Bis(vinylsulfonyl)piperazines as efficient linkers for highly homogeneous antibody-drug conjugates

Eur J Med Chem. 2020 Mar 15:190:112080. doi: 10.1016/j.ejmech.2020.112080. Epub 2020 Jan 22.

Abstract

Disulfide re-bridging strategy has demonstrated significant advantages in the construction of homogeneous antibody drug conjugates (ADCs). However, a major issue that disulfide scrambling at the hinge region of antibody leads to the formation of "half-antibody" has appeared for many re-bridging linkers. We present bis(vinylsulfonyl)piperazines (BVP) as efficient linkers to selectively re-bridge disulfides at the antigen-binding fragment (Fab) regions and produce highly homogeneous conjugates with a loading of two drugs without disulfide scrambling. We also found that optically active (S)-configuration linkers led to more sufficient conjugation compared with (R)-configuration. The BVP-linked ADCs demonstrated superior efficacy and antigen-selectivity in vitro cytotoxicity.

Keywords: Antibody drug conjugates; DAR of two; Disulfides re-bridging; High homogeneity; bis(vinylsulfonyl)piperazines.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / toxicity
  • Cell Line, Tumor
  • Disulfides / chemistry
  • Drug Screening Assays, Antitumor
  • Humans
  • Immunoconjugates / chemistry
  • Immunoconjugates / pharmacology*
  • Immunoconjugates / toxicity
  • Piperazines / chemical synthesis
  • Piperazines / pharmacology*
  • Piperazines / toxicity
  • Sulfones / chemical synthesis
  • Sulfones / pharmacology*
  • Sulfones / toxicity
  • Vinyl Compounds / chemical synthesis
  • Vinyl Compounds / pharmacology*
  • Vinyl Compounds / toxicity

Substances

  • Antineoplastic Agents
  • Disulfides
  • Immunoconjugates
  • Piperazines
  • Sulfones
  • Vinyl Compounds