Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index
RP Lyon, TD Bovee, SO Doronina, PJ Burke… - Nature …, 2015 - nature.com
RP Lyon, TD Bovee, SO Doronina, PJ Burke, JH Hunter, HD Neff-LaFord, M Jonas…
Nature biotechnology, 2015•nature.comThe 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.
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.
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.
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