Targeted cancer therapy with a novel low-dose rate alpha-emitting radioimmunoconjugate

Blood. 2007 Sep 15;110(6):2049-56. doi: 10.1182/blood-2007-01-066803. Epub 2007 May 29.

Abstract

Alpha-emitting radionuclides are highly cytotoxic and are of considerable interest in the treatment of cancer. A particularly interesting approach is in radioimmunotherapy. However, alpha-emitting antibody conjugates have been difficult to exploit clinically due to the short half-life of the radionuclides, low production capability, or limited source materials. We have developed a novel technology based on the low-dose rate alpha-particle-emitting nuclide (227)Th, exemplified here using the monoclonal antibody rituximab. In vitro, this radioimmunoconjugate killed lymphoma cells at Becquerel per milliliter (Bq/mL) levels. A single injection of (227)Th-rituximab induced complete tumor regression in up to 60% of nude mice bearing macroscopic (32-256 mm(3)) human B-lymphoma xenografts at Becquerel per gram (Bq/g) levels without apparent toxicity. Therapy with (227)Th-rituximab was significantly more effective than the control radioimmunoconjugate (227)Th-trastuzumab and the standard beta-emitting radioimmunoconjugate for CD20(+) lymphoma(90)Y-tiuxetan-ibritumomab. Thorium-227 based constructs may provide a novel approach for targeted therapy against a wide variety of cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alpha Particles*
  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, CD20 / immunology
  • Cell Proliferation
  • Female
  • Humans
  • Immunoconjugates / pharmacokinetics
  • Immunoconjugates / therapeutic use*
  • Lymphoma, B-Cell / immunology
  • Lymphoma, B-Cell / metabolism
  • Lymphoma, B-Cell / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / pharmacokinetics
  • Organometallic Compounds / therapeutic use*
  • Radioimmunotherapy*
  • Rituximab
  • Survival Rate
  • Thallium Radioisotopes / pharmacokinetics
  • Tissue Distribution
  • Tumor Cells, Cultured
  • Yttrium Radioisotopes / pharmacokinetics

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, CD20
  • Immunoconjugates
  • Organometallic Compounds
  • Thallium Radioisotopes
  • Yttrium Radioisotopes
  • thallium-4-benzyl-DOTA-rituximab
  • Rituximab