title: Pretargeted radioimmunotherapy of colorectal cancer metastases: models and pharmacokinetics predict influence of the physical and radiochemical properties of the radionuclide.
abstract: OBJECTIVE
  We investigated influences of pretargeting variables, tumor location, and radionuclides in pretargeted radioimmunotherapy (PRIT) as well as estimated tumor absorbed doses.
  
  
  METHODS
  LS-174T human colonic carcinoma cells expressing carcinoembryonic antigen (CEA) were inoculated in nude mice. Biodistribution of a bispecific anti-CEA x anti-hapten antibody, TF2, and of a TF2-pretargeted peptide was assessed and a multi-compartment pharmacokinetic model was devised. Tissue absorbed doses were calculated for (131)I, (177)Lu, (90)Y, (211)At, and (213)Bi using realistic specific activities.
  
  
  RESULTS
  Under conditions optimized for tumor imaging (10:1 TF2 to peptide molar ratio, interval time 15-24 h), tumor uptake reached ∼9 ID/g in subcutaneous tumors at 2 h with very low accretion in normal tissues (tumor to blood ratio >20:1 after 2 h). For a low dose of peptide (0.04 nmol), (211)At is predicted to deliver a high absorbed dose to tumors [41.5 Gy considering a relative biologic effect (RBE) of 5], kidneys being dose-limiting. (90)Y and (213)Bi would also deliver high absorbed doses to tumor (18.6 for (90)Y and 26.5 Gy for (213)Bi, taking RBE into account, for 0.1 nmol) and acceptable absorbed doses to kidneys. With hepatic metastases, a twofold higher tumor absorbed dose is expected. Owing to the low activities measured in blood, the bone marrow absorbed dose is expected to be without significant toxicity.
  
  
  CONCLUSIONS
  Pretargeting achieves high tumor uptake and higher tumor to background ratios compared to direct RIT. Short-lived radionuclides are predicted to deliver high tumor absorbed doses especially (211)At, with kidneys being the dose-limiting organ. (177)Lu and (131)I should be considered for repeated injections.
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, Université de Nantes, Inserm, UMR 892, 8 quai Moncousu, BP 70721, 44007 Nantes cedex 1, France. eric.frampas@chu-nantes.fr
authors.forename: Eric
authors.initials: E
authors.lastname: Frampas
authors.forename: Catherine
authors.initials: C
authors.lastname: Maurel
authors.forename: Patricia
authors.initials: P
authors.lastname: Remaud-Le Saëc
authors.forename: Thibault
authors.initials: T
authors.lastname: Mauxion
authors.forename: Alain
authors.initials: A
authors.lastname: Faivre-Chauvet
authors.forename: François
authors.initials: F
authors.lastname: Davodeau
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
authors.forename: Manuel
authors.initials: M
authors.lastname: Bardiès
authors.forename: Jacques
authors.initials: J
authors.lastname: Barbet
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000556:secondary*; D003198:Computer Simulation; D006801:Humans; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009928:Organ Specificity; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D011868:Radioisotopes