Development of Novel Quaternary Ammonium Linkers for Antibody–Drug Conjugates
| Autor: | Patrick J. Burke, Ivan Stone, Julia H. Cochran, Peter D. Senter, Joshua H. Hunter, Brian E. Toki, Thomas A. Pires, Joseph Z. Hamilton, Jocelyn R. Setter, Scott C. Jeffrey, Kristine A. Gordon, Robert P. Lyon, Kim K. Emmerton, Andrew B. Waight, Weiping Zeng |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Immunoconjugates Tertiary amine Mice 03 medical and health sciences chemistry.chemical_compound Drug Stability Tubulin In vivo Cell Line Tumor Ammonium Compounds Animals Humans Ammonium Molecular Structure Chemistry Antibodies Monoclonal Biological activity Xenograft Model Antitumor Assays Combinatorial chemistry In vitro Rats Disease Models Animal Drug Liberation Kinetics 030104 developmental biology Oncology Biochemistry Amine gas treating Linker Protein Binding Conjugate |
| Zdroj: | Molecular Cancer Therapeutics. 15:938-945 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | A quaternary ammonium-based drug-linker has been developed to expand the scope of antibody–drug conjugate (ADC) payloads to include tertiary amines, a functional group commonly present in biologically active compounds. The linker strategy was exemplified with a β-glucuronidase–cleavable auristatin E construct. The drug-linker was found to efficiently release free auristatin E (AE) in the presence of β-glucuronidase and provide ADCs that were highly stable in plasma. Anti-CD30 conjugates comprised of the glucuronide-AE linker were potent and immunologically specific in vitro and in vivo , displaying pharmacologic properties comparable with a carbamate-linked glucuronide-monomethylauristatin E control. The quaternary ammonium linker was then applied to a tubulysin antimitotic drug that contained an N-terminal tertiary amine that was important for activity. A glucuronide-tubulysin quaternary ammonium linker was synthesized and evaluated as an ADC payload, in which the resulting conjugates were found to be potent and immunologically specific in vitro , and displayed a high level of activity in a Hodgkin lymphoma xenograft. Furthermore, the results were superior to those obtained with a related tubulysin derivative containing a secondary amine N-terminus for conjugation using previously known linker technology. The quaternary ammonium linker represents a significant advance in linker technology, enabling stable conjugation of payloads with tertiary amine residues. Mol Cancer Ther; 15(5); 938–45. ©2016 AACR . This article is featured in Highlights of This Issue, [p. 765][1] [1]: /lookup/volpage/15/765?iss=5 |
| Databáze: | OpenAIRE |
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