Glutamic Acid-valine-citrulline Linkers Ensure Stability and Efficacy of Antibody-drug Conjugates in Mice

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Jun 30

PMID 29955061

Citations 59

Authors

Yasuaki Anami

Chisato M Yamazaki

Wei Xiong

Xun Gui

Ningyan Zhang

Zhiqiang An

Kyoji Tsuchikama

Affiliations

Soon will be listed here.

Abstract

Valine-citrulline linkers are commonly used as enzymatically cleavable linkers for antibody-drug conjugates. While stable in human plasma, these linkers are unstable in mouse plasma due to susceptibility to an extracellular carboxylesterase. This instability often triggers premature release of drugs in mouse circulation, presenting a molecular design challenge. Here, we report that an antibody-drug conjugate with glutamic acid-valine-citrulline linkers is responsive to enzymatic drug release but undergoes almost no premature cleavage in mice. We demonstrate that this construct exhibits greater treatment efficacy in mouse tumor models than does a valine-citrulline-based variant. Notably, our antibody-drug conjugate contains long spacers facilitating the protease access to the linker moiety, indicating that our linker assures high in vivo stability despite a high degree of exposure. This technology could add flexibility to antibody-drug conjugate design and help minimize failure rates in pre-clinical studies caused by linker instability.

Citing Articles

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