomolgus monkey plasma by ligand-binding assay (LBA) and liquid chromatography tandem mass spectrometry (LC-MS/MS), which was used to analyze and quantify the total antibody, bound antibody and free drug in cynomolgus monkey plasma. Based on the LBA method, rabbit anti-RC108 Fab and mouse anti-MMAE (monomethyl auristatin E) mAb were pre-coated in 96-well plates as the total antibody and antibody binding reagents, respectively. The samples to be tested were added, and then the detection reagents were added in turn. Goat anti-human IgG (H+L)-HRP, chromogenic solution tetramethylbenzidine (TMB), H2SO4 terminate the reaction, read data at 450 nm/630 nm wavelength of microplate reader; LC-MS/MS analysis method quantifies MMAE concentration, and refer to relevant regulations for methodological validation. The analytical method for quantifying total antibody, bound antibody and free drug of RC108 drug obtained good accuracy and precision, and the selectivity, dilution linearity, hook effect, parallelism and stability were verified. Meet the requirements of biological analysis. Finally, a bioanalytical method for the determination of the concentration of the test substance RC108 (total antibody, conjugated antibody, free MMAE) in cynomolgus monkey plasma with high sensitivity and high throughput was established by LBA and LC-MS/MS method. Subsequent non-clinical research on PK research in cynomolgus monkeys will provide technical support.

antibody-drug conjugate  /  ligand-binding assay  /  liquid chromatography tandem mass spectrometry  /  quantitative analysis
周宏雨, 王淑娟, 刘志浩, 马克, 王凌, 姜静. 靶向c-Met抗体偶联药物(RC108)在食蟹猴中PK生物分析方法学研究. 药学学报, 2023 , 58 (6) : 1663 -1668 . DOI: 10.16438/j.0513-4870.2022-1350
Hong-yu ZHOU, Shu-juan WANG, Zhi-hao LIU, Ke MA, Ling WANG, Jing JIANG. The PK bioanalysis method study of c-Met antibody-drug conjugate (RC108) in cynomolgus monkey[J]. Acta Pharmaceutica Sinica, 2023 , 58 (6) : 1663 -1668 . DOI: 10.16438/j.0513-4870.2022-1350
