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J Med Chem. 2018 Feb 8;61(3):989-1000. doi: 10.1021/acs.jmedchem.7b01430. Epub 2017 Dec 21.

Discovery of Peptidomimetic Antibody-Drug Conjugate Linkers with Enhanced Protease Specificity.

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Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
WuXi AppTec , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
Proteros Biostructures GmbH , Bunsenstrasse 7a, D-82152 Martinsried, Germany.
Spirogen, QMB Innovation Centre, 42 New Road, London E1 2AX, United Kingdom.


Antibody-drug conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite the progress, improvements in ADC therapeutic index are desired. Peptide-based ADC linkers that are cleaved by lysosomal proteases have shown sufficient stability in serum and effective payload-release in targeted cells. If the linker can be preferentially hydrolyzed by tumor-specific proteases, safety margin may improve. However, the use of peptide-based linkers limits our ability to modulate protease specificity. Here we report the structure-guided discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing linker is hydrolyzed predominantly by cathepsin B while the valine-citrulline dipeptide linker is not. ADCs bearing the nonpeptidic linker are as efficacious and stable in vivo as those with the dipeptide linker. Our results strongly support the application of the peptidomimetic linker and present new opportunities for improving the selectivity of ADCs.

[Indexed for MEDLINE]

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