抗体偶联药物的相关毒性和研究对策

doi:10.19803/j.1672-8629.20240356

中国药物警戒 ›› 2024, Vol. 21 ›› Issue (7): 721-729.
DOI: 10.19803/j.1672-8629.20240356

抗体偶联药物的相关毒性和研究对策

刘连奇, 肖典, 钟武, 周辛波^#, 李松^*

军事医学研究院国家应急防控药物工程技术研究中心,北京 100850

收稿日期:2024-05-27 出版日期:2024-07-15 发布日期:2024-07-31
通讯作者: ^* 李松,男,研究员,中国工程院院士,新药设计与合成。李松,中国工程院院士,现任中国药学会副理事长、军事科学院军事医学研究院研究员。领衔获得国家科技进步奖一等奖2项,国家技术发明二等奖1项、省部级科技进步奖6项。长期从事药物分子设计和合成研究,率先开展计算机辅助药物大规模筛选新技术新方法研究。建立了我国自主防控流感大流行药物的国家能力储备生产线,并出色完成了国家抗流感药品战略储备任务,建成了我军第一个军用特需药物中试基地和高效发现平台。主持研发了5个新药,在国家战略性药物和军队特需药物的研究中做出突出贡献。获国家新药证书10项,军队特需新药证书4项。以第一发明人获得中国、美国、欧盟、日本等国发明专利授权110项。发表研究论文100余篇。E-mail：lis.lisong@gmail.com;^#为共同通信作者。
作者简介:刘连奇,男,助理研究员,新药设计与合成。
基金资助:
国家自然科学基金资助项目（L2324220）

Toxicity associated with antibody-drug conjugates and corresponding research strategies

LIU Lianqi, XIAO Dian, ZHONG Wu, ZHOU Xinbo^#, LI Song^*

National Engineering Research Center for the Strategic Drug of AMMS, Beijing 100850, China

Received:2024-05-27 Online:2024-07-15 Published:2024-07-31

摘要/Abstract

摘要： 目的探讨新兴抗肿瘤药物抗体偶联药物（antibody drug conjugate, ADC）的毒性、毒性诱发原因以及避免毒性的研究对策,以期为下一代新型高效低毒ADC研发提供参考。方法分析整理近年来已上市以及处于临床阶段的ADC毒性数据,从ADC结构入手,理清ADC结构与毒性产生的关系,参考现阶段避免毒性的有效对策,寻找下一代高效低毒ADC的发展方向。结果及结论 针对ADC研发的不同阶段,提供避免毒性的研究对策,其中ADC源头设计理念的更新是解决ADC毒性的关键。

关键词: 抗体偶联药物, 抗肿瘤, 效应分子, 毒性, 安全性

Abstract: Objective To explore the toxicity, causes of toxicity, and strategies to minimize toxicity of antibody-drug conjugates (ADCs), an emerging class of anticancer therapeutics, in order to provide reference for the development of the next generation of ADCs with high efficacy and low toxicity. Methods The data on toxicity of ADCs that had been marketed and were in clinical trials was summarized and analyzed. By focusing on the structure of ADCs, the relationship between structure of ADCs and generated toxicities was revealed. By referring to effective strategies for minimizing toxicities in place, the future developments of the next generation of ADCs with high efficacy and low toxicity were predicted. Results and Conclusion Research strategies for preventing toxicities are provided for different stages of ADC development. Among them, updated and core concepts of the design of ADCs are crucial to addressing the toxicities of ADCs.

Key words: antibody drug conjugate, antitumor, payloads, toxicity, safety

中图分类号:

R979.1

刘连奇, 肖典, 钟武, 周辛波, 李松. 抗体偶联药物的相关毒性和研究对策[J]. 中国药物警戒, 2024, 21(7): 721-729.

