Nuklearmedizin 2011; 50(05): 214-220
DOI: 10.3413/nukmed-0385-11-02
Original article
Schattauer GmbH

211At-AntiCD33 in NMRI nu/nu mice

Biodistribution, in vivo stability and radiotoxicity 211At-AntiCD33 in NMRI-nu/nu-MäusenBiodistribution, In-vivo-Stabilität und Radiotoxizität
A. Walte
1   Klinik für Nuklearmedizin, Medizinische Hochschule Hannover, Germany
,
S. Sriyapureddy
1   Klinik für Nuklearmedizin, Medizinische Hochschule Hannover, Germany
,
D. Krull
1   Klinik für Nuklearmedizin, Medizinische Hochschule Hannover, Germany
,
T. Petrich
1   Klinik für Nuklearmedizin, Medizinische Hochschule Hannover, Germany
,
G.-J. Meyer
1   Klinik für Nuklearmedizin, Medizinische Hochschule Hannover, Germany
,
W. H. Knapp
1   Klinik für Nuklearmedizin, Medizinische Hochschule Hannover, Germany
› Author Affiliations
Further Information

Publication History

received: 14 February 2011

accepted in revised form: 07 June 2011

Publication Date:
28 December 2017 (online)

Summary

The aim of this study is to verify the in vivo stability, to determine the biodistribution and to estimate the unspecific radiotoxicity of an 211At-labelled CD33-antibody (211At-anti-CD33) in mice with a view to therapeutic application in treating leukaemia. Animals, methods: 211At was produced via the 209Bi(α,2n)211At reaction and was linked via 3-211At-succinimidyl-benzoate to the anti-CD33-antibody. The biodistribution and the in vivo stability in serum were determined after i.v.-injection in NMRI nu/nu-mice. For toxicity experiments, mice received either three times 315–650 kBq 211At-antiCD33 or unlabelled antibody and NaCl-solution respectively. Results: 211At-antiCD33 showed a characteristic biodistribution complying with the unspecific antibody retention in the reticular endothelial system. The largest proportion of radioactivity remained in blood and blood-rich tissues with a minor accumulation in the thyroid and stomach. After 21 h, > 85% of activity in serum still represented intact antibody. Mice showed no difference in unspecific toxicity of 211At-labelled antibodies over six months compared to those treated with unlabelled antibody and NaCl-solution respectively, with regard to histopathologic lesions, survival time, behaviour and haemograms. Conclusion: The radiolabelling method yielded adequate in vivo stability of 211At-antiCD33. Biodistribution with rapid elimination of free 211At via kidneys and urine complies with requirements for targeted therapy. Activity doses potentially required for treatment do not elicit radiotoxicity to normal organs in mice. Further development is required to enhance the apparent specific activity and to verify the efficacy in an adequate animal model before phase I clinical studies in leukaemia can be envisaged.

Zusammenfassung

Ziel der Studie war es, die in vivo Stabilität und die Biodistribution eines 211At-markierten Anti-CD33-Antikörpers (211At-AntiCD33) zu untersuchen und dessen unspezifische Radiotoxizität hinsichtlich des Einsatzes in der Leukämietherapie anhand eines Mausmodells abzuschätzen. Tiere, Methoden: 211At wurde über die 209Bi(α,2n)211At-Reaktion am Zyklotron erzeugt und als Succinimidyl-3-211At-benzoat an den Antikörper gebunden. Die Biodistribution und die In-vivo-Stabilität im Serum wurden nach intravenöser Injektion an NMRI-nu/ nu-Mäusen evaluiert. Für die Experimente zur Radiotoxizität wurde den Mäusen dreimal 315–650 kBq 211At-Anti-CD33 bzw. unmarkierter Antikörper oder NaCl-Lösung verabreicht. Ergebnisse: 211At-Anti-CD33 zeigte eine charakteristische Bioverteilung mit einer unspezifischen Retention des Antikörpers im retikuloendothelialen System. Der größte Anteil der Radioaktivität verblieb im Blut und in blutreichen Geweben, eine schwächere Anreicherung wurde in Schilddrüse und Magen beobachtet. Nach 21 h betrug der Anteil an intakten 211At-Anti-CD33 > 85% der Serumaktivität. Zwischen den Behandlungsgruppen war histopathologisch, in der Überlebenszeit und im Blutbild über sechs Monate kein Unterschied in der unspezifischen Toxizität des 211At-Anti-CD33 zu erkennen. Schlussfolgerung: Die Synthesemethode führt zu einem in vivo ausreichend stabilen Produkt. Die Biodistribution mit schneller renaler Ausscheidung ist für eine therapeutische Anwendung geeignet. Eine für therapeutische Zwecke angemessene Dosierung führte zu keinen signifikanten radiotoxischen Organschäden im Mausmodell. Weitere Untersuchungen zur Verbesserung der scheinbaren spezifischen Aktivität und zur Wirksamkeit sind nötig, bevor eine klinische Studie (Phase I) an Leukämie-Patienten geplant werden kann.

 
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