ACS Publications. Most Trusted. Most Cited. Most Read

OR SEARCH CITATIONS

My Activity
Publications
CONTENT TYPES

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:Mol. Pharmaceutics 2015, 12, 6, 1762-1773
RETURN TO ISSUEPREVArticleNEXT

Metabolites of Antibody–Maytansinoid Conjugates: Characteristics and in Vitro Potencies

View Author Information
ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States
*E-mail: [email protected]
Cite this: Mol. Pharmaceutics 2015, 12, 6, 1762–1773
Publication Date (Web):March 31, 2015
https://doi.org/10.1021/mp5007757
Copyright © 2015 American Chemical Society
Request reuse permissions

    Article Views

    1172

    Altmetric

    -

    Citations

    22
    LEARN ABOUT THESE METRICS
    Read OnlinePDF (2 MB)
    Get e-Alerts
    SUBJECTS:

    Abstract

    Abstract Image

    Several antibody–maytansinoid conjugates (AMCs) are in clinical trials for the treatment of various cancers. Each of these conjugates can be metabolized by tumor cells to give cytotoxic maytansinoid metabolites that can kill targeted cells. In preclinical studies in mice, the cytotoxic metabolites initially formed in vivo are further processed in the mouse liver to give several oxidized metabolic species. In this work, the primary AMC metabolites were synthesized and incubated with human liver microsomes (HLMs) to determine if human liver would likely give the same metabolites as those formed in mouse liver. The results of these HLM metabolism studies as well as the subsequent syntheses of the resulting HLM oxidation products are presented. Syntheses of the minor impurities formed during the conjugation of AMCs were also conducted to determine their cytotoxicities and to establish how these impurities would be metabolized by HLM.

    KEYWORDS:

    Cited By

    This article is cited by 22 publications.

