A Calicheamicin Conjugate with a Fully Humanized Anti-MUC1 Antibody Shows Potent Antitumor Effects in Breast and Ovarian Tumor Xenografts

• Published in: Bioconjugate chemistry Vol. 16; no. 2; pp. 354 - 360
• Main Authors: Hamann, Philip R, Hinman, Lois M, Beyer, Carl F, Lindh, Delores, Upeslacis, Janis, Shochat, Dan, Mountain, Andrew
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.03.2005
• Subjects: Animals; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - therapeutic use; Antigens; Biochemistry; Breast cancer; Breast Neoplasms - drug therapy; Cell Line, Tumor; Chemical compounds; Cisplatin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Enediynes; Female; Humans; Immunoconjugates - chemistry; Immunoconjugates - therapeutic use; Immunoglobulins; Mice; Mice, Nude; Mucin-1 - immunology; Neoplasms, Experimental - drug therapy; Ovarian cancer; Ovarian Neoplasms - drug therapy; Peptide Fragments - immunology; Transplantation, Heterologous; Treatment Outcome; Trisaccharides - chemistry; Trisaccharides - therapeutic use; Tumor Burden - drug effects; Tumors
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc049794n

Murine CTM01 is an internalizing murine IgG1 monoclonal antibody that recognizes the MUC1 antigen expressed on many solid tumors of epithelial origin. Calicheamicin conjugates of this antibody have previously been shown to be potent, selective antitumor agents in preclinical models. A conjugate has now been made with a genetically engineered human version of this antibody, hCTM01. The hCTM01 is an IgG4 isotype, has an immunoaffinity approximately 30% higher than mCTM01 by competitive RIA, and is efficiently internalized into target cells. The hCTM01−NAc-gamma calicheamicin DM amide conjugate, referred to as CMB-401, shows targeted killing of MUC1-expressing cells in vitro and produces pronounced dose-related antitumor effects over an 8-fold dose range against a MUC1-expressing, ovarian xenograft tumor, OvCar-3. The specificity of CMB-401 was confirmed by comparing its antitumor effects with those of an isotype-matched nonspecific conjugate against the MX-1 breast carcinoma. CMB-401, given either ip or iv, was highly active in these models in single and multiple dose regimens and gave complete regressions at the highest doses examined with good overall therapeutic ratios. CMB-401 also gave good antitumor effects at similar doses with a cisplatin-resistant MUC1-expressing cell line.