177Lu-DOTA-HH1, a novel anti-CD37 radio-immunoconjugate: a study of toxicity in nude mice

PLoS One. 2014 Jul 28;9(7):e103070. doi: 10.1371/journal.pone.0103070. eCollection 2014.

Abstract

Background: CD37 is an internalizing B-cell antigen expressed on Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia cells (CLL). The anti-CD37 monoclonal antibody HH1 was conjugated to the bifunctional chelator p-SCN-Bn-DOTA and labelled with the beta-particle emitting radionuclide 177Lu creating the radio-immunoconjugate (RIC) 177Lu-DOTA-HH1 (177Lu-HH1, trade name Betalutin). The present toxicity study was performed prior to initiation of clinical studies with 177Lu-HH1.

Methodology/principal findings: Nude mice with or without tumor xenografts were treated with 50 to 1000 MBq/kg 177Lu- HH1 and followed for clinical signs of toxicity up to ten months. Acute, life threatening bone marrow toxicity was observed in animals receiving 800 and 1000 MBq/kg 177Lu-HH1. Significant changes in serum concentrations of liver enzymes were evident for treatment with 1000 MBq/kg 177Lu-HH1. Lymphoid depletion, liver necrosis and atrophy, and interstitial cell hyperplasia of the ovaries were also observed for mice in this dose group.

Conclusions/significance: 177Lu-DOTA-HH1 was well tolerated at dosages about 10 times above those considered relevant for radioimmunotherapy in patients with B-cell derived malignancies.The toxicity profile was as expected for RICs. Our experimental results have paved the way for clinical evaluation of 177Lu-HH1 in NHL patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal*
  • Antigens, Neoplasm
  • Female
  • Immunoconjugates / administration & dosage
  • Immunoconjugates / pharmacology*
  • Immunoconjugates / toxicity
  • Lutetium*
  • Mice
  • Mice, Nude
  • Radioisotopes*
  • Radiopharmaceuticals / administration & dosage
  • Radiopharmaceuticals / pharmacology*
  • Radiopharmaceuticals / toxicity
  • Tetraspanins / antagonists & inhibitors*
  • Tissue Distribution
  • Toxicity Tests
  • Xenograft Model Antitumor Assays

Substances

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

Grant support

The work was supported by the Norwegian Research Council grant No 213633 through the Industrial PhD program and by the company Nordic Nanovector AS, which owns the commercial rights for 177Lu-HH1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.