Targeted alpha therapy for chronic lymphocytic leukaemia and non-Hodgkin's lymphoma with the anti-CD37 radioimmunoconjugate 212Pb-NNV003.

Astri Fjelde Maaland,Amal Saidi,Julien Torgue,Helen Heyerdahl,Tania A Rozgaja Stallons,Arne Kolstad,Jostein Dahle

doi:10.1371/journal.pone.0230526

Abstract

Relapse of chronic lymphocytic leukaemia and non-Hodgkin’s lymphoma after standard of care treatment is common and new therapies are needed. The targeted alpha therapy with 212Pb-NNV003 presented in this study combines cytotoxic α-particles from 212Pb, with the anti-CD37 antibody NNV003, targeting B-cell malignancies. The goal of this study was to explore 212Pb-NNV003 for treatment of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin’s lymphoma in preclinical mouse models.An anti-proliferative effect of 212Pb-NNV003 was observed in both chronic lymphocytic leukaemia (MEC-2) and Burkitt’s lymphoma (Daudi) cells in vitro. In biodistribution experiments, accumulation of 212Pb-NNV003 was 23%ID/g and 16%ID/g in Daudi and MEC-2 tumours 24 h post injection. In two intravenous animal models 90% of the mice treated with a single injection of 212Pb-NNV003 were alive 28 weeks post cell injection. Median survival times of control groups were 5–9 weeks. There was no significant difference between different specific activities of 212Pb-NNV003 with regards to therapeutic effect or toxicity. For therapeutically effective activities, a transient haematological toxicity was observed. This study shows that 212Pb-NNV003 is effective and safe in preclinical models of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin’s lymphoma, warranting future clinical testing.

Highlights

In the USA, chronic lymphocytic leukaemia (CLL) and non-Hodgkin’s lymphoma (NHL) account for 1.2% and 4.3% of all new cancer incidence, with a combined estimated number of new cases of approximately 95,000 in 2019 [1, 2]
In the MEC-2 model, doses of 370 kBq or more were needed to achieve similar effects. This corresponds well with the in vitro data showing that Daudi cells were more sensitive to 212Pb-NNV003 compared to MEC-2 cells
Mice i.v. injected with MEC-2 cells were often euthanised due to weight loss after massive infiltration in several critical organs, while mice injected with Daudi cells were euthanised due to hind leg paralysis caused by localised infiltration of the bone marrow

Summary

Introduction

In the USA, chronic lymphocytic leukaemia (CLL) and non-Hodgkin’s lymphoma (NHL) account for 1.2% and 4.3% of all new cancer incidence, with a combined estimated number of new cases of approximately 95,000 in 2019 [1, 2]. The standard of care for CLL is chemotherapy in combination with anti-CD20 antibodies. The specific roles of these authors are articulated in the ‘author contributions’ section. No additional external funding received for this study

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