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

• Published in: European journal of nuclear medicine and molecular imaging 2016-03, Vol.43 (3), p.489
• Main Authors: Weber, Tobias, Bötticher, Benedikt, Mier, Walter, Sauter, Max, Krämer, Susanne, Leotta, Karin, Keller, Armin, Schlegelmilch, Anne, Grosse-hovest, Ludger, Jäger, Dirk, Haberkorn, Uwe, Arndt, Michaela A, E, Krauss, Jürgen
• Format: Article
• Language: English
• Subjects: Cancer therapies; Immunotherapy; Lymphoma
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-015-3175-6

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 [beta]-emitter ^sup 177^Lu. 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 ^sup 177^Lu-labelled antibodies, in vivo biodistribution experiments were performed. For radioimmunotherapy (RIT) studies, non-obese diabetic recombination activating gene-1 (NOD-Rag1^sup null^) interleukin-2 receptor common gamma chain (IL2rγ ^sup null^) null mice (NRG mice) were xenografted subcutaneously with Raji Burkitt's lymphoma cells. ^sup 177^Lu-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 ^sup 177^Lu-labelled anti-CD22 IgG than of ^sup 177^Lu-labelled rituximab. Treatment with ^sup 177^Lu-conjugated huRFB4 resulted in increased tumour growth inhibition and significantly longer survival than treatment with ^sup 177^Lu-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 ^sup 177^Lu-based CD22-specific RIT in combination with rituximab is a promising new treatment option for refractory B-NHL.