Toxicity associated with antibody-drug conjugates and corresponding research strategies

doi:10.19803/j.1672-8629.20240356

Abstract

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

CLC Number:

R979.1

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.

Add to citation manager EndNote|Ris|BibTeX

URL: https://zgywjj.magtechjournal.com/EN/10.19803/j.1672-8629.20240356

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

References

[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.