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

PLoS One. 2020 Mar 18;15(3):e0230526. doi: 10.1371/journal.pone.0230526. eCollection 2020.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm
  • Antineoplastic Agents, Immunological / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cetuximab / therapeutic use
  • Female
  • Humans
  • Lead Radioisotopes / therapeutic use*
  • Leukemia, Lymphoid / drug therapy*
  • Leukemia, Lymphoid / metabolism
  • Lymphoma, Non-Hodgkin / drug therapy*
  • Lymphoma, Non-Hodgkin / metabolism
  • Mice
  • Mice, SCID
  • Radiometry
  • Tetraspanins / antagonists & inhibitors

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents, Immunological
  • CD37 protein, human
  • Lead Radioisotopes
  • Lead-212
  • Tetraspanins
  • Cetuximab

Grants and funding

This study was partially funded by the Norwegian Research Council, grant number 25690, and by Nordic Nanovector ASA and Orano Med. The funders provided support in the form of salaries for authors AFM, AS, JT, HH, TARS and JD, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. No additional external funding received for this study.