LIU Lianqi, XIAO Dian, ZHONG Wu, ZHOU Xinbo, LI Song. Toxicity associated with antibody-drug conjugates and corresponding research strategies[J]. Chinese Journal of Pharmacovigilance, 2024, 21(7): 721-729.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://zgywjj.magtechjournal.com/CN/10.19803/j.1672-8629.20240356

https://zgywjj.magtechjournal.com/CN/Y2024/V21/I7/721

参考文献

[1] DAI LJ, LI YW, MA D, et al.Next-generation antibody-drug conjugates revolutionize the precise classification and treatment of HER2-expressing breast cancer[J]. Cancer Biology & Medicine, 2023, 20(10): 689.
[2] LI M, ZHAO X, YU C, et al.Antibody-drug conjugate overview: a state-of-the-art manufacturing process and control strategy[J]. Pharmaceutical Research, 2024, 41(3): 419-440.
[3] VENEZIANI AC, SNEHA S, OZA AM.Antibody-drug conjugates: advancing from magic bullet to biological missile[J]. Clinical Cancer Research, 2024, 30(8): 1434-1437.
[4] BAAH S, LAWS M, RAHMAN KM.Antibody-drug conjugates-a tutorial review[J]. Molecules, 2021, 26(10): 2943.
[5] FU Z, LI S, HAN S, et al.Antibody drug conjugate: the“biological missile”for targeted cancer therapy[J]. Signal Transduction and Targeted Therapy, 2022, 7(1): 93.
[6] RICCARDI F, DAL BOM, MACOR P, et al.A comprehensive overview on antibody-drug conjugates: from the conceptualization to cancer therapy[J]. Frontiers in Pharmacology, 2023, 14: 1274088.
[7] NGUYEN TD, BORDEAU BM, BALTHASAR JP.Mechanisms of ADC toxicity and strategies to increase ADC tolerability[J]. Cancers, 2023, 15(3): 713.
[8] GOGIA P, ASHRAF H, BHASIN S, et al.Antibody-drug conjugates: a review of approved drugs and their clinical level of evidence[J]. Cancers, 2023, 15(15): 3886.
[9] ZHU Y, LIU K, WANG K, et al.Treatment-related adverse events of antibody-drug conjugates in clinical trials: a systematic review and Meta-analysis[J]. Cancer, 2023, 129(2): 283-295.
[10] ADVANI A, COIFFIER B, CZUCZMAN MS, et al.Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin’s lymphoma: results of a phase I study[J]. Journal of Clinical Oncology, 2010, 28(12): 2085-2093.
[11] UPPAL H, DOUDEMENT E, MAHAPATRA K, et al.Potential mechanisms for thrombocytopenia development with trastuzumab emtansine (T-DM1)[J]. Clinical Cancer Research, 2015, 21(1): 123-133.
[12] KESIREDDY M, KOTHAPALLI SR, GUNDEPALLI SG, et al.A review of the current FDA-approved antibody-drug conjugates: landmark clinical trials and indications[J]. Pharmaceutical Medicine, 2024, 38(1): 39-54.
[13] LINDGREN ES, YAN R, CIL O, et al.Incidence and mitigation of corneal pseudomicrocysts induced by antibody-drug conjugates(ADCs)[J]. Current Ophthalmology Reports, 2024, 12(2): 13-22.
[14] MITA M, RICART A, MITA A, et al.A phase I study of a CanAg-targeted immunoconjugate, huC242-DM4, in patients with Can Ag-expressing solid tumors[J]. Journal of Clinical Oncology, 2007, 25(18Suppl): 3062.
[15] BORGHAEI H, O’MALLEY DM, SEWARD SM, et al. Phase 1 study of IMGN853, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC) in patients (Pts) with epithelial ovarian cancer (EOC) and other FRA-positive solid tumors[Z]. American Society of Clinical Oncology, 2015.
[16] THOMPSON JA, MOTZER R, MOLINA AM, et al.Phase I studies of anti-ENPP3 antibody drug conjugates (ADCs) in advanced refractory renal cell carcinomas (RRCC)[Z]. American Society of Clinical Oncology, 2015.
[17] TANNIR NM, FORERO-TORRES A, RAMCHANDREN R, et al.Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma[J]. Investigational New Drugs, 2014, 32: 1246-1257.
