Hepatotoxicity with antibody maytansinoid conjugates: A review of preclinical and clinical findings

Taplin, Sarah; Vashisht, Kapil; Walles, Markus; Calise, David; Kluwe, William M.; Bouchard, Page; Johnson, Robert C.

doi:10.1002/jat.3582

Cited by 20 publications

(17 citation statements)

References 118 publications

(226 reference statements)

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“…DM4 is a thiol-bearing maytansinoid that contains methyl disulfide substitutions at the C3 N-acyl-N-methyl-L-alanyl ester side chain of maytansine, being suitable for monoclonal antibody attachment [ 58 ]. It exerts its anticancer activity by inhibiting tubulin assembly into microtubules and arresting cell cycle in the G2/M phase [ 59 ]. Finally, topoisomerase I inhibitors are also used.…”

Section: Adcs In Gynecological Tumors: Structure and Functionmentioning

confidence: 99%

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

2021

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In the last decade, antibody-drug conjugates (ADCs), normally formed by a humanized antibody and a small drug via a chemical cleavable or non-cleavable linker, have emerged as a potential treatment strategy in cancer disease. They allow to get a selective delivery of the chemotherapeutic agents at the tumor level, and, consequently, to improve the antitumor efficacy and, especially to decrease chemotherapy-related toxicity. Currently, nine antibody-drug conjugate-based formulations have been already approved and more than 80 are under clinical trials for the treatment of several tumors, especially breast cancer, lymphomas, and multiple myeloma. To date, no ADCs have been approved for the treatment of gynecological formulations, but many formulations have been developed and have reached the clinical stage, especially for the treatment of ovarian cancer, an aggressive disease with a low five-year survival rate. This manuscript analyzes the ADCs formulations that are under clinical research in the treatment of gynecological carcinomas, specifically ovarian, endometrial, and cervical tumors.

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Section: Adcs In Gynecological Tumors: Structure and Functionmentioning

confidence: 99%

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

2021

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“…Metabolites and catabolites of the drug molecule, with or without the linker, may also be detected [206][207][208][209][210][211]. Pharmacokinetic profiling highlights the impact of the DAR [212] and other perfectible parameters on the biological properties of ADCs, notably the rate of drug loss (from deconjugation and instability) and the clearance of the species with different DARs [213].…”

Section: Adc Bioanalyticsmentioning

confidence: 99%

Cutting-edge multi-level analytical and structural characterization of antibody-drug conjugates: present and future

Beck

D’Atri

Ehkirch

et al. 2019

Expert Review of Proteomics

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Introduction: The development and optimization of antibody drug conjugates (ADCs) rely on improving their analytical and bioanalytical characterization, by assessing critical quality attributes (CQAs). Among the CQAs, the glycoprofile, drug load distribution (DLD), the amount of unconjugated antibody (D0), the average drug-to-antibody ratio (DAR), the drug conjugation sites and the residual drug-linker and related product proportions (SMDs) in addition to high and low molecular weight species (H/LMWS) are the most important ones. Areas covered: The analytical and structural toolbox for the characterization of 1 st , 2 d and 3 d generation ADCs was significantly extended in the last 3 years. Here, we reviewed state-ofthe-art techniques, such as liquid chromatography, high resolution native and ion mobility mass spectrometry, multidimensional LC and capillary electrophoresis hyphenated to mass spectrometry, reported mainly since 2016. Expert commentary: These emerging techniques allow a deep insight into important CQAs that are related to ADC Chemistry Manufacturing and Control (CMC) as well as an improved understanding of in vitro and in vivo ADC biotransformations. This knowledge and the development of quantitative bioanalytical assays will continue to contribute to earlydevelopability assessment for the optimization of all the ADC components (i.e., antibody, drug, and linker) and help to bring next-generation candidate ADC into the clinic and hopefully to the market.

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“…Maytansine was first isolated in 1972 from the plant Maytenus ovatus [1] and showed potent cytotoxic effects in cell-based systems and efficacy in animal tumor models by binding to tubulin and blocking microtubule assembly [1][2][3][4][5]. However, maytansine failed as an anticancer drug in human clinical trials because of its unacceptable systemic toxicity [5][6][7]. Many maytansinoids, chemical derivatives of maytansine, showed higher cytotoxicity-by 100-1000 times-than other tubulin inhibitors, vincristine and vinblastine, in cancer cell lines in vitro [7,8].…”

Section: Introductionmentioning

confidence: 99%

“…However, maytansine failed as an anticancer drug in human clinical trials because of its unacceptable systemic toxicity [5][6][7]. Many maytansinoids, chemical derivatives of maytansine, showed higher cytotoxicity-by 100-1000 times-than other tubulin inhibitors, vincristine and vinblastine, in cancer cell lines in vitro [7,8]. The structure-antitumor activity relationship revealed that the ester side chain of maytansine plays an important role in the anti-tumor activity as well as tubulin binding [8].…”

Section: Introductionmentioning

confidence: 99%

Mertansine Inhibits mRNA Expression and Enzyme Activities of Cytochrome P450s and Uridine 5′-Diphospho-Glucuronosyltransferases in Human Hepatocytes and Liver Microsomes

et al. 2020

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Mertansine, a tubulin inhibitor, is used as the cytotoxic component of antibody–drug conjugates (ADCs) for cancer therapy. The effects of mertansine on uridine 5′-diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes and its effects on the mRNA expression of cytochrome P450s (CYPs) and UGTs in human hepatocytes were evaluated to assess the potential for drug–drug interactions (DDIs). Mertansine potently inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-β-glucuronidation, and UGT1A4-catalyzed trifluoperazine N-β-d-glucuronidation, with Ki values of 13.5 µM, 4.3 µM, and 21.2 µM, respectively, but no inhibition of UGT1A6, UGT1A9, and UGT2B7 enzyme activities was observed in human liver microsomes. A 48 h treatment of mertansine (1.25–2500 nM) in human hepatocytes resulted in the dose-dependent suppression of mRNA levels of CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C9, CYP2C19, UGT1A1, and UGT1A9, with IC50 values of 93.7 ± 109.1, 36.8 ± 18.3, 160.6 ± 167.4, 32.1 ± 14.9, 578.4 ± 452.0, 539.5 ± 233.4, 856.7 ± 781.9, and 54.1 ± 29.1 nM, respectively, and decreased the activities of CYP1A2-mediated phenacetin O-deethylase, CYP2B6-mediated bupropion hydroxylase, and CYP3A4-mediated midazolam 1′-hydroxylase. These in vitro DDI potentials of mertansine with CYP1A2, CYP2B6, CYP2C8/9/19, CYP3A4, UGT1A1, and UGT1A9 substrates suggest that it is necessary to carefully characterize the DDI potentials of ADC candidates with mertansine as a payload in the clinic.

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Hepatotoxicity with antibody maytansinoid conjugates: A review of preclinical and clinical findings

Cited by 20 publications

References 118 publications

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

Cutting-edge multi-level analytical and structural characterization of antibody-drug conjugates: present and future

Mertansine Inhibits mRNA Expression and Enzyme Activities of Cytochrome P450s and Uridine 5′-Diphospho-Glucuronosyltransferases in Human Hepatocytes and Liver Microsomes

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