title: Preparation, biological evaluation, and pharmacokinetics of the human anti-HER1 monoclonal antibody panitumumab labeled with 86Y for quantitative PET of carcinoma.
abstract: Panitumumab, a human monoclonal antibody that binds to the epidermal growth factor receptor (HER1), was approved by the Food and Drug Administration in 2006 for the treatment of patients with HER1-expressing carcinoma. In this article, we describe the preclinical development of (86)Y-CHX-A''-diethylenetriaminepentaacetic acid (DTPA)-panitumumab for quantitative PET of HER1-expressing carcinoma. Panitumumab was conjugated to CHX-A''-DTPA and radiolabeled with (86)Y. In vivo biodistribution, PET, blood clearance, area under the curve, area under the moment curve, and mean residence time were determined for mice bearing HER1-expressing human colorectal (LS-174T), prostate (PC-3), and epidermoid (A431) tumor xenografts. Receptor specificity was demonstrated by coinjection of 0.1 mg of panitumumab with the radioimmunoconjugate.
  
  
  RESULTS
  (86)Y-CHX-A''-DTPA-panitumumab was routinely prepared with a specific activity exceeding 2 GBq/mg. Biodistribution and PET studies demonstrated a high HER1-specific tumor uptake of the radioimmunoconjugate. In mice bearing LS-174T, PC-3, or A431 tumors, the tumor uptake at 3 d was 34.6 +/- 5.9, 22.1 +/- 1.9, and 22.7 +/- 1.7 percentage injected dose per gram (%ID/g), respectively. The corresponding tumor uptake in mice coinjected with 0.1 mg of panitumumab was 9.3 +/- 1.5, 8.8 +/- 0.9, and 10.0 +/- 1.3 %ID/g, respectively, at the same time point, demonstrating specific blockage of the receptor. Normal organ and tumor uptake quantified by PET was closely related (r(2) = 0.95) to values determined by biodistribution studies. The LS-174T tumor had the highest area under the curve (96.8 +/- 5.6 %ID d g(-1)) and area under the moment curve (262.5 +/- 14.9 %ID d(2) g(-1)); however, the tumor mean residence times were identical for all 3 tumors (2.7-2.8 d).
  
  
  CONCLUSIONS
  This study demonstrates the potential of (86)Y-CHX-A''-DTPA-panitumumab for quantitative noninvasive PET of HER1-expressing tumors and represents the first step toward clinical translation.
authors.affiliation: Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. tapann@gmail.com
authors.forename: Tapan K
authors.initials: TK
authors.lastname: Nayak
authors.forename: Kayhan
authors.initials: K
authors.lastname: Garmestani
authors.forename: Kwamena E
authors.initials: KE
authors.lastname: Baidoo
authors.forename: Diane E
authors.initials: DE
authors.lastname: Milenic
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001692:Biological Transport; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D000077544:Panitumumab; D004369:Pentetic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D018570:Risk Assessment; D015021:Yttrium Radioisotopes
chemical_list: D000911:Antibodies, Monoclonal; D015021:Yttrium Radioisotopes; C408383:cyclohexyldiethylenetriamine pentaacetic acid; D000077544:Panitumumab; D004369:Pentetic Acid; C512478:EGFR protein, human; D066246:ErbB Receptors