Targeted cancer therapy with a novel low-dose rate alpha-emitting radioimmunoconjugate.
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.
Dahle
Jostein
J
Department of Radiation Biology, Norwegian Radium Hospital, Oslo, Norway. jostein.dahle@rr-research.no
Borrebaek
Jørgen
J
Jonasdottir
Thora J
TJ
Hjelmerud
Anne Kristine
AK
Melhus
Katrine B
KB
Bruland
Øyvind S
ØS
Press
Oliver W
OW
Larsen
Roy H
RH
D000512:Alpha Particles; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009942:Organometallic Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016499:Radioimmunotherapy; D000069283:Rituximab; D015996:Survival Rate; D013794:Thallium Radioisotopes / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D018796:Immunoconjugates; D009942:Organometallic Compounds; D013794:Thallium Radioisotopes; D015021:Yttrium Radioisotopes; C513751:thorium-4-benzyl-DOTA-rituximab; D000069283:Rituximab