A calicheamicin conjugate with a fully humanized anti-MUC1 antibody shows potent antitumor effects in breast and ovarian tumor xenografts.
Murine CTM01 is an internalizing murine IgG(1) 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 IgG(4) 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.
Hamann
Philip R
PR
Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. hamannp@wyeth.com
Hinman
Lois M
LM
Beyer
Carl F
CF
Lindh
Delores
D
Upeslacis
Janis
J
Shochat
Dan
D
Mountain
Andrew
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002945:Cisplatin; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D053281:Enediynes; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D018396:Mucin-1 / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010446:Peptide Fragments / Q000276:immunology*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D014312:Trisaccharides / Q000737:chemistry / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects
D000911:Antibodies, Monoclonal; D053281:Enediynes; D018796:Immunoconjugates; C116055:MUC1 tandem repeat peptide; D018396:Mucin-1; D010446:Peptide Fragments; D014312:Trisaccharides; C121659:calicheamicin gamma(1)I aryltrisaccharide; D002945:Cisplatin