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Discovery of Peptidomimetic Antibody–Drug Conjugate Linkers with Enhanced Protease Specificity

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posted on 11.12.2017, 00:00 by BinQing Wei, Janet Gunzner-Toste, Hui Yao, Tao Wang, Jing Wang, Zijin Xu, Jinhua Chen, John Wai, Jim Nonomiya, Siao Ping Tsai, Josefa Chuh, Katherine R. Kozak, Yichin Liu, Shang-Fan Yu, Jeff Lau, Guangmin Li, Gail D. Phillips, Doug Leipold, Amrita Kamath, Dian Su, Keyang Xu, Charles Eigenbrot, Stefan Steinbacher, Rachana Ohri, Helga Raab, Leanna R. Staben, Guiling Zhao, John A. Flygare, Thomas H. Pillow, Vishal Verma, Luke A. Masterson, Philip W. Howard, Brian Safina
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.