Monodisperse polysarcosine-based highly-loaded antibody-drug conjugates† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c9sc00285e

• Published in: Chemical science (Cambridge) Vol. 10; no. 14; pp. 4048 - 4053
• Main Authors: Viricel, Warren, Fournet, Guy, Beaumel, Sabine, Perrial, Emeline, Papot, Sébastien, Dumontet, Charles, Joseph, Benoît
• Format: Journal Article
• Language: English
• Published: Royal Society of Chemistry 06-03-2019
• Subjects: Chemistry
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/c9sc00285e

A new antibody-drug conjugate (ADC) chemical drug-linker platform based on polysarcosine enables increased drug-loading, improved pharmacokinetics and exquisite
in vivo
potency.
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 (
i.e.
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
in vivo
antitumor efficacy of the resulting conjugates.