title: Novel Phosphate Modified Cathepsin B Linkers: Improving Aqueous Solubility and Enhancing Payload Scope of ADCs.
abstract: In an effort to examine the utility of antibody-drug conjugates (ADCs) beyond oncology indications, a novel phosphate bridged Cathepsin B sensitive linker was developed to enable the targeted delivery of glucocorticoids. Phosphate bridging of the Cathepsin B sensitive linkers allows for payload attachment at an aliphatic alcohol. As small molecule drug-linkers, these aqueous soluble phosphate containing drug-linkers were found to have robust plasma stability coupled with rapid release of payload in a lysosomal environment. Site-specific ADCs were successfully made between these drug-linkers and an antibody against human CD70, a receptor specifically expressed in immune cells but also found aberrantly expressed in multiple human carcinomas. These ADCs demonstrated in vitro targeted delivery of glucocorticoids to a representative cell line as measured by changes in glucocorticoid receptor (GR) mediated gene mRNA levels. This novel linker expands the scope of potential ADC payloads by allowing an aliphatic alcohol to be a stable, yet cleavable attachment site. This phosphate linker may have broad utility for internalizing ADCs as well as other targeted delivery platforms.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Kern
authors.forename: Deborah
authors.initials: D
authors.lastname: Dooney
authors.forename: Rena
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Biologics, Merck & Co., Inc. , 901 California Avenue, Palo Alto, California 94304, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Liang
authors.forename: Philip E
authors.initials: PE
authors.lastname: Brandish
authors.forename: Mangeng
authors.initials: M
authors.lastname: Cheng
authors.forename: Guo
authors.initials: G
authors.lastname: Feng
authors.affiliation: Ambrx , 10975 North Torrey Pines Road, San Diego, California 92121, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Beck
authors.affiliation: Ambrx , 10975 North Torrey Pines Road, San Diego, California 92121, United States.
authors.forename: Damien
authors.initials: D
authors.lastname: Bresson
authors.affiliation: Ambrx , 10975 North Torrey Pines Road, San Diego, California 92121, United States.
authors.forename: Juhi
authors.initials: J
authors.lastname: Firdos
authors.affiliation: Ambrx , 10975 North Torrey Pines Road, San Diego, California 92121, United States.
authors.forename: Dennis
authors.initials: D
authors.lastname: Gately
authors.affiliation: Ambrx , 10975 North Torrey Pines Road, San Diego, California 92121, United States.
authors.forename: Nick
authors.initials: N
authors.lastname: Knudsen
authors.affiliation: Ambrx , 10975 North Torrey Pines Road, San Diego, California 92121, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: Manibusan
authors.affiliation: Ambrx , 10975 North Torrey Pines Road, 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: D000438:Alcohols / Q000737:chemistry; D002254:Carbonates / Q000737:chemistry; D002401:Cathepsin B / Q000378:metabolism*; D004355:Drug Stability; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D010710:Phosphates / Q000737:chemistry*; D012995:Solubility; D014867:Water / Q000737:chemistry*
chemical_list: D000438:Alcohols; D002254:Carbonates; D018796:Immunoconjugates; D010710:Phosphates; D014867:Water; D002401:Cathepsin B