Preclinical evaluation of cathepsin-degradable peptide linkers for radioimmunoconjugates

Gerald L Denardo, Sally J. DeNardo, James J. Peterson, Laird A. Miers, Kit Lam, Christine Hartmann-Siantar, Kathleen R. Lamborn

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18 Scopus citations


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.

Original languageEnglish (US)
JournalClinical Cancer Research
Issue number10 II
StatePublished - Oct 1 2003


ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Denardo, G. L., DeNardo, S. J., Peterson, J. J., Miers, L. A., Lam, K., Hartmann-Siantar, C., & Lamborn, K. R. (2003). Preclinical evaluation of cathepsin-degradable peptide linkers for radioimmunoconjugates. Clinical Cancer Research, 9(10 II).