title: Development of Novel Quaternary Ammonium Linkers for Antibody-Drug Conjugates.
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 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.
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington. pburke@seagen.com.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Burke
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Joseph Z
authors.initials: JZ
authors.lastname: Hamilton
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Pires
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Jocelyn R
authors.initials: JR
authors.lastname: Setter
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Joshua H
authors.initials: JH
authors.lastname: Hunter
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Julia H
authors.initials: JH
authors.lastname: Cochran
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Waight
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Kristine A
authors.initials: KA
authors.lastname: Gordon
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Toki
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Kim K
authors.initials: KK
authors.lastname: Emmerton
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Ivan J
authors.initials: IJ
authors.lastname: Stone
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Senter
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Lyon
authors.affiliation: Seattle Genetics, Inc., Bothell, Washington.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Jeffrey
mesh_terms: D064751:Ammonium Compounds / Q000737:chemistry*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D065546:Drug Liberation; D004355:Drug Stability; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D015394:Molecular Structure; D011485:Protein Binding; D051381:Rats; D014404:Tubulin; D023041:Xenograft Model Antitumor Assays
chemical_list: D064751:Ammonium Compounds; D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D014404:Tubulin