title: (6-Maleimidocaproyl)hydrazone of doxorubicin--a new derivative for the preparation of immunoconjugates of doxorubicin.
abstract: The (6-maleimidocaproyl)hydrazone of doxorubicin was synthesized and conjugated to several mAbs, including chimeric BR96, via a Michael addition reaction to thiol-containing mAbs. DTT reduction of disulfides present in the mAb was a reliable and general method for generating a consistent number of reactive SH groups. The conjugates, after purification by Bio-Beads, were free of unreacted linker and/or doxorubicin. All conjugates released doxorubicin under acidic conditions that mimic the lysosomal environment, while they were relatively stable at neutral pH. BR96 conjugates showed antigen-specific cytotoxicity.
authors.affiliation: Bristol-Myers Squibb Company, Wallingford, Connecticut 06492-7660.
authors.forename: D
authors.initials: D
authors.lastname: Willner
authors.forename: P A
authors.initials: PA
authors.lastname: Trail
authors.forename: S J
authors.initials: SJ
authors.lastname: Hofstead
authors.forename: H D
authors.initials: HD
authors.lastname: King
authors.forename: S J
authors.initials: SJ
authors.lastname: Lasch
authors.forename: G R
authors.initials: GR
authors.lastname: Braslawsky
authors.forename: R S
authors.initials: RS
authors.lastname: Greenfield
authors.forename: T
authors.initials: T
authors.lastname: Kaneko
authors.forename: R A
authors.initials: RA
authors.lastname: Firestone
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000138:chemical synthesis* / Q000737:chemistry; D004229:Dithiothreitol / Q000737:chemistry; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004355:Drug Stability; D000939:Epitopes; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry; D000922:Immunotoxins / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000737:chemistry
chemical_list: D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D000939:Epitopes; D006835:Hydrazones; D000922:Immunotoxins; D013438:Sulfhydryl Compounds; C085780:doxorubicin(6-maleimidocaproyl)hydrazone; D004317:Doxorubicin; D004229:Dithiothreitol