title: Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index.
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.
authors.affiliation: Department of Chemistry, Seattle Genetics, Bothell, Washington, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Lyon
authors.affiliation: Department of Chemistry, Seattle Genetics, Bothell, Washington, USA.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Bovee
authors.affiliation: Department of Chemistry, Seattle Genetics, Bothell, Washington, USA.
authors.forename: Svetlana O
authors.initials: SO
authors.lastname: Doronina
authors.affiliation: Department of Chemistry, Seattle Genetics, Bothell, Washington, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Burke
authors.affiliation: Department of Chemistry, Seattle Genetics, Bothell, Washington, USA.
authors.forename: Joshua H
authors.initials: JH
authors.lastname: Hunter
authors.affiliation: Department of Pharmacology and Toxicology, Seattle Genetics, Bothell, Washington, USA.
authors.forename: Haley D
authors.initials: HD
authors.lastname: Neff-LaFord
authors.affiliation: Department of Translational Research, Seattle Genetics, Bothell, Washington, USA.
authors.forename: Mechthild
authors.initials: M
authors.lastname: Jonas
authors.affiliation: Department of Preclinical Research, Seattle Genetics, Bothell, Washington, USA.
authors.forename: Martha E
authors.initials: ME
authors.lastname: Anderson
authors.affiliation: Department of Chemistry, Seattle Genetics, Bothell, Washington, USA.
authors.forename: Jocelyn R
authors.initials: JR
authors.lastname: Setter
authors.affiliation: Department of Chemistry, Seattle Genetics, Bothell, Washington, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Senter
mesh_terms: D000818:Animals; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D018796:Immunoconjugates / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D016513:Mice, SCID; D008956:Models, Chemical; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry
chemical_list: D018796:Immunoconjugates; D004364:Pharmaceutical Preparations