正文
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抗体偶联药物(antibody-drug conjugate, ADC)因具有更强的靶向性和对细胞的杀伤力已成为肿瘤新药研发的热点[1-3]。ADC是由重组单克隆抗体与细胞毒素小分子化合物通过化学连接物共价偶联的复合物, 可利用抗体介导的高亲和力传递, 选择性地靶向癌细胞表面的抗原, 进而被肿瘤细胞吞噬进入溶酶体, 释放效应小分子[4, 5]。目前, 艾伯维公司研发的靶向细胞间质上皮转换因子(cellular-mesenchymal epithelial transition factor, c-Met)的ADC药物telisotuzumab vedotin于2022年8月在国内启动临床Ⅲ期试验, 另外恒瑞医药开发的靶向c-Met的SHR-A140已完成临床Ⅰ期试验, 尽管如此, 针对c-Met的ADC仍然比较空缺。
ADC药物相较传统化疗药物具有靶向特异性和高效的肿瘤细胞杀伤力, 但是由于ADC的组成形式, 导致其分子结构复杂且不均一性, 用于ADC的药代动力学(pharmacokinetic, PK)研究的生物分析方法的建立和选择具有很大的挑战性[6, 7]。因此, 需要建立一种准确稳健的分析方法来监测体内各成分的动力学的变化, 这对ADC药物研发的非临床及临床阶段PK研究至关重要。
RC108是由荣昌生物制药(烟台)股份有限公司自主研发的靶向c-Met单抗通过可裂解valine-citrulline (vc-Linker)偶联MMAE的ADC[8, 9]。本实验建立了食蟹猴血清中RC108的总抗体(total antibody)、结合抗体(conjugated antibody)和游离小分子单甲基澳瑞他汀E (free-MMAE)的酶联免疫法(ligand-binding assay, LBA)和液相色谱与串联质谱联用法(liquid chromatography-tandem mass spectrometry, LC-MS/MS)分析方法[10, 11], 并依从现行法规进行了验证, 为ADC药物临床前及临床研究提供技术支持。
材料与方法
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药品与试剂  RC108-ADC (批号: RC108-X2-YY201908001)和抗MMAE抗体(mouse anti-MMAE mAb, 批号: 20130924)由荣昌生物制药(烟台)股份有限公司提供; 食蟹猴血清基质来自军科正源(北京)药物研究有限责任公司(批号: GDCySe21Oct2019-25Oct2019DYDC/CySe21Oct2019-27Dec2019JJL); 抗RC-108抗原结合片段抗体(rabbit anti-RC108 Fab)购自北京Sino Biological; 辣根过氧化物酶标记的山羊抗人IgG的抗体(goat anti-human IgG (H+L)-HRP)购自美国Bethyl Laboratories; MMAE购自加拿大Toronto Research Chemicals; 内标物MMAE-D8购买于美国Medchem Express; 四甲基联苯胺(tetramethylbenzidine, TMB)显色液、乙腈、甲酸、甲醇购自美国Thermo Fisher Scientific。
仪器  酶标仪Spectra Max 340PC384购自美国Molecular Devices公司; LC-MS/MS系统包括API 5000质谱仪(美国Applied Biosystems/Sciex)和超高效液相色谱系统LC-20AD (岛津); 洗板机405LSRS购自BioTek公司。
LBA法分析RC108的总抗体浓度和结合抗体浓度  基于Spectra Max的LBA平台, 分析RC108的总抗体和结合抗体。分别配制1 ng·mL-1的抗RC-108抗原结合片段抗体和抗MMAE抗体作为总抗体和结合抗体的捕获试剂, 每孔100 µL, 2~8 ℃过夜包被, 洗板机加入PBST (每孔300 µL)清洗三次, 随后加入每孔250 µL的3% BSA, 室温封闭2 h后, PBST洗板三次, 用1% BSA-PBST稀释10倍后加入对应的标准曲线和质控样品, 每孔100 µL, 室温孵育2 h, PBST洗板三次后, 加入辣根过氧化物酶标记的山羊抗人IgG的抗体1∶10 000稀释入孔, 100 µL /孔, 室温孵育1 h后洗板三次, 随后以每孔100 µL的TMB作为辣根过氧化物酶底物的显色剂, 用每孔50 µL的1 mol·L-1 H2SO4终止后, 在检测波长450 nm和参考波长650 nm下检测吸光度, 颜色的强度与总抗体/结合抗体的浓度呈正比。
