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

Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index.

Author information

1
Department of Chemistry, Seattle Genetics, Bothell, Washington, USA.
2
Department of Pharmacology and Toxicology, Seattle Genetics, Bothell, Washington, USA.
3
Department of Translational Research, Seattle Genetics, Bothell, Washington, USA.
4
Department of Preclinical Research, Seattle Genetics, Bothell, Washington, USA.

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.

PMID:
26076429
DOI:
10.1038/nbt.3212
[Indexed for MEDLINE]

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