    1. Wei Li, Karen H. Veale, Qifeng Qiu, Kerstin W. Sinkevicius, Erin K. Maloney, Juliet A. Costoplus, Janet Lau, Helen L. Evans, Yulius Setiady, Olga Ab, Stephen M. Abbott, Jenny Lee, Somsinee Wisitpitthaya, Anna Skaletskaya, Lintao Wang, Thomas A. Keating, Ravi V. J. Chari, Wayne C. Widdison. Synthesis and Evaluation of Camptothecin Antibody–Drug Conjugates. ACS Medicinal Chemistry Letters 2019, 10 (10) , 1386-1392. https://doi.org/10.1021/acsmedchemlett.9b00301
    2. Kelsey E. Knewtson, Chamani Perera, David Hymel, Zhe Gao, Molly M. Lee, Blake R. Peterson. Antibody–Drug Conjugate that Exhibits Synergistic Cytotoxicity with an Endosome–Disruptive Peptide. ACS Omega 2019, 4 (7) , 12955-12968. https://doi.org/10.1021/acsomega.9b01585
    3. Jose F. Ponte, Xiuxia Sun, Nicholas C. Yoder, Nathan Fishkin, Rassol Laleau, Jennifer Coccia, Leanne Lanieri, Megan Bogalhas, Lintao Wang, Sharon Wilhelm, Wayne Widdison, Jan Pinkas, Thomas A. Keating, Ravi Chari, Hans K. Erickson, and John M. Lambert . Understanding How the Stability of the Thiol-Maleimide Linkage Impacts the Pharmacokinetics of Lysine-Linked Antibody–Maytansinoid Conjugates. Bioconjugate Chemistry 2016, 27 (7) , 1588-1598. https://doi.org/10.1021/acs.bioconjchem.6b00117
    4. Patricia Griffin, Wendy A. Hill, Fabio Rossi, Rebecca Boohaker, Karr Stinson, Igor Sherman. High anti-tumor activity of a novel alpha-fetoprotein-maytansinoid conjugate targeting alpha-fetoprotein receptors in colorectal cancer xenograft model. Cancer Cell International 2023, 23 (1) https://doi.org/10.1186/s12935-023-02910-0
    5. Sandra Kannampuzha, Reshma Murali, Abilash Valsala Gopalakrishnan, Anirban Goutam Mukherjee, Uddesh Ramesh Wanjari, Arunraj Namachivayam, Alex George, Abhijit Dey, Balachandar Vellingiri. Novel biomolecules in targeted cancer therapy: a new approach towards precision medicine. Medical Oncology 2023, 40 (11) https://doi.org/10.1007/s12032-023-02168-6
    6. Giulio Lovato, Luigi Ciriolo, Miryam Perrucci, Luca Federici, Rodolfo Ippoliti, Stefano Iacobelli, Emily Capone, Marcello Locatelli, Gianluca Sala. HPLC-DAD validated method for DM4 and its metabolite S-Me-DM4 quantification in biological matrix for clinical and pharmaceutical applications. Journal of Pharmaceutical and Biomedical Analysis 2023, 235 , 115642. https://doi.org/10.1016/j.jpba.2023.115642
    7. Sameen Zafar, Muhammad Armaghan, Khushbukhat Khan, Nazia Hassan, Javad Sharifi-Rad, Solomon Habtemariam, Marek Kieliszek, Monica Butnariu, Iulia-Cristina Bagiu, Radu Vasile Bagiu, William C. Cho. New insights into the anticancer therapeutic potential of maytansine and its derivatives. Biomedicine & Pharmacotherapy 2023, 165 , 115039. https://doi.org/10.1016/j.biopha.2023.115039
    8. Tingting Cai, Liqi Shi, Huihui Guo, Ruixing Li, Weiqun Cao, Liang Shen, Mingshe Zhu, Yi Tao. Detection and Characterization of In Vitro Payload-Containing Catabolites of Noncleavable Antibody-Drug Conjugates by High-Resolution Mass Spectrometry and Multiple Data Mining Tools. Drug Metabolism and Disposition 2023, 51 (5) , 591-598. https://doi.org/10.1124/dmd.122.001135
    9. Dengyang Zhang, Chunxiao He, Yao Guo, Jianfeng Li, Bo Li, Yuming Zhao, Liuting Yu, Zhiguang Chang, Hanzhong Pei, Ming Yang, Na Li, Qi Zhang, Yulong He, Yihang Pan, Zhizhuang Joe Zhao, Changhua Zhang, Yun Chen. Efficacy of SCF drug conjugate targeting c-KIT in gastrointestinal stromal tumor. BMC Medicine 2022, 20 (1) https://doi.org/10.1186/s12916-022-02465-3
    10. Zoia Ehsan Khattak, Hamza Hashmi, Sana Irfan Khan, Sobia Aamir, Uroosa Arif, Atif Irfan Khan, Alicia Darwin, Arun D. Singh, Jack Khouri, Faiz Anwer. Dawn of a new era of antibody-drug conjugates and bispecific T-cell engagers for treatment of multiple myeloma: a systematic review of literature. Annals of Hematology 2021, 100 (9) , 2155-2172. https://doi.org/10.1007/s00277-021-04599-5
    11. Qiang Wang, Jiankun Guan, Jiangling Wan, Zifu Li. Disulfide based prodrugs for cancer therapy. RSC Advances 2020, 10 (41) , 24397-24409. https://doi.org/10.1039/D0RA04155F
    12. Hyunbo Shim. Bispecific Antibodies and Antibody–Drug Conjugates for Cancer Therapy: Technological Considerations. Biomolecules 2020, 10 (3) , 360. https://doi.org/10.3390/biom10030360
    13. Hanlan Liu, Jayaprakasam Bolleddula, Andrew Nichols, Lei Tang, Zhiyang Zhao, Chandra Prakash. Metabolism of bioconjugate therapeutics: why, when, and how?. Drug Metabolism Reviews 2020, 52 (1) , 66-124. https://doi.org/10.1080/03602532.2020.1716784
    14. Donglu Zhang, Peter S. Dragovich, Shang-Fan Yu, Yong Ma, Thomas H. Pillow, Jack D. Sadowsky, Dian Su, Wei Wang, Andrew Polson, S. Cyrus Khojasteh, Cornelis E.C.A. Hop. Exposure-Efficacy Analysis of Antibody-Drug Conjugates Delivering an Excessive Level of Payload to Tissues. Drug Metabolism and Disposition 2019, 47 (10) , 1146-1155. https://doi.org/10.1124/dmd.119.087023
    15. Wayne C. Widdison. Maytansinoid Payloads for Antibody–Drug Conjugates (ADCs). 2019, 100-116. https://doi.org/10.1039/9781788012898-00100
    16. Grégory Menchon, Andrea E. Prota, Daniel Lucena-Agell, Pascal Bucher, Rolf Jansen, Herbert Irschik, Rolf Müller, Ian Paterson, J. Fernando Díaz, Karl-Heinz Altmann, Michel O. Steinmetz. A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin. Nature Communications 2018, 9 (1) https://doi.org/10.1038/s41467-018-04535-8
    17. Marion Lepelley, Marion Allouchery, Jérôme Long, Dorothée Boucherle, Yves Ranchoup, François Le Marc’Hadour, Céline Villier, Nathalie Sturm. Nodular Regenerative Hyperplasia Induced by Trastuzumab Emtansine: Role of Emtansine?. Annals of Hepatology 2018, 17 (6) , 1067-1071. https://doi.org/10.5604/01.3001.0012.7207
    18. Sarah Taplin, Kapil Vashisht, Markus Walles, David Calise, William Kluwe, Page Bouchard, Robert Johnson. Hepatotoxicity with antibody maytansinoid conjugates: A review of preclinical and clinical findings. Journal of Applied Toxicology 2018, 38 (5) , 600-615. https://doi.org/10.1002/jat.3582
    19. Kyoji Tsuchikama, Zhiqiang An. Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein & Cell 2018, 9 (1) , 33-46. https://doi.org/10.1007/s13238-016-0323-0
    20. Paul Malik, Colin Phipps, Andrea Edginton, Jonathan Blay. Pharmacokinetic Considerations for Antibody-Drug Conjugates against Cancer. Pharmaceutical Research 2017, 34 (12) , 2579-2595. https://doi.org/10.1007/s11095-017-2259-3
    21. M. Walles, B. Rudolph, T. Wolf, J. Bourgailh, M. Suetterlin, T. Moenius, G. Peraus, O. Heudi, W. Elbast, C. Lanshoeft, S. Bilic. New Insights in Tissue Distribution, Metabolism, and Excretion of [3H]-Labeled Antibody Maytansinoid Conjugates in Female Tumor-Bearing Nude Rats. Drug Metabolism and Disposition 2016, 44 (7) , 897-910. https://doi.org/10.1124/dmd.115.069021
    22. Ola M Saad, Ben-Quan Shen, Keyang Xu, S Cyrus Khojasteh, Sandhya Girish, Surinder Kaur. Bioanalytical approaches for characterizing catabolism of antibody–drug conjugates. Bioanalysis 2015, 7 (13) , 1583-1604. https://doi.org/10.4155/bio.15.87
    Download PDF

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    MENDELEY PAIRING EXPIRED
    Your Mendeley pairing has expired. Please reconnect