UPLC-MS/MS定量分析RC108游离MMAE浓度  所有标准曲线、质控样本、空白样本等在食蟹猴血浆中配制。在96深孔板中加入相应的基质样品100 µL, 随后依次加入30 µL含内标的乙腈水(1∶1)、20 µL的2 mol·L-1 Na2CO3水溶液、600 µL甲基叔丁基醚, 1 000 r·min-1震荡10 min, 在4 ℃、2 000 ×g条件下离心10 min, 吸取上清液400 µL至新96孔板中, 40 ℃氮吹, 之后每孔加入150 µL 0.1%甲酸的30%乙腈水溶液复溶, 4 ℃、2 000 ×g条件下离心5 min, 15 µL进样进行LC-MS/MS分析。
质谱条件  定量分析使用岛津LC-20AD超高效液相与Sciex API5000质谱仪串联系统。质谱仪采用正离子电喷雾离子化模式监测分析物, MMAE和内标MMAE-D8的母离子和子离子质荷比(m/z)分别为718.700→686.6和726.592→694.5, 解簇电压(DP)为140 V, 碰撞能量(CE)分别为40和43 V, 入口电压(EP)为10 V, 碰撞室出口电压(CXP)为15 V。质谱其他参数为IS: 5 500 V; TEM: 550 ℃; GS1: 55 psi (1 psi ≈ 6.9 kPa); GS2: 55 psi; CUR: 20 psi; CAD: 10 psi。
色谱条件  待测分析物使用岛津MG C18 (50 mm × 2.1 mm, 3 µm)色谱柱进行分离, 0.1%甲酸水和0.1%甲酸乙腈溶液分别作为流动相A和B, 柱温保持45 ℃, 进样量为15 µL, 在0.60 mL·min-1流速下进行梯度洗脱, 洗脱程序为: 0~0.01 min, 20% B; 0.01~0.8 min, 20%~60% B; 0.8~1.5 min, 60%~95% B; 1.5~2.5 min, 95% B; 2.5~2.51 min, 95%~20% B; 2.51~3.5 min, 20% B。
数据处理  总抗体和结合抗体的OD值由Spectra Max 340PC384软件读取, 曲线拟合使用4PL权重1/y2模型拟合数据, 分析物MMAE和内标MMAE-D8峰面积由Sciex质谱所带的Analyst 1.6.2采集处理, 使用线性回归权重1/x2拟合数据, 质控和验证样品浓度均由随行的标准曲线计算。
结果
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1 LBA测定总抗体和结合抗体的分析方法验证与结果分析
1.1 方法的精密度与准确度
通过LBA法建立RC108在食蟹猴中的总抗体和结合抗体的分析方法, 结果如图 1所示, 总抗体的定量范围为31.25~2 000 ng·mL-1, 包括ULOQ (2 000 ng·mL-1)、HQC (1 600 ng·mL-1)、MQC (400 ng·mL-1)、LQC (80 ng·mL-1)和LLOQ (31.25 ng·mL-1); 结合抗体的定量范围为39.3~5 000 ng·mL-1, 质控样本为ULOQ (2 500 ng·mL-1)、HQC (2 000 ng·mL-1)、MQC (400 ng·mL-1)、LQC (100 ng·mL-1)和LLOQ (39.3 ng·mL-1), 质控样品各浓度点平行6个样品, 在不同天内进行6批次的验证分析, 所有质控样品的批内、批间精密度CV%为1.6%~13.2%之间, 准确度RE%在-16.3%~9.0%内, 总误差在6.5%~24.7%内, 其分析方法满足精密度与准确度的法规要求。
1.2 选择性
选择性的验证结果如图 2A、B所示, 10个不同来源正常个体基质的LLOQ和ULOQ浓度的血清样本, 未加分析物的空白基质随行质控样本分析, 表明总抗体和结合抗体的空白基质检测结果均为低于定量下限; ULOQ水平的80%样品回算浓度的准确度均在-16.0%~12.0%内, 结合抗体的LLOQ水平70%样品回算浓度的准确度在-24.7%~4.1%内, 虽未满足接受标准, 但结合方法学开发过程, 推断是由于方法的变异造成的, 与个体差异无关。综上所述, 个体存在非相关物质下, 测定待测物是可靠的。
