Mouse-human chimeric anti-epidermal growth factor receptor antibody C225 inhibits the growth of human renal cell carcinoma xenografts in nude mice.
The epidermal growth factor (EGF) receptor and its ligand transforming growth factor-alpha (TGF-alpha) are overexpressed in human renal cell carcinoma (RCC). The chimeric anti-EGF receptor monoclonal antibody C225 was used to determine the effects of blocking the EGF receptor on RCC growth both in vitro and in vivo. A panel of RCC cell lines all tested positive at various levels for EGF receptor cell surface expression. C225 inhibited DNA synthesis of cultured A498, Caki-1, SK-RC-4, SK-RC-29, and SW839 cells in a dose-dependent manner, ranging from 20 to 45% inhibition compared with untreated controls. C225 also inhibited exogenous ligand-stimulated tyrosine phosphorylation of EGF receptor on RCC cells. The antitumor effects of C225 on RCC tumor growth were evaluated in ascites, s.c., and orthotopic RCC xenograft models. Mice treated with C225 in a Caki-1 ascites xenograft model showed a significant increase in survival (P = 0.002). All control mice died with ascites tumors by week 9, whereas >70% of C225-treated mice survived beyond 12 weeks. C225 also inhibited the growth of s.c. SK-RC-29 tumors in a dose-dependent manner. Mice treated with C225 (1 mg/dose) displayed a significant decrease in tumor volume compared with mice treated with control antibody (P < 0.05) or vehicle alone (P < 0.01). Lastly, C225 inhibited the growth and metastasis of RCC tumors growing orthotopically in the renal subcapsule of nude mice. Histological examination of RCC tumors from mice treated with C225 showed a substantial decrease in proliferating cell nuclear antigen staining and an increase in tumor cell apoptosis. These data suggest that C225 affects growth of RCC tumors by inhibiting EGF receptor-dependent proliferation and demonstrate the potential for therapeutic application of C225 in the treatment of human renal cancer.
Prewett
M
M
Department of Immunology, ImClone Systems Incorporated, New York, New York 10014, USA.
Rothman
M
M
Waksal
H
H
Feldman
M
M
Bander
N H
NH
Hicklin
D J
DJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000473:pathology / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects; D000068818:Cetuximab; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D066246:ErbB Receptors; D000068818:Cetuximab