Initial evaluation of 227Th-p-benzyl-DOTA-rituximab for low-dose rate α-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 a-particle immunotherapy, including problems with chelation chemistry and nontarget tissue toxicity. The alpha-emitting radioimmunoconjugate Th-227-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 radioimmunoconjugate. To evaluate in vivo stability, Uptake in balb/c mice of the alpha-particle-emitting nuclide Th-227 alone, the chelated form. Th-227-p-nitrobenzyl-DOTA and the radioimmunoconjugate Th-227-DOTA-p-benzyl-rituximab was compared in a range of organs at increasing time points after injection. The immunoreactive fraction of Th-227-DOTA-p-benzyl-rituximab was 56-65%. During the 28 days after injection of radioimmunoconjugate only, very modest amounts of the Th-227 had detached from DOTA-p-benzyl-rituximab, indicating a relevant stability in vivo. The half-life of Th-227-DOTA-p-benzyl-rituximab in blood was 7.4 days. Incubation of lymphoma cells with Th-227-DOTA-p-benzyl-rituximab resulted in a significant antigen-dependent inhibition of cell growth. The data presented here warrant further studies of Th-227-DOTA-p-benzyl-rituximab. (c) 2006 Elsevier Inc. All rights reserved.