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Viricel, Warren; Fournet, Guy; Beaumel, Sabine; Perrial, Emeline; Papot, Sébastien; Dumontet, Charles; Joseph, Benoît
Chemical science (Cambridge), 04/2019, Volume: 10, Issue: 14Journal Article
Antibody-drug conjugates (ADCs) convey highly potent anticancer drugs to antigen-expressing tumor cells, thereby sparing healthy tissues throughout the body. Pharmacokinetics and tolerability of ADCs are predominantly influenced by the drug-antibody ratio (DAR) of the conjugates, which is to-date limited to a value of 3-4 drugs per antibody in ADCs under clinical investigations. Here, we report the synthesis of monodisperse ( discrete) polysarcosine compounds and their use as a hydrophobicity masking entity for the construction of highly-loaded homogeneous β-glucuronidase-responsive antibody-drug conjugates (ADCs). The highly hydrophilic drug-linker platform described herein improves drug-loading, physicochemical properties, pharmacokinetics and antitumor efficacy of the resulting conjugates.
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