Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model.
The epidermal growth factor receptor (EGFR) is a protein tyrosine kinase expressed on many types of tumor cells, including breast, ovarian, bladder, head and neck, and prostatic carcinoma. There seems to be an association between up-regulation of the EGFR and poor clinical prognosis for a number of human cancers. The 225 antibody is a highly specific murine monoclonal antibody that binds specifically to the human EGFR with an affinity equal to its ligand, competes with the ligand for binding, and blocks activation of the receptor tyrosine kinase. In addition, 225 has been shown to inhibit the growth of human tumor xenografts in athymic nude mice. The 225 antibody has recently been chimerized with human IgG1 in its constant region to increase its clinical utility by decreasing the potential for generation of human antimouse antibodies in recipients. This report compares the biological effects of 225 and its chimeric counterpart (designated C225) against established A431 tumor xenografts in nude mice. The results of these experiments indicated that C225 was more effective than 225 in inhibiting tumor growth in this model. In addition, many of the animals treated with C225 were tumor free at the end of each treatment protocol. It was determined that the dissociation constant of C225 was about 5-fold lower than 225. This suggested that the increased capacity of C225 to compete with ligand for binding to the EGFR was responsible for its enhanced in vivo antitumor effect.
Goldstein
N I
NI
Departments of Immunology/Monoclonal Antibodies and Protein Chemistry, ImClone Systems, Inc., New York, New York 10014, USA.
Prewett
M
M
Zuklys
K
K
Rockwell
P
P
Mendelsohn
J
J
D000818:Animals; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use*; D007135:Immunoglobulin Variable Region / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D007074:Immunoglobulin G; D007135:Immunoglobulin Variable Region; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D066246:ErbB Receptors