title: Doxorubicin immunoconjugates containing bivalent, lysosomally-cleavable dipeptide linkages.
abstract: Bivalent doxorubicin (DOX)-dipeptides (16a-c) were prepared and conjugated to the monoclonal antibody BR96. The dipeptides are cleaved by lysosomal proteases following internalization of the resulting immunoconjugates. Conjugate 18b demonstrated antigen-specific in vitro tumor cell killing activity (IC(50)=0.2 microM) that was equipotent to DOX with a near doubling of drug molecules/MAb. Size exclusion chromatography showed 18b to be a noncovalent dimer that was formed immediately upon conjugation.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5100, Wallingford, CT 06492-7660, USA. gene.dubowchik@bms.com
authors.forename: Gene M
authors.initials: GM
authors.lastname: Dubowchik
authors.forename: Shilpa
authors.initials: S
authors.lastname: Radia
authors.forename: Harold
authors.initials: H
authors.lastname: Mastalerz
authors.forename: Michael A
authors.initials: MA
authors.lastname: Walker
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Firestone
authors.forename: H
authors.initials: H
authors.lastname: Dalton King
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Hofstead
authors.forename: David
authors.initials: D
authors.lastname: Willner
authors.forename: Shirley J
authors.initials: SJ
authors.lastname: Lasch
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Trail
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D001665:Binding Sites; D002401:Cathepsin B / Q000097:blood / Q000378:metabolism; D002850:Chromatography, Gel; D019281:Dimerization; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy; D008247:Lysosomes / Q000201:enzymology; D013237:Stereoisomerism; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C092612:BR96-doxorubicin immunoconjugate; D004151:Dipeptides; D018796:Immunoconjugates; D013438:Sulfhydryl Compounds; D004317:Doxorubicin; D002401:Cathepsin B