title: α- Versus β-Emitting Radionuclides for Pretargeted Radioimmunotherapy of Carcinoembryonic Antigen-Expressing Human Colon Cancer Xenografts.
abstract: Pretargeted radioimmunotherapy (PRIT) with the β-emitting radionuclide177Lu is an attractive approach to treat carcinoembryonic antigen (CEA)-expressing tumors. The therapeutic efficacy of PRIT might be improved using α-emitting radionuclides such as213Bi. Herein, we report and compare the tumor-targeting properties and therapeutic efficacy of213Bi and177Lu for PRIT of CEA-expressing xenografts, using the bispecific monoclonal antibody TF2 (anti-CEA × anti-histamine-succinyl-glycine [HSG]) and the di-HSG-DOTA peptide IMP288.Methods:The in vitro binding characteristics of213Bi-IMP288 were compared with those of177Lu-IMP288. Tumor targeting of213Bi-IMP288 and177Lu-IMP288 was studied in mice bearing subcutaneous LS174T tumors that were pretargeted with TF2. Finally, the effect of213Bi-IMP288 (6, 12, or 17 MBq) and177Lu-IMP288 (60 MBq) on tumor growth and survival was assessed. Toxicity was determined by monitoring body weight, analyzing blood samples for hematologic and renal toxicity (hemoglobin, leukocytes, platelets, creatinine), and immunohistochemical analysis of the kidneys.Results:The in vitro binding characteristics of213Bi-IMP288 (dissociation constant, 0.45 ± 0.20 nM) to TF2-pretargeted LS174T cells were similar to those of177Lu-IMP288 (dissociation constant, 0.53 ± 0.12 nM). In vivo accumulation of213Bi-IMP288 in LS174T tumors was observed as early as 15 min after injection (9.2 ± 2.0 percentage injected dose [%ID]/g).213Bi-IMP288 cleared rapidly from the circulation; at 30 min after injection, the blood levels were 0.44 ± 0.28 %ID/g. Uptake in normal tissues was low, except for the kidneys, where uptake was 1.8 ± 1.1 %ID/g at 30 min after injection. The biodistribution of213Bi-IMP288 was comparable to that of177Lu-IMP288. Mice treated with a single dose of213Bi-IMP288 or177Lu-IMP288 showed significant inhibition of tumor growth. Median survival for the groups treated with phosphate-buffered saline, 6 MBq213Bi-IMP288, 12 MBq213Bi-IMP288, and 60 MBq177Lu-IMP288 was 22, 31, 45, and 42 d, respectively. Mice receiving 17 MBq213Bi-IMP288 showed significant weight loss, resulting in a median survival of only 24 d. No changes in hemoglobin, platelets, or leukocytes were observed in the treatment groups. However, immunohistochemical analysis of the kidneys of mice treated with 17 or 12 MBq213Bi-IMP288 showed signs of tubular damage, indicating nephrotoxicity.Conclusion:To our knowledge, this study shows for the first time that PRIT with TF2 and213Bi-IMP288 is feasible and at least as effective as177Lu-IMP288. However, at higher doses, kidney toxicity was observed. Future studies are warranted to determine the optimal dosing schedule to improve therapeutic efficacy while reducing renal toxicity.
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands sandra.heskamp@radboudumc.nl.
authors.forename: Sandra
authors.initials: S
authors.lastname: Heskamp
authors.affiliation: Medical Physics Department, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Reinier
authors.initials: R
authors.lastname: Hernandez
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Janneke D M
authors.initials: JDM
authors.lastname: Molkenboer-Kuenen
authors.affiliation: Klinik und Poliklinik fur Nuklearmedizin, University of Bonn, Bonn, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Essler
authors.affiliation: European Commission, Joint Research Centre-Directorate for Nuclear Safety and Security, Karlsruhe, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.affiliation: European Commission, Joint Research Centre-Directorate for Nuclear Safety and Security, Karlsruhe, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Steenbergen
authors.affiliation: Medical Physics Department, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Weibo
authors.initials: W
authors.lastname: Cai
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany.|Department of Obstetrics and Gynecology, Technische Universität München, Munich, Germany; and.
authors.forename: Christof
authors.initials: C
authors.lastname: Seidl
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: William J
authors.initials: WJ
authors.lastname: McBride
authors.affiliation: Immunomedics, Inc., Morris Plains, New Jersey.
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
mesh_terms: D000512:Alpha Particles / Q000627:therapeutic use; D000818:Animals; D001610:Beta Particles / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods*; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D002272:Carcinoembryonic Antigen; D011868:Radioisotopes
keywords: Bi-213; CEA; pretargeting; radiochemistry; radionuclide therapy; targeted alpha therapy