1.3 稀释线性和钩状效应
在PK实际样本检测时, 有个别药物浓度点会高于标准曲线的定量上限, 需要稀释后落入标准曲线内才可定量, 因此考察稀释线性和钩状效应是必要的。稀释线性是分别1∶10 000、1∶1 000、1∶100和1∶10稀释配制成1 000 000、100 000、10 000和800 ng·mL-1, 其回算浓度的准确度RE%在-17.5%~-0.1%之间。结果表明, 浓度均在1 000 000 ng·mL-1呈现钩状效应, 其他浓度点无钩状效应。
1.4 稳定性
稳定性考察是在食蟹猴空白血清中加入RC108, 总抗体和结合抗体分别配制其对应的HQC和LQC浓度的质控样品。短期稳定性: 室温放置一定时间后, RE%在-15.9%~-6.6%之间, CV%均≤ 3.3%; 冻融稳定性: 在-75 ℃ ± 15 ℃冻融12 h和室温解冻, 共冻融5个循环, RE%在-6.7%~9.7%内, CV% ≤ 6.0%; 长期稳定性: 分别在-75 ℃ ± 15 ℃下冻存1个月和2个月, RE%在-14.5%~3.8%范围内, CV% ≤ 4.0%; 综上所有条件的稳定性均满足接受标准。
2 UPLC-MS/MS法分析Free-MMAE的开发与验证
2.1 专属性
在优化质谱液相参数后, 空白基质和定量下限的图谱见图 3所示, 研究表明MMAE保留时间为1.28 min, 空白基质中在目标分析物的出峰位置无干扰。
2.2 标准曲线
精密称取MMAE对照品2.523 mg溶于DMSO, 配制成1.0 mg·mL-1的母液, 用稀释液50%乙腈分别配制为200、160、100、40、10、4、0.8、0.4 ng·mL-1的工作液, 随后在血清基质中加入上述工作液, 得到10、8、5、2、0.5、0.2、0.04、0.02 ng·mL-1的标准曲线样品, 按照LC-MS/MS定量分析MMAE进行样品处理, 在不同天内完成5个批次的测定, 结果表明标准曲线为0.02~10 ng·mL-1, R2 ≥ 0.99, 显示了良好的线性, 批间和批内准确度RE%在-12.8%~8.5%之间, 精密度≤ 5.4%。
2.3 准确度与精密度
质控样本同标准曲线样本处理一致, 包括HQC (7.5 ng·mL-1)、MQC (4 ng·mL-1)LQC (0.06 ng·mL-1)和LLOQ (0.02 ng·mL-1), 每个浓度6个重复, 随行标准曲线考察, 结果证明了批内准确度RE%在-13.7%~12.2%之间, 精密度CV% ≤ 6.3%; 批间准确度RE%在-5.5%~6.5%内, 精密度CV%在4.3%~8.1%内, 满足接受标准。
2.4 选择性
选择性考察了6个不同来源正常个体基质和1个来源的食蟹猴个体溶血基质, 分别配制LLOQ血清样本和空白基质样本, 结果表明, 在分析物保留时间处的干扰最大为2.9%, 内标保留时间处无干扰, 其分析物和内标的干扰均满足要求。
2.5 稳定性
稳定性考察是在LQC和HQC下进行的, 自动进样器稳定性: 在自动进样器4 ℃放置151 h, 其准确度RE%为-14.8%~-4.8%内, CV%在3.8%~6.3%之间; 冻融稳定性: 在-75 ℃ ± 15 ℃冻融12 h和室温解冻, 共冻融5个循环, 准确度RE%为-11.5%~ -1.3%内, CV%均≤ 6.2%; 长期稳定性: 在-75 ℃ ± 15 ℃放置29天, 其准确度RE%为-12.8%~4.5%内, CV%在2.2%~6.6%之间。在所有条件下, 稳定性均符合生物分析的方法学要求。
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随着药物研究发展得越来越快, 大分子药物优点已逐渐显现出来, 其中ADC药物因其高效低毒已被广大药物研发人员关注[12]。但是ADC药物本身因其结构的复杂性, 结合了小分子药物和大分子生物治疗药物的分子特征, 这一事实为PK生物分析带来了根本挑战[6, 7]。通常, 对于单克隆抗体或小分子药物明确定义, 分析治疗药物在血浆或血清中的随时间浓度变化, 用于体内研究, 哪怕生物治疗药物可能存在些微异质性, 或小分子药物存在代谢产物, 但生物分析通常只分析主要母体分子种类随时间浓度的变化, 利用时间-浓度曲线来计算药物的PK参数, 探索药物的安全性与疗效的潜在关系[13, 14]。
