Glutamic acid–valine–citrulline linkers ensure stability and efficacy of antibody–drug conjugates in mice

Yasuaki Anami, Chisato M. Yamazaki, Wei Xiong, Xun Gui, Ningyan Zhang, Zhiqiang An and Kyoji Tsuchikama ()
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Yasuaki Anami: The University of Texas Health Science Center at Houston
Chisato M. Yamazaki: The University of Texas Health Science Center at Houston
Wei Xiong: The University of Texas Health Science Center at Houston
Xun Gui: The University of Texas Health Science Center at Houston
Ningyan Zhang: The University of Texas Health Science Center at Houston
Zhiqiang An: The University of Texas Health Science Center at Houston
Kyoji Tsuchikama: The University of Texas Health Science Center at Houston

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04982-3

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