Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 24, Issue 19, Pages 4830-4834Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201800859
Keywords
antibodies; antibody-drug conjugates; drug delivery; indole; selective estrogen receptor down-regulator
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A novel strategy to attach indole-containing payloads to antibodies through a carbamate moiety and a self-immolating, disulfide-based linker is described. This new strategy was employed to connect a selective estrogen receptor down-regulator (SERD) to various antibodies in a site-selective manner. The resulting conjugates displayed potent, antigen-dependent down-regulation of estrogen receptor levels in MCF7-neo/HER2 and MCF7-hB7H4 cells. They also exhibited similar antigen-dependent modulation of the estrogen receptor in tumors when administered intravenously to mice bearing MCF7-neo/HER2 tumor xenografts. The indole-carbamate moiety present in the new linker was stable in whole blood from various species and also exhibited good invivo stability properties in mice.
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