title: Discovery of Pyrophosphate Diesters as Tunable, Soluble, and Bioorthogonal Linkers for Site-Specific Antibody-Drug Conjugates.
abstract: 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.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Kern
authors.forename: Mark
authors.initials: M
authors.lastname: Cancilla
authors.forename: Deborah
authors.initials: D
authors.lastname: Dooney
authors.forename: Kristen
authors.initials: K
authors.lastname: Kwasnjuk
authors.forename: Rena
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Biologics, Merck & Co., Inc. , Palo Alto, California 94304, United States.
authors.forename: Maribel
authors.initials: M
authors.lastname: Beaumont
authors.affiliation: Biologics, Merck & Co., Inc. , Palo Alto, California 94304, United States.
authors.forename: Isabel
authors.initials: I
authors.lastname: Figueroa
authors.affiliation: Biologics, Merck & Co., Inc. , Palo Alto, California 94304, United States.
authors.forename: SuChun
authors.initials: S
authors.lastname: Hsieh
authors.affiliation: Biologics, Merck & Co., Inc. , Palo Alto, California 94304, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Liang
authors.affiliation: Biologics, Merck & Co., Inc. , Palo Alto, California 94304, United States.
authors.forename: Daniela
authors.initials: D
authors.lastname: Tomazela
authors.affiliation: Biologics, Merck & Co., Inc. , Palo Alto, California 94304, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Zhang
authors.forename: Philip E
authors.initials: PE
authors.lastname: Brandish
authors.forename: Anthony
authors.initials: A
authors.lastname: Palmieri
authors.forename: Peter
authors.initials: P
authors.lastname: Stivers
authors.forename: Mangeng
authors.initials: M
authors.lastname: Cheng
authors.forename: Guo
authors.initials: G
authors.lastname: Feng
authors.forename: Prasanthi
authors.initials: P
authors.lastname: Geda
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Shah
authors.affiliation: Ambrx , San Diego, California 92121, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Beck
authors.affiliation: Ambrx , San Diego, California 92121, United States.
authors.forename: Damien
authors.initials: D
authors.lastname: Bresson
authors.affiliation: Ambrx , San Diego, California 92121, United States.
authors.forename: Juhi
authors.initials: J
authors.lastname: Firdos
authors.affiliation: Ambrx , San Diego, California 92121, United States.
authors.forename: Dennis
authors.initials: D
authors.lastname: Gately
authors.affiliation: Ambrx , San Diego, California 92121, United States.
authors.forename: Nick
authors.initials: N
authors.lastname: Knudsen
authors.affiliation: Ambrx , San Diego, California 92121, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: Manibusan
authors.affiliation: Ambrx , San Diego, California 92121, United States.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.affiliation: Ambrx , San Diego, California 92121, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
mesh_terms: D011756:Diphosphates / Q000737:chemistry*; D004952:Esters; D005938:Glucocorticoids / Q000737:chemistry*; D018796:Immunoconjugates / Q000737:chemistry*
chemical_list: D011756:Diphosphates; D004952:Esters; D005938:Glucocorticoids; D018796:Immunoconjugates