相比之下, ADC药物在体内是一种复杂且动态变化的混合物, 包括生物转化、体内药物抗体比值(drug-to-antibody ratio, DRA)动态变化或这些过程的组合引起的, 难以确定究竟是哪一种待测物决定或影响ADC的生物学功能, 因此, ADC的PK生物分析一般会在多维度去分析。基于此, 理论上根据ADC药物体内的混合物成分潜在的分析物包含: ①总抗体, 是指ADC药物中所有的抗体包括结合抗体和游离抗体。它的测定对于了解ADC是否具有抗体的一般PK特性, 在体内的清除可能表明抗体与体内抗原的结合是否是稳定的, 作为靶向递送剂是否是合适的。②结合型ADC, 结合抗体指与小分子结合的抗体, 不包含游离抗体的部分; 结合药物指在小分子角度, 结合在抗体上所有小分子的结合型ADC, 不包含游离小分子。通过测定结合型ADC可以了解抗体载药量的信息, 与总抗体的数据进行比较, 可以大致评估ADC体内平均DAR值的变化, 这有利于了解ADC的整体命运, 为ADC体内生物转化提供理论依据。③游离药物, 是指抗体上解离下来的小分子药物。游离小分子药物的浓度被认定为与毒性相关, 若游离小分子药物广泛地分布在血浆中, 可能发生脱靶作用, 产生毒性[15, 16]。
由于ADC的异质性和复杂性, 多种物质可能会有助于ADC的功效或导致其毒性, 在临床前阶段, 尽可能测定多种分析物来了解ADC各个组成部分的PK特性。目前在本行业中推荐用上述待测物总抗体、结合抗体和游离有效载荷作为ADC的PK的主要分析物, 因此建立准确、可靠的生物分析方法至关重要[17, 18]。
对于ADC药物的检测, LBA方法跟LC-MS/MS法已有较为成熟的研究与应用[19-22]。比如在Peng等[23]的研究中, 他们通过LBA的方法能够精准检测大鼠血浆中抗体偶联药物浓度, 有很高的精确度, 但依然要依赖于捕获试剂、孵育时间等条件。在Huang等[24]的研究中, 使用定量完整的高分辨质谱和替代分析物来表征抗体-药物偶联物的药代动力学和体内生物转化, 他们建立的方法有着高通量的优势, 可以较为快速、大批量地检测药物浓度, 但是在灵敏度上仍有不足。因此, 若将LBA和LC-MS/MS两者结合起来, 既满足灵敏度, 又不依赖于捕获试剂、孵育时间等, 并且LC-MS/MS可同时检测多个分析物(总抗体和小分子), 这将大大提高对ADC的定量分析, 但是其前处理较繁琐, 这也是现阶段的挑战之一, 随着仪器性能的提高, 后期LBA & LC-MS/MS将更广泛地应用到ADC药物监测中。
作者贡献: 周宏雨主要负责数据整理、实验方法学开发、撰写论文; 王淑娟主要负责数据整理、实验方法学开发; 刘志浩主要负责数据整理; 马克负责实验方法学开发; 王凌主要负责数据整理; 姜静主要负责构思、文章审查和编辑、实验监督、资金获取。
利益冲突: 所有作者均声明不存在利益冲突。
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  • 山东省自然科学基金项目(R2021MH220)
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2023年第58卷第6期
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doi: 10.16438/j.0513-4870.2022-1350
  • 接收时间：2022-12-08
  • 首发时间：2025-11-21
  • 出版时间：2023-06-12
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  • 收稿日期：2022-12-08
  • 修回日期：2023-04-01
基金
山东省自然科学基金项目(R2021MH220)
作者信息
    1.滨州医学院, 山东 烟台 264003
    2.荣昌生物制药(烟台)股份有限公司, 山东 烟台 265503
    3.军科正源(北京)药物研究有限责任公司, 北京 102206

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
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红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
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