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Radioimmunotherapy: a specific treatment protocol for cancer by cytotoxic radioisotopes conjugated to antibodies.

ABSTRACT: Radioimmunotherapy (RIT) represents a selective internal radiation therapy, that is, the use of radionuclides conjugated to tumor-directed monoclonal antibodies (including those fragments) or peptides. In a clinical field, two successful examples of this treatment protocol are currently extended by (90)Y-ibritumomab tiuxetan (Zevalin) and (131)I-tositumomab (Bexxar), both of which are anti-CD20 monoclonal antibodies coupled to cytotoxic radioisotopes and are approved for the treatment of non-Hodgkin lymphoma patients. In addition, some beneficial observations are obtained in preclinical studies targeting solid tumors. To date, in order to reduce the unnecessary exposure and to enhance the therapeutic efficacy, various biological, chemical, and treatment procedural improvements have been investigated in RIT. This review outlines the fundamentals of RIT and current knowledge of the preclinical/clinical trials for cancer treatment.

SUBMITTER: Kawashima H

PROVIDER: S-EPMC4213411 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Radioimmunotherapy: a specific treatment protocol for cancer by cytotoxic radioisotopes conjugated to antibodies.

Kawashima Hidekazu H

TheScientificWorldJournal 20141014

Radioimmunotherapy (RIT) represents a selective internal radiation therapy, that is, the use of radionuclides conjugated to tumor-directed monoclonal antibodies (including those fragments) or peptides. In a clinical field, two successful examples of this treatment protocol are currently extended by (90)Y-ibritumomab tiuxetan (Zevalin) and (131)I-tositumomab (Bexxar), both of which are anti-CD20 monoclonal antibodies coupled to cytotoxic radioisotopes and are approved for the treatment of non-Hod ...[more]

PMID: 25379535

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Project description:UnlabelledTargeted α-particle radiation using the radioisotope (225)Ac is a promising form of therapy for various types of cancer. Historic obstacles to the use of (225)Ac have been the difficulty in finding suitable chelators to stably attach it to targeting vehicles such as peptides and monoclonal antibodies, the low specific activities of the products, and the lack of cost-effective radiolabeling procedures. We initially solved the first problem with a procedure involving 2 chemical steps that has been used as a standard in preclinical and clinical studies. However, this procedure involves the loss of 90% of the input (225)Ac. A more efficient, economical process is needed to facilitate the more widespread use of (225)Ac.MethodsWe conjugated representative antibodies with 2 forms of DOTA as well as other chelators as controls. We developed conditions to radiolabel these constructs in 1 chemical step and characterized their stability, immunoreactivity, biodistribution, and therapeutic efficacy in healthy and tumor-bearing mice.ResultsDOTA-antibody constructs were labeled to a wide range of specific activities in 1 chemical step at 37°C. Radiochemical yields were approximately 10-fold higher, and specific activities were up to 30-fold higher than with the previous approach. The products retained immunoreactivity and were stable to serum challenge in vitro and in mice. Labeling kinetics of DOTA-antibody constructs linked through a benzyl isothiocyanate linkage were more favorable than those linked through an N-hydroxysuccinimide linkage. Tissue distribution was similar but not identical between the constructs. The constructs produced specific therapeutic responses in a mouse model of acute myeloid leukemia.ConclusionWe have characterized an efficient, 1-step radiolabeling method that produces stable, therapeutically active conjugates of antibodies with (225)Ac at high specific activity. We propose that this technology greatly expands the possible clinical applications of (225)Ac monoclonal antibodies.

Dataset Information

Radioimmunotherapy: a specific treatment protocol for cancer by cytotoxic radioisotopes conjugated to antibodies.

Publications

Radioimmunotherapy: a specific treatment protocol for cancer by cytotoxic radioisotopes conjugated to antibodies.

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