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In vitro experimental 211At-anti-CD33 antibody therapy of leukaemia cells overcomes cellular resistance seen in vivo against gemtuzumab ozogamicin

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Monoclonal anti-CD33 antibodies conjugated with toxic calicheamicin derivative (gemtuzumab ozogamicin, GO) are a novel therapy option for acute myeloid leukaemia (AML). Key prognostic factors for patients with AML are high CD33 expression on the leukaemic cells and the ability to overcome mechanisms of resistance to cytotoxic chemotherapies, including drug efflux or other mechanisms decreasing apoptosis. Alpha particle-emitting radionuclides overwhelm such anti-apoptotic mechanisms by producing numerous DNA double-stranded breaks (DSBs) accompanied by decreased DNA repair.

Methods

We labelled anti-CD33 antibodies with the alpha-emitter 211At and compared survival of leukaemic HL-60 and K-562 cells treated with the 211At-labelled antibodies, GO or unlabelled antibodies as controls. We also measured caspase-3/7 activity, DNA fragmentation and necrosis in HL-60 cells after treatment with the different antibodies or with free 211At.

Results

The mean labelling ratio of 211At-labelled antibodies was 1:1,090 ± 364 (range: 1:738–1:1,722) in comparison to 2–3:1 for GO. Tumour cell binding of 211At-anti-CD33 was high in the presence of abundant CD33 expression and could be specifically blocked by unlabelled anti-CD33. 211At-anti-CD33 decreased survival significantly more than did GO at comparable dilution (1:1,000). No significant differences in induction of apoptosis or necrosis or DNA DSB or in decreased survival were observed after 211At-anti-CD33 (1:1,090) versus GO (1:1) treatment.

Conclusion

Our results suggest that 211At is a promising, highly cytotoxic radioimmunotherapy in CD33-positive leukaemia and kills tumour cells more efficiently than does calicheamicin-conjugated antibody. Labelling techniques leading to higher chemical yield and specific activities must be developed to increase 211At-anti-CD33 therapeutic effects.

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Acknowledgement

This work was supported by Deutsche José Carreras Leukämie Stiftung (no. DJCLS 04/21). We thank R.J. Marlowe (Jersey City, NJ, USA) for critically reading the manuscript.

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None.

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Authors and Affiliations

  1. Department of Nuclear Medicine, Hanover University School of Medicine, Carl-Neuberg-Str. 1, 30625, Hanover, Germany

    Thorsten Petrich, Zekiye Korkmaz, Doris Krull, Geerd J. Meyer & Wolfram H. Knapp

  2. Department of Biometry, Hanover University School of Medicine, Carl-Neuberg-Str. 1, 30625, Hanover, Germany

    Cornelia Frömke

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  1. Thorsten Petrich
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  2. Zekiye Korkmaz
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Correspondence to Thorsten Petrich.

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Petrich, T., Korkmaz, Z., Krull, D. et al. In vitro experimental 211At-anti-CD33 antibody therapy of leukaemia cells overcomes cellular resistance seen in vivo against gemtuzumab ozogamicin. Eur J Nucl Med Mol Imaging 37, 851–861 (2010). https://doi.org/10.1007/s00259-009-1356-x

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