Journal of the American Chemical Society p. 1430 - 1445 (2016)
Update date:2022-08-17
Topics:
Kern, Jeffrey C.
Cancilla, Mark
Dooney, Deborah
Kwasnjuk, Kristen
Zhang, Rena
Beaumont, Maribel
Figueroa, Isabel
Hsieh, SuChun
Liang, Linda
Tomazela, Daniela
Zhang, Jeffrey
Brandish, Philip E.
Palmieri, Anthony
Stivers, Peter
Cheng, Mangeng
Feng, Guo
Geda, Prasanthi
Shah, Sanjiv
Beck, Andrew
Bresson, Damien
Firdos, Juhi
Gately, Dennis
Knudsen, Nick
Manibusan, Anthony
Schultz, Peter G.
Sun, Ying
Garbaccio, Robert M.
As part of an effort to examine the utility of antibody-drug conjugates (ADCs) beyond oncology indications, a novel pyrophosphate ester linker was discovered to enable the targeted delivery of glucocorticoids. As small molecules, these highly soluble phosphate ester drug linkers were found to have ideal orthogonal properties: robust plasma stability coupled with rapid release of payload in a lysosomal environment. Building upon these findings, site-specific ADCs were made between this drug linker combination and an antibody against human CD70, a receptor specifically expressed in immune cells but also found aberrantly expressed in multiple human carcinomas. Full characterization of these ADCs enabled procession to in vitro proof of concept, wherein ADCs 1-22 and 1-37 were demonstrated to afford potent, targeted delivery of glucocorticoids to a representative cell line, as measured by changes in glucocorticoid receptor-mediated gene mRNA levels. These activities were found to be antibody-, linker-, and payload-dependent. Preliminary mechanistic studies support the notion that lysosomal trafficking and enzymatic linker cleavage are required for activity and that the utility for the pyrophosphate linker may be general for internalizing ADCs as well as other targeted delivery platforms.
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