The anti-MUC1 antibody, CTM01, has been chosen to target the potently cytotoxic
calicheamicin antitumor
antibiotics to solid
tumors of epithelial origin that express this
antigen. Earlier
calicheamicin conjugates relied on the attachment of a
hydrazide derivative to the oxidized
carbohydrates that occur naturally on
antibodies. This produced a "
carbohydrate conjugate" capable of releasing active drug by hydrolysis in the lysosomes where the pH is low. Conjugates have now been made that are formed by reacting a
calicheamicin derivative containing an activated
ester with the lysines of
antibodies. This gives an "
amide conjugate" that is stable to hydrolysis, leaving the
disulfide that is present in all
calicheamicin conjugates as the only likely site of drug release from the conjugate. As previously shown for the
carbohydrate conjugate, this
amide conjugate of CTM01 produces complete regressions of xenograft
tumors at doses of 300 microg/kg (
calicheamicin equivalents) given three times. This indicates that hydrolytic drug release is not necessary for potent, selective cytotoxicity for
calicheamicin conjugates of CTM01. Although the unconjugated
calicheamicins are in general less active in cells expressing the multidrug resistance phenotype, both in vitro and in vivo results of studies reported here suggest that the efficacy of the
calicheamicins toward such
tumors is unexpectedly enhanced by antibody conjugation, especially for the "
amide conjugate". These hydrolytically stable conjugates are also active toward
cisplatin-resistant ovarian
carcinoma cells as well. Such studies indicate that the
calicheamicin amide conjugate of CTM01 may have potential for the treatment of MUC1-positive solid
tumors, including some types of resistant
tumors.