Targeting B-cell malignancies with the beta-emitting anti-CD37 radioimmunoconjugate 177Lu-NNV003

The aim of this study was to explore the β-emitting lutetium-177 labelled anti-CD37 antibody NNV003 ( 177 Lu-NNV003, Humalutin®) for the treatment of non-Hodgkin’s lymphoma in in vitro studies and in animal models. Cytotoxicity of 177 Lu-NNV003 was measured in REC-1 (mantle cell lymphoma) and DOHH-2 (diffuse large B cell lymphoma) cell lines. Biodistribution was studied in mice bearing subcutaneous DOHH-2 or MEC-2 (chronic lymphocytic leukaemia) xenografts. The therapeutic effect of a single injection of 177 Lu-NNV003 was measured in mice intravenously or subcutaneously injected with REC-1 cells. Haematological and histopathological assessments were used to evaluate the toxic effect of 177 Lu-NNV003. The immunotherapeutic effect of NNV003 was assessed by measuring binding to Fcγ receptors, activation of ADCC and ADCP. NNV003’s immunogenicity potential was assessed using in silico immunogenicity prediction tools. 177 Lu-NNV003 showed an activity dependent antiproliferative effect in all cell lines. Maximum tumour uptake in vivo was 45% of injected activity/g in MEC-2 tumours and 15% injected activity/g in DOHH-2 tumours. In mice injected intravenously with REC-1 cells, 177 Lu-NNV003 (50–100 MBq/kg) improved survival compared to control groups ( p < 0.02). In mice with subcutaneous REC-1 xenografts, 500 MBq/kg 177 Lu-NNV003 extended survival compared to the control treatments ( p < 0.005). Transient haematological toxicity was observed in all mice treated with radioactivity. NNV003 induced ADCC and ADCP and was predicted to have a lower immunogenicity potential than its murine counterpart. 177 Lu-NNV003 had a significant anti-tumour effect and a favourable toxicity profile. These results warrant further clinical testing in patients with CD37-expressing B cell malignancies.