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

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. 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-Rag1^null) interleukin-2 receptor common gamma chain (IL2r γ ^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. 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. 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. (orig.)