Mild method for succinimide hydrolysis on ADCs: impact on ADC potency, stability, exposure, and efficacy

Bioconjug Chem. 2014 Oct 15;25(10):1871-80. doi: 10.1021/bc500357n. Epub 2014 Oct 6.


The stability of the connection between the antibody and the toxin can have a profound impact on ADC safety and efficacy. There has been increasing evidence in recent years that maleimide-based ADCs are prone to payload loss via a retro-Michael type reaction. Herein, we report a mild method for the hydrolysis of the succinimide-thioether ring which results in a "ring-opened" linker. ADCs containing this hydrolyzed succinimide linker show equivalent cytotoxicity, improved in vitro stability, improved PK exposure, and improved efficacy as compared to their nonhydrolyzed counterparts. This method offers a simple way to improve the stability, exposure, and efficacy of maleimide-based ADCs.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Drug Stability
  • Humans
  • Hydrolysis
  • Immunotoxins / blood
  • Immunotoxins / chemistry*
  • Immunotoxins / therapeutic use
  • Mice
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Protein Stability
  • Succinimides / chemistry*
  • Sulfides / chemistry*


  • Immunotoxins
  • Succinimides
  • Sulfides
  • succinimide