Conjugation of Indoles to Antibodies through a Novel Self‐Immolating Linker

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 in vivo stability properties in mice. Indoles in play: A novel strategy for attaching indole‐containing payloads to antibodies was developed using a self‐immolative disulfide linker. Several conjugates prepared using this methodology displayed good extracellular stability properties as well as antigen‐dependent bioactivity (consistent with efficient intracellular indole release) in both in vitro and in vivo experiments.