An Anti-MUC1 Antibody-Calicheamicin Conjugate for Treatment of Solid Tumors. Choice of Linker and Overcoming Drug Resistance
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- 作者：Philip R. Hamann ; Lois M. Hinman ; Carl F. Beyer ; Lee M. Greenberger ; Clara Lin ; Delores Lindh ; Ana T. Menendez ; Rosalyn Wallace ; Frederick E. Durr ; and Janis Upeslacis
- 刊名：Bioconjugate Chemistry
- 出版年：2005
- 出版时间：March 2005
- 年：2005
- 卷：16
- 期：2
- 页码：346 - 353
- 全文大小：160K
- 年卷期：v.16,no.2(March 2005)
- ISSN：1520-4812
文摘
The anti-MUC1 antibody, CTM01, has been chosen to target the potently cytotoxic calicheamicinantitumor antibiotics to solid tumors of epithelial origin that express this antigen. Earlier calicheamicinconjugates relied on the attachment of a hydrazide derivative to the oxidized carbohydrates that occurnaturally on antibodies. This produced a "carbohydrate conjugate" capable of releasing active drugby hydrolysis in the lysosomes where the pH is low. Conjugates have now been made that are formedby 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 inall calicheamicin conjugates as the only likely site of drug release from the conjugate. As previouslyshown for the carbohydrate conjugate, this amide conjugate of CTM01 produces complete regressionsof xenograft tumors at doses of 300 
r.gif">g/kg (calicheamicin equivalents) given three times. This indicatesthat hydrolytic drug release is not necessary for potent, selective cytotoxicity for calicheamicinconjugates of CTM01. Although the unconjugated calicheamicins are in general less active in cellsexpressing the multidrug resistance phenotype, both in vitro and in vivo results of studies reportedhere suggest that the efficacy of the calicheamicins toward such tumors is unexpectedly enhanced byantibody conjugation, especially for the "amide conjugate". These hydrolytically stable conjugates arealso active toward cisplatin-resistant ovarian carcinoma cells as well. Such studies indicate that thecalicheamicin amide conjugate of CTM01 may have potential for the treatment of MUC1-positive solidtumors, including some types of resistant tumors.
r.gif">g/kg (calicheamicin equivalents) given three times. This indicatesthat hydrolytic drug release is not necessary for potent, selective cytotoxicity for calicheamicinconjugates of CTM01. Although the unconjugated calicheamicins are in general less active in cellsexpressing the multidrug resistance phenotype, both in vitro and in vivo results of studies reportedhere suggest that the efficacy of the calicheamicins toward such tumors is unexpectedly enhanced byantibody conjugation, especially for the "amide conjugate". These hydrolytically stable conjugates arealso active toward cisplatin-resistant ovarian carcinoma cells as well. Such studies indicate that thecalicheamicin amide conjugate of CTM01 may have potential for the treatment of MUC1-positive solidtumors, including some types of resistant tumors.