[18] YOUNES A, BARTLETT NL, LEONARD JP, et al.Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas[J]. New England Journal of Medicine, 2010, 363(19): 1812-1821.
[19] VAKLAVAS C, FORERO-TORRES A.Safety and efficacy of brentuximab vedotin in patients with Hodgkin lymphoma or systemic anaplastic large cell lymphoma[J]. Therapeutic Advances in Hematology, 2012, 3(4): 209-225.
[20] YOUNES A, GOPAL AK, SMITH SE, et al.Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma[J]. Journal of Clinical Oncology, 2012, 30(18): 2183.
[21] TIJINK BM, BUTER J, DE BREE R, et al.A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus[J]. Clinical Cancer Research, 2006, 12(20): 6064-6072.
[22] TARANTINO P, RICCIUTI B, PRADHAN SM, et al.Optimizing the safety of antibody-drug conjugates for patients with solid tumours[J]. Nature Reviews Clinical Oncology, 2023, 20(8): 558-576.
[23] GUFFROY M, FALAHATPISHEH H, FINKELSTEIN M.Improving the safety profile of ADCs[M]//Innovations for Next-Generation Antibody-Drug Conjugates. USA: Humana Cham, 2018: 45-71.
[24] SABER H, LEIGHTON JK.An FDA oncology analysis of antibody-drug conjugates[J]. Regulatory Toxicology and Pharmacology, 2015, 71(3): 444-452.
[25] MASTERS JC, NICKENS DJ, XUAN D, et al.Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads[J]. Investigational New Drugs, 2018, 36: 121-135.
[26] ROSENBERG J, SRIDHAR SS, ZHANG J, et al.EV-101: a phase I study of single-agent enfortumab vedotin in patients with nectin-4-positive solid tumors, including metastatic urothelial carcinoma[J]. Journal of Clinical Oncology, 2020, 38(10): 1041.
[27] LIU X, DENG J, ZHANG R, et al.The clinical development of antibody-drug conjugates for non-small cell lung cancer therapy[J]. Frontiers in Immunology, 2023, 14: 1335252.
[28] SABER H, SIMPSON N, RICKS TK, et al.An FDA oncology analysis of toxicities associated with PBD-containing antibody-drug conjugates[J]. Regulatory Toxicology and Pharmacology, 2019, 107: 104429.
[29] LÓPEZ DE SÁA, DÍAZ-TEJEIRO C, POYATOS-RACIONEROE, et al. Considerations for the design of antibody drug conjugates (ADCs) for clinical development: lessons learned[J]. Journal of Hematology & Oncology, 2023, 16(1): 118.
[30] PONZIANI S, DI VITTORIO G, PITARI G, et al.Antibody-drug conjugates: the new frontier of chemotherapy[J]. International Journal of Molecular Sciences, 2020, 21(15): 5510.
[31] POLSON AG, CALEMINE-FENAUX J, CHAN P, et al.Antibody-drug conjugates for the treatment of non-hodgkin’s lymphoma: target and linker-drug selection[J]. Cancer Research, 2009, 69(6): 2358-2364.
[32] DRAGO JZ, MODI S, CHANDARLAPATY SJ.Unlocking the potential of antibody-drug conjugates for cancer therapy[J]. Nature Reviews Clinical Oncology, 2021, 18(6): 327-344.
[33] CHALLITA-EID PM, SATPAYEV D, YANG P, et al.Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models[J]. Cancer Research, 2016, 76(10): 3003-3013.
[34] GOROVITS B, KRINOS-FIOROTTI CJ.Proposed mechanism of off-target toxicity for antibody-drug conjugates driven by mannose receptor uptake[J]. Cancer Immunology, Immunotherapy, 2013, 62: 217-223.
[35] STEPAN LP, TRUEBLOOD ES, HALE K, et al.Expression of Trop2 cell surface glycoprotein in normal and tumor tissues: potential implications as a cancer therapeutic target[J]. Journal of Histochemistry & Cytochemistry, 2011, 59(7): 701-710.
[36] HONG DS, CONCIN N, VERGOTE I, et al.Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer[J]. Clinical Cancer Research, 2020, 26(6): 1220-1228.
[37] DRAKE PM, RABUKA D.Recent developments in ADC technology: preclinical studies signal future clinical trends[J]. BioDrugs, 2017, 31(6): 521-531.
