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

作者：Weber Tobias; Boetticher Benedikt; Mier Walter; Sauter Max; Kraemer Susanne; Leotta Karin; Keller Armin; Schlegelmilch Anne; Grosse Hovest Ludger; Jaeger Dirk; Haberkorn Uwe; Arndt Michaela A E; Krauss Juergen^*

来源：European Journal of Nuclear Medicine and Molecular Imaging, 2016, 43(3): 489-498.

DOI：10.1007/s00259-015-3175-6

• Lu-177
• CD22
• Lymphoma
• huRFB4
• Radioimmunotherapy

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 Lu-177. 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-AaEuro(3)-DTPA-conjugated antibodies to target cells was analysed by flow cytometry. To assess tumour targeting of Lu-177-labelled antibodies, in vivo biodistribution experiments were performed. For radioimmunotherapy (RIT) studies, non-obese diabetic recombination activating gene-1 (NOD-Rag1 (null) ) interleukin-2 receptor common gamma chain (IL2r gamma (null) ) null mice (NRG mice) were xenografted subcutaneously with Raji Burkitt's lymphoma cells. Lu-177-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 Lu-177-labelled anti-CD22 IgG than of Lu-177-labelled rituximab. Treatment with Lu-177-conjugated huRFB4 resulted in increased tumour growth inhibition and significantly longer survival than treatment with Lu-177-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 Lu-177-based CD22-specific RIT in combination with rituximab is a promising new treatment option for refractory B-NHL.

• 出版日期2016-3