title: Preparation and characterization of monoclonal antibody conjugates of the calicheamicins: a novel and potent family of antitumor antibiotics.
abstract: The calicheamicin family of antitumor antibiotics are capable of producing double-stranded DNA breaks at sub-picomolar concentrations. Their potency suggested that the calicheamicins would be excellent candidates for targeted delivery and a hydrazide prepared from the most potent and abundant of the naturally occurring derivative, gamma 1I, was linked to oxidized sugars on CT-M-01, an internalizing anti-polyepithelial mucin antibody. The conjugates retained the immunoreactivity of the unmodified antibody and were specifically cytotoxic toward antigen positive tumor cells in vitro and in vivo. Hydrazide analogues of less potent calicheamicin derivatives were also prepared and conjugated to CT-M-01. Comparison of the therapeutic efficacy of the conjugates against the MX-1 xenograft tumor implanted s.c. in nude mice showed that conjugates of derivatives missing the rhamnose, a sugar residue that is part of the DNA binding region of the drug, were not as promising as antitumor therapies. However, conjugates of two derivatives, alpha 3I and N-acetyl-gamma 1I, in which the rhamnose residue is present but the amino sugar residue of the parent drug is either missing or modified, significantly inhibited tumor growth over a 4-fold dose range and produced long-term tumor-free survivors. Sterically hindering methyl groups adjacent to the disulfide in the linker further increased the therapeutic window of these potent conjugates.
authors.affiliation: Medical Research Division, American Cyanamid Company, Lederle Laboratories, Pearl River, New York 10965.
authors.forename: L M
authors.initials: LM
authors.lastname: Hinman
authors.forename: P R
authors.initials: PR
authors.lastname: Hamann
authors.forename: R
authors.initials: R
authors.lastname: Wallace
authors.forename: A T
authors.initials: AT
authors.lastname: Menendez
authors.forename: F E
authors.initials: FE
authors.lastname: Durr
authors.forename: J
authors.initials: J
authors.lastname: Upeslacis
mesh_terms: D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D000911:Antibodies, Monoclonal; D001943:Breast Neoplasms / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal