Functional selection of protease inhibitory antibodies

Proceedings of the National Academy of Sciences of the United States of America
Tyler LopezXin Ge

Abstract

Critical for diverse biological processes, proteases represent one of the largest families of pharmaceutical targets. To inhibit pathogenic proteases with desired selectivity, monoclonal antibodies (mAbs) hold great promise as research tools and therapeutic agents. However, identification of mAbs with inhibitory functions is challenging because current antibody discovery methods rely on binding rather than inhibition. This study developed a highly efficient selection method for protease inhibitory mAbs by coexpressing 3 recombinant proteins in the periplasmic space of Escherichia coli-an antibody clone, a protease of interest, and a β-lactamase modified by insertion of a protease cleavable peptide sequence. During functional selection, inhibitory antibodies prevent the protease from cleaving the modified β-lactamase, thereby allowing the cell to survive in the presence of ampicillin. Using this method to select from synthetic human antibody libraries, we isolated panels of mAbs inhibiting 5 targets of 4 main protease classes: matrix metalloproteinases (MMP-14, a predominant target in metastasis; MMP-9, in neuropathic pain), β-secretase 1 (BACE-1, an aspartic protease in Alzheimer's disease), cathepsin B (a cysteine protease in ...Continue Reading

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Citations

May 30, 2020·Proceedings of the National Academy of Sciences of the United States of America·Bing MengBei Yang
Aug 21, 2020·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Christopher R DonnellyRu-Rong Ji
Sep 10, 2020·MedChemComm·Geetha B KumarDavid B C Martin
Jan 11, 2020·Frontiers in Oncology·Saray Quintero-FabiánMaría Elizbeth Alvarez-Sánchez
Jan 9, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Longguang JiangMingdong Huang
Jan 18, 2021·Drug Discovery Today·Arne Christian Rufer
Jun 3, 2021·Bioorganic & Medicinal Chemistry·Yaping ChengXiaoqing Cai
Jun 3, 2021·International Journal of Molecular Sciences·Daniel SojkaLuïse Robbertse
May 28, 2020·Journal of Medicinal Chemistry·Pauline ZipfelPatrick Dallemagne

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