Development of Novel Quaternary Ammonium Linkers for Antibody-Drug Conjugates.
Mol Cancer Ther
; 15(5): 938-45, 2016 05.
Article
in En
| MEDLINE
| ID: mdl-26944920
ABSTRACT
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 ß-glucuronidase-cleavable auristatin E construct. The drug-linker was found to efficiently release free auristatin E (AE) in the presence of ß-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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Immunoconjugates
/
Ammonium Compounds
/
Antibodies, Monoclonal
Limits:
Animals
/
Humans
Language:
En
Journal:
Mol Cancer Ther
Journal subject:
ANTINEOPLASICOS
Year:
2016
Document type:
Article