Conjugation of Indoles to Antibodies through a Novel Self-Immolating Linker.
Peter S DragovichRobert A BlakeChunjiao ChenJinhua ChenJosefa ChuhWillem den BestenFang FanAimee FourieSteven J HartmanChangrong HeJintang HeEllen Rei IngallaKatherine R KozakSteven R LeongJiawei LuYong MaLingyao MengMichelle NanniniJason OehRachana OhriGail Lewis PhillipsThomas H PillowRebecca K RowntreeDeepak SampathRichard VandlenBreanna VollmarJohn WaiIngrid E WertzKeyang XuZijin XuDonglu ZhangPublished in: Chemistry (Weinheim an der Bergstrasse, Germany) (2018)
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.