Targeted Cancer Therapy with a Novel Anti-CD37 Beta-Particle Emitting Radioimmunoconjugate for Treatment of Non-Hodgkin Lymphoma

PLoS One. 2015 Jun 11;10(6):e0128816. doi: 10.1371/journal.pone.0128816. eCollection 2015.

Abstract

177Lu-DOTA-HH1 (177Lu-HH1) is a novel anti-CD37 radioimmunoconjugate developed to treat non-Hodgkin lymphoma. Mice with subcutaneous Ramos xenografts were treated with different activities of 177Lu-HH1, 177Lu-DOTA-rituximab (177Lu-rituximab) and non-specific 177Lu-DOTA-IgG1 (177Lu-IgG1) and therapeutic effect and toxicity of the treatment were monitored. Significant tumor growth delay and increased survival of mice were observed in mice treated with 530 MBq/kg 177Lu-HH1 as compared with mice treated with similar activities of 177Lu-rituximab or non-specific 177Lu-IgG1, 0.9% NaCl or unlabeled HH1. All mice injected with 530 MBq/kg of 177Lu-HH1 tolerated the treatment well. In contrast, 6 out of 10 mice treated with 530 MBq/kg 177Lu-rituximab experienced severe radiation toxicity. The retention of 177Lu-rituximab in organs of the mononuclear phagocyte system was longer than for 177Lu-HH1, which explains the higher toxicity observed in mice treated with 177Lu-rituximab. In vitro internalization studies showed that 177Lu-HH1 internalizes faster and to a higher extent than 177Lu-rituximab which might be the reason for the better therapeutic effect of 177Lu-HH1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / chemistry*
  • Antibodies / immunology
  • Antigen-Antibody Reactions
  • Antigens, Neoplasm / chemistry
  • Antigens, Neoplasm / immunology*
  • Antigens, Neoplasm / metabolism
  • Beta Particles
  • Cell Line, Tumor
  • Disease Models, Animal
  • Humans
  • Immunoconjugates / chemistry
  • Immunoconjugates / pharmacokinetics
  • Immunoconjugates / therapeutic use*
  • Iodine Radioisotopes / chemistry
  • Lutetium / chemistry
  • Lymphoma, Non-Hodgkin / drug therapy*
  • Lymphoma, Non-Hodgkin / mortality
  • Lymphoma, Non-Hodgkin / pathology
  • Mice
  • Mice, Nude
  • Radioisotopes
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Radiopharmaceuticals / therapeutic use*
  • Rituximab / chemistry
  • Rituximab / immunology
  • Tetraspanins / chemistry
  • Tetraspanins / immunology*
  • Tetraspanins / metabolism
  • Tissue Distribution
  • Transplantation, Heterologous

Substances

  • Antibodies
  • Antigens, Neoplasm
  • CD37 protein, human
  • Immunoconjugates
  • Iodine Radioisotopes
  • Radioisotopes
  • Radiopharmaceuticals
  • Tetraspanins
  • Rituximab
  • Lutetium

Grants and funding

This study was partially funded by the Norwegian Research Council (http://www.forskningsradet.no) grant numbers 213633 and 219454 and by Nordic Nanovector ASA (http://www.nordicnanovector.com). Co-authors Ada H. V. Repetto-Llamazares and Jostein Dahle are employed by Nordic Nanovector ASA. Nordic Nanovector ASA provided support in the form of salaries for authors AHVR-L 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. Co-author Roy H. Larsen is affiliated to Sciencons AS. Sciencons AS is a shareholder of Nordic Nanovector ASA. Sciencons AS did not provide support in the form of salary for author RHL, and 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.