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

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.

• Authors: Jostein Dahle, Jørgen Borrebaek, Thora J Jonasdottir, Anne Kristine Hjelmerud, Katrine B Melhus, Øyvind S Bruland, Oliver W Press, Roy H Larsen
• Journal: Blood (Blood) Vol. 110 Issue 6 Pg. 2049-56 (Sep 15 2007) ISSN: 0006-4971 [Print] United States
• PMID: 17536011 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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