An anti-MUC1 antibody-calicheamicin conjugate for treatment of solid tumors. Choice of linker and overcoming drug resistance.
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.
Hamann
Philip R
PR
Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. hamannp@wyteh.com
Hinman
Lois M
LM
Beyer
Carl F
CF
Greenberger
Lee M
LM
Lin
Clara
C
Lindh
Delores
D
Menendez
Ana T
AT
Wallace
Rosalyn
R
Durr
Frederick E
FE
Upeslacis
Janis
J
D000577:Amides; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D053281:Enediynes; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D018396:Mucin-1 / Q000276:immunology*; D009369:Neoplasms / Q000188:drug therapy*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010446:Peptide Fragments / Q000276:immunology*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D014312:Trisaccharides / Q000737:chemistry / Q000627:therapeutic use*
D000577:Amides; D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D053281:Enediynes; D018796:Immunoconjugates; C116055:MUC1 tandem repeat peptide; D018396:Mucin-1; D010446:Peptide Fragments; D014312:Trisaccharides; C121659:calicheamicin gamma(1)I aryltrisaccharide