title: Radioiodinated versus radiometal-labeled anti-carcinoembryonic antigen single-chain Fv-Fc antibody fragments: optimal pharmacokinetics for therapy.
abstract: Antibody fragments with optimized pharmacokinetic profiles hold potential for detection and therapy of tumor malignancies. We studied the behavior of three anti-carcinoembryonic antigen (CEA) single-chain Fv-Fc (scFv-Fc) variants (I253A, H310A, and H310A/H435Q; Kabat numbering system) that exhibited differential serum persistence. Biodistribution studies done on CEA-positive tumor xenografted mice revealed that the 111In-labeled I253A fragment with the slowest clearance kinetics (T1/2beta, 27.7 h) achieved the highest tumor uptake (44.6% ID/g at 24 h), whereas the radiometal-labeled H310A/H435Q fragment with the most rapid elimination (T1/2beta, 7.05 h) reached a maximum of 28.0% ID/g at 12 h postinjection. The H310A protein was characterized by both intermediate serum half-life and tumor uptake. The 111In-based biodistribution studies showed that all three fragments were eliminated primarily through the liver, and hepatic radiometal activity correlated with the rate of fragment clearance. The 111In-labeled H310A/H435Q protein exhibited the highest liver uptake (23.5% ID/g at 24 h). Metabolism of the 125I-labeled scFv-Fc proteins resulted in low normal organ activity. Finally, the 125I/111In biodistribution data allowed for dose estimations, which suggest the 131I-labeled scFv-Fc H310A/H435Q as a promising candidate for radioimmunotherapy.
authors.affiliation: Division of Molecular Biology, Beckman Research Institute of the City of Hope, Department of Radioimmunotherapy, Duarte, CA, USA.
authors.forename: Vania
authors.initials: V
authors.lastname: Kenanova
authors.forename: Tove
authors.initials: T
authors.lastname: Olafsen
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Williams
authors.forename: Nora H
authors.initials: NH
authors.lastname: Ruel
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Longmate
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Yazaki
authors.forename: John E
authors.initials: JE
authors.lastname: Shively
authors.forename: David
authors.initials: D
authors.lastname: Colcher
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Raubitschek
authors.forename: Anna M
authors.initials: AM
authors.lastname: Wu
mesh_terms: D000818:Animals; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics*; D007128:Immunoglobulin Fragments / Q000276:immunology / Q000378:metabolism*; D007205:Indium Radioisotopes / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D007553:Isotope Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D002272:Carcinoembryonic Antigen; D006573:Heterocyclic Compounds, 1-Ring; D018796:Immunoconjugates; D007128:Immunoglobulin Fragments; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid