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

Publication Type:

Journal Article

Source:

Blood, Volume 110, Issue 6, p.2049-56 (2007)

Keywords:

Alpha Particles, Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Murine-Derived, Antigens, CD20, Cell Proliferation, Female, Humans, Immunoconjugates, Lymphoma, B-Cell, MICE, Mice, Inbred BALB C, Mice, Nude, Organometallic Compounds, Radioimmunotherapy, Survival Rate, Thallium Radioisotopes, TISSUE DISTRIBUTION, Tumor Cells, Cultured, Yttrium Radioisotopes

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.