Discovery of Pyrophosphate Diesters as Tunable, Soluble, and Bioorthogonal Linkers for Site-Specific Antibody–Drug Conjugates

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• 作者：Jeffrey C. Kern ; Mark Cancilla ; Deborah Dooney ; Kristen Kwasnjuk ; Rena Zhang ; Maribel Beaumont ; Isabel Figueroa ; SuChun Hsieh ; Linda Liang ; Daniela Tomazela ; Jeffrey Zhang ; Philip E. Brandish ; Anthony Palmieri ; Peter Stivers ; Mangeng Cheng ; Guo Feng ; Prasanthi Geda ; Sanjiv Shah ; Andrew Beck ; Damien Bresson ; Juhi Firdos ; Dennis Gately ; Nick Knudsen ; Anthony Manibusan ; Peter G. Schultz ; Ying Sun ; Robert M. Garbaccio
• 刊名：Journal of the American Chemical Society
• 出版年：2016
• 出版时间：February 3, 2016
• 年：2016
• 卷：138
• 期：4
• 页码：1430-1445
• 全文大小：774K
• ISSN：1520-5126

文摘

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.