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Blood, 15 September 2007, Vol. 110, No. 6, pp. 2049-2056.
Prepublished online as a Blood First Edition Paper on May 29, 2007; DOI 10.1182/blood-2007-01-066803.


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NEOPLASIA

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

Jostein Dahle1, Jørgen Borrebæk2, Thora J. Jonasdottir3, Anne Kristine Hjelmerud1, Katrine B. Melhus1, Øyvind S. Bruland4, Oliver W. Press5, and Roy H. Larsen1

1 Department of Radiation Biology, Norwegian Radium Hospital, Oslo, Norway; 2 Algeta, Oslo, Norway; 3 Small Animal Section, Department of Companion Animal Clinical Sciences, Norwegian School of Veterinary Science, Oslo, Norway; 4 University of Oslo and Department of Oncology, Norwegian Radium Hospital, Oslo, Norway; 5 Fred Hutchinson Cancer Research Center, Seattle, WA

{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 227Th, 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 227Th-rituximab induced complete tumor regression in up to 60% of nude mice bearing macroscopic (32-256 mm3) human B-lymphoma xenografts at Becquerel per gram (Bq/g) levels without apparent toxicity. Therapy with 227Th-rituximab was significantly more effective than the control radioimmunoconjugate 227Th-trastuzumab and the standard ß-emitting radioimmunoconjugate for CD20+ lymphoma90Y-tiuxetan-ibritumomab. Thorium-227 based constructs may provide a novel approach for targeted therapy against a wide variety of cancers.


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