title: Evaluation of cetuximab as a candidate for targeted α-particle radiation therapy of HER1-positive disseminated intraperitoneal disease.
abstract: Although the epidermal growth factor receptor (EGFR), also known as HER1, has been studied for over a decade, it continues to be a molecule of great interest and focus of investigators for development of targeted therapies. The marketed monoclonal antibody cetuximab binds to HER1, and thus might serve as the basis for creation of imaging or therapies that target this receptor. The potential of cetuximab as a vehicle for the delivery of α-particle radiation was investigated in an intraperitoneal tumor mouse model. The effective working dose of 10 μCi of (212)Pb-cetuximab was determined from a dose (10-50 μCi) escalation study. Toxicity, as indicated by the lack of animal weight loss, was not evident at the 10 μCi dose of (212)Pb-cetuximab. A subsequent study demonstrated (212)Pb-cetuximab had a therapeutic efficacy similar to that of (212)Pb-trastuzumab (p = 0.588). Gemcitabine given 24 h prior to (212)Pb-cetuximab increased the median survival from 174 d to 283 d, but carboplatin suppressed the effectiveness of (212)Pb-cetuximab. Notably, concurrent treatment of tumor-bearing mice with (212)Pb-labeled cetuximab and trastuzumab provided therapeutic benefit that was greater than either antibody alone. In conclusion, cetuximab proved to be an effective vehicle for targeting HER1-expressing tumors with α-radiation for the treatment of disseminated intraperitoneal disease. These studies provide further evidence that the multimodality therapy regimens may have greater efficacy and benefit in the treatment of cancer patients.
authors.affiliation: a Radioimmune & Inorganic Chemistry Section; Radiation Oncology Branch; Center for Cancer Research; National Cancer Institute; National Institutes of Health ; Bethesda MD USA.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Milenic
authors.forename: Kwamena E
authors.initials: KE
authors.lastname: Baidoo
authors.forename: Young-Seung
authors.initials: YS
authors.lastname: Kim
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
mesh_terms: D000512:Alpha Particles; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D007554:Isotopes; D051379:Mice; D008819:Mice, Nude; D010534:Peritoneal Neoplasms / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D016499:Radioimmunotherapy / Q000379:methods*; D000093542:Gemcitabine
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007554:Isotopes; D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab; D000093542:Gemcitabine
keywords: %ID/g, percent injected dose per gram; 212Pb; BSA, bovine serum albumin; EGFR, epidermal growth factor receptor; HER1; HulgG, human immunoglobulin; MS, median survival; PBS, phosphate-buffered saline; PET, positron emission tomography; RIT, radioimmunotherapy; TCMC, 1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoyl methyl)-cyclododecane; cetuximab; i.p., intraperitoneal; mAb, monoclonal antibody; radioimmunotherapy; s.c, subcutaneous; α-particle