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High treatment efficacy by dual targeting of Burkitt’s lymphoma xenografted mice with a 177Lu-based CD22-specific radioimmunoconjugate and rituximab

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

Abstract

Purpose

Dual-targeted therapy has been shown to be a promising treatment option in recurrent and/or refractory B-cell non-Hodgkin’s lymphoma (B-NHL). We generated radioimmunoconjugates (RICs) comprising either a novel humanized anti-CD22 monoclonal antibody, huRFB4, or rituximab, and the low-energy β-emitter 177Lu. Both RICs were evaluated as single agents in a human Burkitt’s lymphoma xenograft mouse model. To increase the therapeutic efficacy of the anti-CD22 RIC, combination therapy with unlabelled anti-CD20 rituximab was explored.

Methods

The binding activity of CHX-A″-DTPA-conjugated antibodies to target cells was analysed by flow cytometry. To assess tumour targeting of 177Lu-labelled antibodies, in vivo biodistribution experiments were performed. For radioimmunotherapy (RIT) studies, non-obese diabetic recombination activating gene-1 (NOD-Rag1null) interleukin-2 receptor common gamma chain (IL2rγ null) null mice (NRG mice) were xenografted subcutaneously with Raji Burkitt’s lymphoma cells. 177Lu-conjugated antibodies were administered at a single dose of 9.5 MBq per mouse. For dual-targeted therapy, rituximab was injected at weekly intervals (0.5 – 1.0 mg). Tumour accumulation of RICs was monitored by planar scintigraphy.

Results

Conjugation of CHX-A”-DTPA resulted in highly stable RICs with excellent antigen-binding properties. Biodistribution experiments revealed higher tumour uptake of the 177Lu-labelled anti-CD22 IgG than of 177Lu-labelled rituximab. Treatment with 177Lu-conjugated huRFB4 resulted in increased tumour growth inhibition and significantly longer survival than treatment with 177Lu-conjugated rituximab. The therapeutic efficacy of the anti-CD22 RIC could be markedly enhanced by combination with unlabelled rituximab.

Conclusion

These findings suggest that dual targeting with 177Lu-based CD22-specific RIT in combination with rituximab is a promising new treatment option for refractory B-NHL.

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Acknowledgments

We thank Tim Holland-Letz for help with statistical analyses. This study was supported by the ‟Deutsche José Carreras Leukämie-Stiftung” (grant no. DJCLS R 12/16).

Conflicts of Interest

None.

Compliance with Ethical Standards

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Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not describe any studies with human participants performed by any of the authors.

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Authors and Affiliations

  1. Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany

    Tobias Weber, Benedikt Bötticher, Armin Keller, Anne Schlegelmilch, Dirk Jäger, Michaela A. E. Arndt & Jürgen Krauss

  2. Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany

    Walter Mier, Max Sauter, Susanne Krämer, Karin Leotta & Uwe Haberkorn

  3. Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Max Sauter & Uwe Haberkorn

  4. Department of Immunology, University of Tübingen, Tübingen, Germany

    Ludger Grosse-Hovest

  5. Immunotherapy Program, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Michaela A. E. Arndt

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  1. Tobias Weber
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  2. Benedikt Bötticher
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  3. Walter Mier
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Correspondence to Jürgen Krauss.

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Tobias Weber and Benedikt Bötticher contributed equally to this work.

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Weber, T., Bötticher, B., Mier, W. et al. High treatment efficacy by dual targeting of Burkitt’s lymphoma xenografted mice with a 177Lu-based CD22-specific radioimmunoconjugate and rituximab. Eur J Nucl Med Mol Imaging 43, 489–498 (2016). https://doi.org/10.1007/s00259-015-3175-6

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