Stabilizing a Tubulysin Antibody-Drug Conjugate To Enable Activity Against Multidrug-Resistant Tumors
| Autor: | Geoffrey Del Rosario, Jun Guo, Jinhua Chen, Zijin Xu, Shang-Fan Yu, Gang Yan, Andrew Polson, Luna Liu, Rachana Ohri, Jeffrey Lau, Bing Zheng, Byoung-Chul Lee, H. Zhou, Keyang Xu, Jiawei Lu, John S. Wai, Leanna Staben, Josefa dela Cruz-Chuh, Thomas H. Pillow, Gail Lewis Phillips, Katherine R. Kozak, Wenwen Cai |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Drug Antibody-drug conjugate Tertiary amine 010405 organic chemistry Chemistry media_common.quotation_subject medicine.medical_treatment Organic Chemistry Pharmacology 01 natural sciences Biochemistry 0104 chemical sciences Targeted therapy 03 medical and health sciences 030104 developmental biology Mechanism of action In vivo Drug Discovery medicine medicine.symptom Cytotoxicity media_common Conjugate |
| Zdroj: | ACS medicinal chemistry letters. 8(10) |
| ISSN: | 1948-5875 |
| Popis: | The tubulysins are promising anticancer cytotoxic agents due to the clinical validation of their mechanism of action (microtubule inhibition) and their particular activity against multidrug-resistant tumor cells. Yet their high potency and subsequent systemic toxicity make them prime candidates for targeted therapy, particularly in the form of antibody–drug conjugates (ADCs). Here we report a strategy to prepare stable and bioreversible conjugates of tubulysins to antibodies without loss of activity. A peptide trigger along with a quaternary ammonium salt linker connection to the tertiary amine of tubulysin provided ADCs that were potent in vitro. However, we observed metabolism of a critical acetate ester of the drug in vivo, resulting in diminished conjugate activity. We were able to circumvent this metabolic liability with the judicious choice of a propyl ether replacement. This modified tubulysin ADC was stable and effective against multidrug-resistant lymphoma cell lines and tumors. |
| Databáze: | OpenAIRE |
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