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β-Glucuronide Enzymatically Cleavable Linkers
Empowering Peptide Innovation
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As extension of the linkerology toolbox the design of linkers with improved stability during systemic circulation is highly desired. As the drug-releasing lysosomal enzyme β-glucuronidase is abundantly present within lysosomes and overexpressed in some tumor types but low outside cells, β-glucuronic acid-based linkers provide the potential for high ADC stability in the systemic circulation and selective intracellular drug release. Especially for ADCs based on highly hydrophobic drugs, the incorporation of the highly hydrophilic β-glucuronides may circumvent the tendency of aggregation. For example, a drug-linker consisting of a β-glucuronide linked to auristatin MMAF was prepared. Rat plasma stability analysis revealed an extrapolated half-life of 81 days compared with about 6 days for the corresponding valine-citrulline dipeptide-linked MMAF.
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References: f Expanded Utility of the β-Glucuronide Linker: ADCs That Deliver Phenolic Cytotoxic Agents; S. C. Jeffrey, J. De Brabander, J. Miyamoto, and P. D. Senter; ACS Med. Chem. Lett. 2010; 1: 277-280. https://doi.org/10.1021/ml100039h. f Development and Properties of β-Glucuronide Linkers for Monoclonal Antibody-Drug Conjugates; S. C. Jeffrey, J. B. Andreyka, S. X. Bernhardt, K. M. Kissler, T. Kline, J. S. Lenox, R. F. Moser, M. T. Nguyen, N. M. Okeley, I. J. Stone, X. Zhang, P. D. Senter; Bioconjugate Chem. 2006, 17: 831-840. https:// doi.org/10.1021/bc0600214. f Linker Technologies for Antibody–Drug Conjugates; B. Nolting; Antibody-Drug Conjugates L. Ducry 2013; 1045: 71-100. https://doi.org/10.1007/978-162703-541-5_5.
