title: The nonuniformity of antibody distribution in the kidney and its influence on dosimetry.
abstract: The therapeutic efficacy of radiolabeled antibody fragments can be limited by nephrotoxicity, particularly when the kidney is the major route of extraction from the circulation. Conventional dose estimates in kidney assume uniform dose deposition, but we have shown increased antibody localization in the cortex after glomerular filtration. The purpose of this study was to measure the radioactivity in cortex relative to medulla for a range of antibodies and to assess the validity of the assumption of uniformity of dose deposition in the whole kidney and in the cortex for these antibodies with a range of radionuclides. Storage phosphor plate technology (radioluminography) was used to acquire images of the distributions of a range of antibodies of various sizes, labeled with 125I, in kidney sections. This allowed the calculation of the antibody concentration in the cortex relative to the medulla. Beta-particle point dose kernels were then used to generate the dose-rate distributions from 14C, 131I, 186Re, 32P and 90Y. The correlation between the actual dose-rate distribution and the corresponding distribution calculated assuming uniform antibody distribution throughout the kidney was used to test the validity of estimating dose by assuming uniformity in the kidney and in the cortex. There was a strong inverse relationship between the ratio of the radioactivity in the cortex relative to that in the medulla and the antibody size. The nonuniformity of dose deposition was greatest with the smallest antibody fragments but became more uniform as the range of the emissions from the radionuclide increased. Furthermore, there was a strong correlation between the actual dose-rate distribution and the distribution when assuming a uniform source in the kidney for intact antibodies along with medium- to long-range radionuclides, but there was no correlation for small antibody fragments with any radioisotope or for short-range radionuclides with any antibody. However, when the cortex was separated from the whole kidney, the correlation between the actual dose-rate distribution and the assumed dose-rate distribution, if the source was uniform, increased significantly. During radioimmunotherapy, the extent of nonuniformity of dose deposition in the kidney depends on the properties of the antibody and radionuclide. For dosimetry estimates, the cortex should be taken as a separate source region when the radiopharmaceutical is small enough to be filtered by the glomerulus.
authors.affiliation: CRC Targeting and Imaging Group, Department of Oncology, Royal Free and University College Medical School, University College London, London, NW3 2PF, United Kingdom. aiden.a.flynn@gsk.com
authors.forename: Aiden A
authors.initials: AA
authors.lastname: Flynn
authors.forename: R Barbara
authors.initials: RB
authors.lastname: Pedley
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Green
authors.forename: Jason L
authors.initials: JL
authors.lastname: Dearling
authors.forename: Ethaar
authors.initials: E
authors.lastname: El-Emir
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Boxer
authors.forename: Robert
authors.initials: R
authors.lastname: Boden
authors.forename: Richard H J
authors.initials: RH
authors.lastname: Begent
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics*; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics; D007668:Kidney / Q000528:radiation effects*; D007672:Kidney Cortex / Q000528:radiation effects; D007679:Kidney Medulla / Q000528:radiation effects; D051379:Mice; D008819:Mice, Nude; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy; D011874:Radiometry; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates