Expanded utility of the β-glucuronide linker: ADCs that deliver phenolic cytotoxic agents

Scott C. Jeffrey, Jef De Brabander, Jamie Miyamoto, Peter D. Senter

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

The β-glucuronide linker has been used for antibody-drug conjugates (ADCs) to deliver amine-containing cytotoxic agents. The linker is stable in circulation, hydrophilic and provides ADCs that are highly active in vitro and in vivo. To extend the utility of the β-glucuronide linker toward phenol-containing drugs, an N,N′-dimethylethylene diamine self-immolative spacer was incorporated with the linker for release of the potent cytotoxic phenol psymberin A. Exposure of the drug-linker to β-glucuronidase resulted in facile drug release. The corresponding ADCs were active and immunologically selective against CD30-positive L540cy and CD70-positive Caki-1 cell lines.

Original languageEnglish (US)
Pages (from-to)277-280
Number of pages4
JournalACS Medicinal Chemistry Letters
Volume1
Issue number6
DOIs
StatePublished - Sep 9 2010

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Keywords

  • CD30-positive L540cy cell line
  • CD70-positive Caki-1 cell line
  • N,N′-dimethylethylene diamine
  • antibody-drug conjugates
  • phenolic cytotoxic agents
  • β-Glucuronide linker

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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