PREPARATION AND CHARACTERIZATION OF MONOCLONAL-ANTIBODY CONJUGATES OFTHE CALICHEAMICINS - A NOVEL AND POTENT FAMILY OF ANTITUMOR ANTIBIOTICS

The calicheamicin family of antitumor antibiotics are capable of produ cing double-stranded DNA breaks at sub-picomolar concentrations. Their potency suggested that the calicheamicins would be excellent candidat es for targeted delivery and a hydrazide prepared from the most potent and abundant of the naturally occurring derivative, gamma1I, was link ed to oxidized sugars on CT-M-01, an internalizing anti-polyepithelial mucin antibody. The conjugates retained the immunoreactivity of the u nmodified antibody and were specifically cytotoxic toward antigen posi tive tumor cells in vitro and in vivo. Hydrazide analogues of less pot ent 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 conj ugates of derivatives missing the rhamnose, a sugar residue that is pa rt of the DNA binding region of the drug, were not as promising as ant itumor therapies. However, conjugates of two derivatives, alpha3I and N-acetyl-gamma1I, in which the rhamnose residue is present but the ami no sugar residue of the parent drug is either missing or modified, sig nificantly inhibited tumor growth over a 4-fold dose range and produce d long-term tumor-free survivors. Sterically hindering methyl groups a djacent to the disulfide in the linker further increased the therapeut ic window of these potent conjugates.