Characterization of in Vivo Biotransformations for Trastuzumab Emtansine by High-resolution Accurate-mass Mass Spectrometry

Overview

Journal MAbs

Specialty Allergy & Immunology

Date 2018 Jun 30

PMID 29958059

Citations 9

Authors

Jintang He

Shang-Fan Yu

Sharon Yee

Surinder Kaur

Keyang Xu

Affiliations

Soon will be listed here.

Abstract

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) designed for the treatment of HER2-positive cancers. T-DM1 is composed of the humanized monoclonal antibody trastuzumab connected to a maytansine derivative cytotoxic drug, via a nonreducible thioether linker at random lysine residues, and therefore has a very complex molecular structure. It was anticipated that T-DM1 undergoes biotransformations in circulation. However, there was limited knowledge on these structural changes due to bioanalytical challenges. Here, we have investigated the in vivo biotransformations of T-DM1 using a high-resolution accurate-mass (HR/AM) mass spectrometry approach. Three types of biotransformations were characterized for T-DM1 in circulation in tumor-bearing mice, including cysteine or glutathione adduct formation via maleimide exchange, loss of maytansinol via ester hydrolysis, as well as addition of HO via linker-drug hydrolysis. These results provide new insights into in vivo catabolism of T-DM1.

Citing Articles

Antibody-Drug Conjugates in Non-Small Cell Lung Cancer: State of the Art and Future Perspectives.

Zanchetta C, De Marchi L, Macerelli M, Pelizzari G, Costa J, Aprile G Int J Mol Sci. 2025; 26(1.

PMID: 39796075 PMC: 11719753. DOI: 10.3390/ijms26010221.

Multiepitope recognition technology promotes the in-depth analysis of antibody‒drug conjugates.

Lei Y, Shen Y, Chen F, He R, Zhang Z, Zhou Y Acta Pharm Sin B. 2024; 14(11):4962-4976.

PMID: 39664422 PMC: 11628813. DOI: 10.1016/j.apsb.2024.06.007.

Extensive Biotransformation Profiling of AZD8205, an Anti-B7-H4 Antibody-Drug Conjugate, Elucidates Pathways Underlying Its Stability .

Huang Y, Tan H, Yuan J, Mu R, Yang J, Ball K Anal Chem. 2024; 96(42):16525-16533.

PMID: 39392424 PMC: 11503519. DOI: 10.1021/acs.analchem.4c02309.

The clinical development of antibody-drug conjugates for non-small cell lung cancer therapy.

Liu X, Deng J, Zhang R, Xing J, Wu Y, Chen W Front Immunol. 2024; 14:1335252.

PMID: 38162667 PMC: 10755013. DOI: 10.3389/fimmu.2023.1335252.

Current Analytical Strategies for Antibody-Drug Conjugates in Biomatrices.

Qin Q, Gong L Molecules. 2022; 27(19).

PMID: 36234836 PMC: 9572530. DOI: 10.3390/molecules27196299.

References

Carter P, Senter P . Antibody-drug conjugates for cancer therapy. Cancer J. 2008; 14(3):154-69. DOI: 10.1097/PPO.0b013e318172d704. View

Kaur S, Xu K, Saad O, Dere R, Carrasco-Triguero M . Bioanalytical assay strategies for the development of antibody-drug conjugate biotherapeutics. Bioanalysis. 2013; 5(2):201-26. DOI: 10.4155/bio.12.299. View

Nanna A, Li X, Walseng E, Pedzisa L, Goydel R, Hymel D . Harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates. Nat Commun. 2017; 8(1):1112. PMC: 5653646. DOI: 10.1038/s41467-017-01257-1. View

Lambert J, Chari R . Ado-trastuzumab Emtansine (T-DM1): an antibody-drug conjugate (ADC) for HER2-positive breast cancer. J Med Chem. 2014; 57(16):6949-64. DOI: 10.1021/jm500766w. View

Polakis P . Antibody Drug Conjugates for Cancer Therapy. Pharmacol Rev. 2015; 68(1):3-19. DOI: 10.1124/pr.114.009373. View

Pillow T, Tien J, Parsons-Reponte K, Bhakta S, Li H, Staben L . Site-specific trastuzumab maytansinoid antibody-drug conjugates with improved therapeutic activity through linker and antibody engineering. J Med Chem. 2014; 57(19):7890-9. DOI: 10.1021/jm500552c. View

Xu K, Liu L, Dere R, Mai E, Erickson R, Hendricks A . Characterization of the drug-to-antibody ratio distribution for antibody-drug conjugates in plasma/serum. Bioanalysis. 2013; 5(9):1057-71. DOI: 10.4155/bio.13.66. View

Barok M, Joensuu H, Isola J . Trastuzumab emtansine: mechanisms of action and drug resistance. Breast Cancer Res. 2014; 16(2):209. PMC: 4058749. DOI: 10.1186/bcr3621. View

Lewis Phillips G, Li G, Dugger D, Crocker L, Parsons K, Mai E . Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008; 68(22):9280-90. DOI: 10.1158/0008-5472.CAN-08-1776. View

10.

Jaracz S, Chen J, Kuznetsova L, Ojima I . Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005; 13(17):5043-54. DOI: 10.1016/j.bmc.2005.04.084. View

11.

He J, Su D, Ng C, Liu L, Yu S, Pillow T . High-Resolution Accurate-Mass Mass Spectrometry Enabling In-Depth Characterization of in Vivo Biotransformations for Intact Antibody-Drug Conjugates. Anal Chem. 2017; 89(10):5476-5483. DOI: 10.1021/acs.analchem.7b00408. View

12.

Erickson H, Park P, Widdison W, Kovtun Y, Garrett L, Hoffman K . Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 2006; 66(8):4426-33. DOI: 10.1158/0008-5472.CAN-05-4489. View

13.

Panowski S, Bhakta S, Raab H, Polakis P, Junutula J . Site-specific antibody drug conjugates for cancer therapy. MAbs. 2014; 6(1):34-45. PMC: 3929453. DOI: 10.4161/mabs.27022. View

14.

Amiri-Kordestani L, Blumenthal G, Xu Q, Zhang L, Tang S, Ha L . FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res. 2014; 20(17):4436-41. DOI: 10.1158/1078-0432.CCR-14-0012. View

15.

Shen B, Bumbaca D, Saad O, Yue Q, Pastuskovas C, Khojasteh S . Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine (T-DM1): an emphasis on preclinical and clinical catabolism. Curr Drug Metab. 2012; 13(7):901-10. DOI: 10.2174/138920012802138598. View

16.

Saad O, Shen B, Xu K, Khojasteh S, Girish S, Kaur S . Bioanalytical approaches for characterizing catabolism of antibody-drug conjugates. Bioanalysis. 2015; 7(13):1583-604. DOI: 10.4155/bio.15.87. View

17.

Xu K, Liu L, Saad O, Baudys J, Williams L, Leipold D . Characterization of intact antibody-drug conjugates from plasma/serum in vivo by affinity capture capillary liquid chromatography-mass spectrometry. Anal Biochem. 2011; 412(1):56-66. DOI: 10.1016/j.ab.2011.01.004. View

18.

Beck A, Goetsch L, Dumontet C, Corvaia N . Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017; 16(5):315-337. DOI: 10.1038/nrd.2016.268. View

19.

Ovrebo K, Svardal A . The effect of glutathione modulation on the concentration of homocysteine in plasma of rats. Pharmacol Toxicol. 2000; 87(3):103-7. DOI: 10.1111/j.0901-9928.2000.870301.x. View

20.

Iciek M, Chwatko G, Lorenc-Koci E, Bald E, Wlodek L . Plasma levels of total, free and protein bound thiols as well as sulfane sulfur in different age groups of rats. Acta Biochim Pol. 2004; 51(3):815-24. View