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.