[38] DE GOEIJ BE, LAMBERT JM .New developments for antibody-drug conjugate-based therapeutic approaches[J]. Current Opinion in Immunology, 2016, 40: 14-23.
[39] DUVALL JR, BUKHALID RA, CETINBAS NM, et al.XMT-2056, a HER2-targeted Immunosynthen STING-agonist antibody-drug conjugate, binds a novel epitope of HER2 and shows increased anti-tumor activity in combination with trastuzumab and pertuzumab[J]. Cancer Res, 2022, 82(12Suppl): 3503-3503.
[40] Mersana Therapeutics. Mersana Therapeutics Announces Clinical Hold on XMT-2056 Phase 1 Clinical Trial[EB/OL].(2023-03-13)[2024-01-29]. https://ir.mersana.com/news-releases/news-release-details/mersana-therapeutics-announces-clinical-hold-xmt-2056-phase-1.
[41] DESLIGNIÈRE E, EHKIRCH A, DUIVELSHOF BL, et al. State-of-the-art native mass spectrometry and ion mobility methods to monitor homogeneous site-specific antibody-drug conjugates synthesis[J]. Pharmaceuticals, 2021, 14(6): 498.
[42] AOYAMA M, TADA M, YOKOO H, et al.Fcγ receptor-dependent internalization and off-target cytotoxicity of antibody-drug conjugate aggregates[J]. Pharmaceutical Research, 2022, 39(1): 89-103.
[43] SUN X, PONTE JF, YODER NC, et al.Effects of drug-antibody ratio on pharmacokinetics, biodistribution, efficacy, and tolerability of antibody-maytansinoid conjugates[J]. Bioconjugate Chemistry, 2017, 28(5): 1371-1381.
[44] JUNUTULA JR, RAAB H, CLARK S, et al.Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index[J]. Nature Biotechnology, 2008, 26(8): 925-932.
[45] CHUPRAKOV S, OGUNKOYA AO, BARFIELD RM, et al.Tandem-cleavage linkers improve the in vivo stability and tolerability of antibody-drug conjugates[J]. Bioconjugate Chemistry, 2021, 32(4): 746-754.
[46] ANAMI Y, YAMAZAKI CM, XIONG W, et al.Glutamic acid-valine-citrulline linkers ensure stability and efficacy of antibody-drug conjugates in mice[J]. Nature Communications 2018, 9(1): 2512.
[47] HA SY, ANAMI Y, YAMAZAKI CM, et al.An enzymatically cleavable tripeptide linker for maximizing the therapeutic index of antibody-drug conjugates[J]. Molecular Cancer Therapeutics, 2022, 21(9): 1449-1461.
[48] BURKE PJ, HAMILTON JZ, JEFFREY SC, et al.Optimization of a PEGylated glucuronide-monomethylauristatin E linker for antibody-drug conjugates[J]. Molecular Cancer Therapeutics, 2017, 16(1): 116-123.
[49] SIMMONS JK, BURKE PJ, COCHRAN JH, et al.Reducing the antigen-independent toxicity of antibody-drug conjugates by minimizing their non-specific clearance through PEGylation[J]. Toxicology and Applied Pharmacology, 2020, 392: 114932.
[50] LEE A.Loncastuximab tesirine: first approval[J]. Drugs, 2021, 81(10): 1229-1233.
[51] SYED YY.Sacituzumab govitecan: first approval[J]. Drugs, 2020, 80(10): 1019-1025.
[52] WANG Y, XIAO D, LI J, et al.From prodrug to pro-prodrug: hypoxia-sensitive antibody-drug conjugates[J]. Signal Transduction and Targeted Therapy, 2022, 7(1): 20.
[53] XIAO D, LIU L, XIE F, et al.Azobenzene-based linker strategy for selective activation of antibody-drug conjugates[J]. Angewandte Chemie, 2024, 63(16): e202310318.
[54] MILLER ML, FISHKIN NE, LI W, et al.A new class of antibody-drug conjugates with potent DNA alkylating activity[J]. Molecular Cancer Therapeutics, 2016, 15(8): 1870-1878.
[55] CASTAIGNE S, PAUTAS C, TERRÉ C, et al.Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study[J]. Lancet, 2012, 379(9825): 1508-1516.
[56] SAPRA P, BETTS A, BONI J.Preclinical and clinical pharmacokinetic/pharmacodynamic considerations for antibody-drug conjugates[J]. Expert Review of Clinical Pharmacology, 2013, 6(5): 541-555.

抗体偶联药物的相关毒性和研究对策

Toxicity associated with antibody-drug conjugates and corresponding research strategies

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

[1]	魏曼莉, 吕林艳, 郑志远, 尹纪业, 麦志雄. 血栓通注射液临床前遗传毒性研究[J]. 中国药物警戒, 2024, 21(9): 1014-1018.
[2]	刘畅, 施畅, 尹纪业. 嵌合抗原受体T细胞产品非临床免疫毒性评价思考[J]. 中国药物警戒, 2024, 21(9): 1051-1055.
[3]	刘婷, 曹忠强, 何文佳, 袁秀丽, 陈泽彬, 李学娟. 培门冬酶注射液致急性重症胰腺炎1例分析[J]. 中国药物警戒, 2024, 21(9): 1075-1077.
[4]	郑丽, 张凯华, 孙雪林. 小细胞肺癌治疗新药Tarlatamab药理作用及临床评价[J]. 中国药物警戒, 2024, 21(9): 1078-1080.
[5]	王岩, 滕晶晶, 杨同金, 夏新, 喻丹丹, 占海兵, 杨文明. 智脑胶囊长期毒性研究[J]. 中国药物警戒, 2024, 21(8): 878-883.
[6]	孙一鑫, 聂晓璐, 王晓玲, 郭鹏. 国内外基于真实世界数据的药品上市后安全性主动监测系统对比分析[J]. 中国药物警戒, 2024, 21(8): 892-899.
[7]	刘倩, 李博, 疏欣扬. 蓝芩口服液联合抗菌药物治疗急性扁桃体炎有效性与安全性的系统评价与Meta分析[J]. 中国药物警戒, 2024, 21(8): 916-920.
[8]	姜海伦, 周辛波, 肖典, 钟武, 李松. 蛋白水解靶向嵌合体类药物及其潜在风险分析[J]. 中国药物警戒, 2024, 21(7): 730-734.
[9]	刘亚迪, 张晓朦, 蔡海丽, 陈思颖, 王雨, 张冰. 阿霉素心脏毒性的中药防治用药分析及证素实证研究[J]. 中国药物警戒, 2024, 21(7): 759-764.
[10]	蔡海丽, 张晓朦, 刘亚迪, 刘淑佳, 高福君, 王雨, 张冰. 药源性心脏毒性模型的构建与评价进展[J]. 中国药物警戒, 2024, 21(7): 765-770.
[11]	胡笑文, 张才煜, 王峰峰, 濮恒婷, 刘阳, 陈华. 基于规定日服用剂量改进药物肝毒性预测方法的研究[J]. 中国药物警戒, 2024, 21(7): 776-780.
[12]	程毅菁, 李涛, 刘军廷, 黄贵民, 钟旭丽, 林爱华, 潘守东, 李龙, 白东升, 占小俊, 刘振江, 任韡, 聂晓璐, 邰隽. 基于真实世界数据的注射用尖吻蝮蛇血凝酶儿童用药安全性评价[J]. 中国药物警戒, 2024, 21(7): 787-790.
[13]	葛运炫, 王宇光, 张卓, 马增春, 高月. 附子中次乌头碱调控miR-134对心肌细胞hERG通道的影响[J]. 中国药物警戒, 2024, 21(6): 606-610.
[14]	敖婷, 王宁宁, 周磊, 邓慧芳, 杨兴鑫, 周维, 沈磐, 高月. 基于临床用药特点的补骨脂斑马鱼肝毒性确证与机制探讨[J]. 中国药物警戒, 2024, 21(6): 611-616.
[15]	苏海, 昝孟晴, 牛剑钊, 马铃云, 刘倩. 高效液相色谱法测定乙醇对格列吡嗪控释片体外释放行为的影响[J]. 中国药物警戒, 2024, 21(6): 638-643.