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

Astri Fjelde Maaland,Jan Terje Andersen,Helen Heyerdahl,Bergthora Eiriksdottir,Adam O’Shea,Jostein Dahle,Véronique Pascal,Arne Kolstad

doi:10.1007/s00259-019-04417-1

Astri Fjelde Maaland, Jan Terje Andersen + Show 6 more

Open Access

https://doi.org/10.1007/s00259-019-04417-1

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Abstract

PurposeThe aim of this study was to explore the β-emitting lutetium-177 labelled anti-CD37 antibody NNV003 (177Lu-NNV003, Humalutin®) for the treatment of non-Hodgkin’s lymphoma in in vitro studies and in animal models.MethodsCytotoxicity of 177Lu-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 177Lu-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 177Lu-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.Results177Lu-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, 177Lu-NNV003 (50–100 MBq/kg) improved survival compared to control groups (p < 0.02). In mice with subcutaneous REC-1 xenografts, 500 MBq/kg 177Lu-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.Conclusion177Lu-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.

Highlights

Non-Hodgkin’s lymphoma (NHL) accounts for 2.7% of all cancers and 2.4% of all cancer deaths worldwide [1]
We have explored the efficacy of unlabelled and lutetium-177 labelled NNV003 chimeric antibody in Chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL) models
The binding properties of NNV003 and its mouse counterpart lilotomab to the classical human and murine forms of the FcγRs are shown in Figs. 1a and b

Summary

Introduction

Non-Hodgkin’s lymphoma (NHL) accounts for 2.7% of all cancers and 2.4% of all cancer deaths worldwide [1]. Chronic lymphocytic leukaemia (CLL), another B cell malignancy, is the most common leukaemia. Targeted therapies like Bruton’s tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors are emerging as novel treatment options, in MCL and CLL [3, 4, 6]. Survival rates for these haematological diseases have improved over recent decades [7,8,9]. In this study we evaluate a new compound, a generation radioimmunoconjugate (RIC), for treatment of B cell malignancies. The RIC, 177LuNNV003, consists of a chimeric mouse-human anti-CD37 antibody (NNV003), conjugated with p-SCN-Bn-DOTA (DOTA) that chelates the β-emitting radionuclide lutetium-177

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