Cetuximab: preclinical evaluation of a monoclonal antibody targeting EGFR for radioimmunodiagnostic and radioimmunotherapeutic applications.
The monoclonal antibody, cetuximab, binds to epidermal growth-factor receptor and thus provides an opportunity to create both imaging and therapies that target this receptor. The potential of cetuximab as a radioimmunoconjugate, using the acyclic bifunctional chelator, CHX-A"-DTPA, was investigated. The pharmacokinetic behavior in the blood was determined in mice with and without tumors. Tumor targeting and scintigraphic imaging were evaluated in mice bearing xenografts of LS-174T (colorectal), SHAW (pancreatic), SKOV3 (ovarian), DU145 (prostate), and HT-29 (colorectal). Excellent tumor targeting was observed in each of the models with peak tumor uptakes of 59.8 +/- 18.1, 22.5 +/- 4.7, 33.3 +/- 5.7, 18.2 +/- 7.8, and 41.7 +/- 10.8 injected dose per gram (%ID/g) at 48-72 hours, respectively. In contrast, the highest tumor %ID/g obtained in mice bearing melanoma (A375) xenografts was 6.3 +/- 1.1 at 72 hours. The biodistribution of (111)In-cetuximab was also evaluated in nontumor-bearing mice. The highest %ID/g was observed in the liver (9.3 +/- 1.3 at 24 hours) and the salivary glands (8.1 +/- 2.8 at 72 hours). Scintigraphy showed excellent tumor targeting at 24 hours. Blood pool was evident, as expected, but cleared over time. At 168 hours, the tumor was clearly discernible with negligible background.
Milenic
Diane E
DE
Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Wong
Karen J
KJ
Baidoo
Kwamena E
KE
Ray
Geoffrey L
GL
Garmestani
Kayhan
K
Williams
Mark
M
Brechbiel
Martin W
MW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000068818:Cetuximab; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007205:Indium Radioisotopes / Q000494:pharmacology; D008545:Melanoma / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy / Q000379:methods*; D012469:Salivary Glands / Q000473:pathology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D066246:ErbB Receptors; D000068818:Cetuximab