Reducing Hydrophobicity of Homogeneous Antibody-Drug Conjugates Improves Pharmacokinetics and Therapeutic Index

Nat Biotechnol. 2015 Jul;33(7):733-5. doi: 10.1038/nbt.3212. Epub 2015 Jun 15.

Abstract

The in vitro potency of antibody-drug conjugates (ADCs) increases with the drug-to-antibody ratio (DAR); however, ADC plasma clearance also increases with DAR, reducing exposure and in vivo efficacy. Here we show that accelerated clearance arises from ADC hydrophobicity, which can be modulated through drug-linker design. We exemplify this using hydrophilic auristatin drug linkers and PEGylated ADCs that yield uniform, high-DAR ADCs with superior in vivo performance.

MeSH terms

  • Animals
  • Cell Line
  • Chemistry, Pharmaceutical*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Immunoconjugates* / chemistry
  • Immunoconjugates* / pharmacokinetics
  • Mice
  • Mice, SCID
  • Models, Chemical
  • Models, Molecular
  • Pharmaceutical Preparations* / chemistry

Substances

  • Immunoconjugates
  • Pharmaceutical Preparations