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Preclinical Evaluation of Cathepsin-degradable Peptide Linkers for Radioimmunoconjugates¹

Department of Internal Medicine, School of Medicine [G. L. D., S. J. D., L. A. M., K. S. L.], and Department of Chemistry [J. K. P.], University of California Davis, Sacramento, CA 95816; Lawrence Livermore National Laboratory, Livermore, California 94550 [C. H. S.]; and Department of Neurological Surgery, University of California San Francisco, School of Medicine, San Francisco, California 94143 [K. R. L.]

Purpose: Immunoglobulins are catabolized in the hepatocytes, primarily by cathepsins. The liver becomes the likely dose-limiting tissue for radiometals, like ⁹⁰Y, in radioimmunoconjugates (RICs) used for radioimmunotherapy in combination with bone marrow support. To assess whether in vitro cathepsin-degradable peptide linkers between the chelated radiometal and the antibody decreased hepatic radiation dose, cumulated activity was used as a surrogate for radiation dose.

Experimental design: Four different cathepsin-degradable peptides used to link 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-chelated ¹¹¹In to two different monoclonal antibodies were studied in athymic mouse models of human breast cancer or lymphoma. Measured concentrations of activity during 5 days were used to reflect pharmacokinetic behavior for normal tissues and tumor. With the use of linear regression to fit a monoexponential decay function, cumulated activities in the liver and xenografts were calculated.

Results: The pharmacokinetic behavior of the cathepsin-degradable peptide-linked RICs was similar to that for the 2-iminothiolane (2IT) nondegradable linked RICs except for the liver. The liver cumulated activities of peptide-linked RICs were significantly decreased from those of the corresponding 2IT-linked RICs, varying between reductions of 59 and 68%. Cumulated activities of peptide-linked RICs in the xenografts were as great as those of 2IT RICs, so that the therapeutic indices (tumor:liver cumulated activity ratios) were substantially better for cathepsin-degradable peptide-linked RICs.

Conclusions: Cathepsin-degradable peptides used to link chelated radiometals to antibodies reduce liver radiation dose and improve the therapeutic index for radioimmunotherapy given in combination with bone marrow support.