Initial evaluation of (227)Th-p-benzyl-DOTA-rituximab for low-dose rate alpha-particle radioimmunotherapy.
Radioimmunotherapy has proven clinically effective in patients with non-Hodgkin's lymphoma. Radioimmunotherapy trials have so far been performed with beta-emitting isotopes. In contrast to beta-emitters, the shorter range and high linear energy transfer (LET) of alpha particles allow for more efficient and selective killing of individually targeted tumor cells. However, there are several obstacles to the use of alpha-particle immunotherapy, including problems with chelation chemistry and nontarget tissue toxicity. The alpha-emitting radioimmunoconjugate (227)Th-DOTA-p-benzyl-rituximab is a new potential anti-lymphoma agent that might overcome some of these difficulties. The present study explores the immunoreactivity, in vivo stability and biodistribution, as well as the effect on in vitro cell growth, of this novel radioimmunoconjugate. To evaluate in vivo stability, uptake in balb/c mice of the alpha-particle-emitting nuclide (227)Th alone, the chelated form, (227)Th-p-nitrobenzyl-DOTA and the radioimmunoconjugate (227)Th-DOTA-p-benzyl-rituximab was compared in a range of organs at increasing time points after injection. The immunoreactive fraction of (227)Th-DOTA-p-benzyl-rituximab was 56-65%. During the 28 days after injection of radioimmunoconjugate only, very modest amounts of the (227)Th had detached from DOTA-p-benzyl-rituximab, indicating a relevant stability in vivo. The half-life of (227)Th-DOTA-p-benzyl-rituximab in blood was 7.4 days. Incubation of lymphoma cells with (227)Th-DOTA-p-benzyl-rituximab resulted in a significant antigen-dependent inhibition of cell growth. The data presented here warrant further studies of (227)Th-DOTA-p-benzyl-rituximab.
Dahle
Jostein
J
Department of Radiation Biology, Rikshospitalet-Radiumhospitalet HE, Montebello, 0310 Oslo, Norway. jostein.dahle@labmed.uio.no
Borrebaek
Jørgen
J
Melhus
Katrine B
KB
Bruland
Oyvind S
OS
Salberg
Gro
G
Olsen
Dag Rune
DR
Larsen
Roy H
RH
D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008223:Lymphoma / Q000378:metabolism* / Q000532:radiotherapy*; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D009928:Organ Specificity; D009942:Organometallic Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016499:Radioimmunotherapy / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use; D011879:Radiotherapy Dosage; D000069283:Rituximab; D014018:Tissue Distribution; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; C513751:thorium-4-benzyl-DOTA-rituximab; D000069283:Rituximab