Selecting an intervention time for intravascular enzymatic cleavage of peptide linkers to clear radioisotope from normal tissues

Christine L. Hartmann Siantar, Gerald L Denardo, Kit Lam, Aina Yuan, Thomas Daly, Sally J. DeNardo

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Protease degradable linkers have been proposed to improve the therapeutic index (TI) (i.e., tumor to normal tissue) of molecular targeted radioisotope therapy by reducing unbound radiotargeting agent in the blood and other normal tissues. If the radioisotope is detached from the circulating targeting agent once the radioisotope level in the tumors has been maximized, the success of this system depends on the ability to anticipate a preferred intervention time that will lead to significantly improved TIs. This paper presents a method to predict preferred intervention times and TIs by using pharmacokinetic tracer studies carried out without intervention. Methods: Pharmacokinetic data for the blood and tumors from tracer doses of 111In-labeled chimeric and mouse monoclonal antibodies in patients and in mice were used as surrogates for corresponding 90Y radioimmunoconjugates. Data were fit with simple pharmacokinetic functions. A set of formulas was then developed to estimate the improvement in therapeutic index and the preferred intervention time, using simple modeling assumptions. Results: A modeled introduction of enzymatic cleavable linkers resulted in an increase in the tumor-to-blood TI by a factor of 3.2-1.6 for the systems analyzed. As expected, the preferred intervention times varied depending on the pharmacokinetic data, but could be predicted based on a priori knowledge of the actual or anticipated pharmacokinetics in the absence of intervention. Conclusions: These results highlight the potential value of cleavable linkers in substantially increasing the TI, and provide an approach for estimating a preferred intervention time, using actual or predicted pharmacokinetic data obtained without intervention.

Original languageEnglish (US)
Pages (from-to)556-563
Number of pages8
JournalCancer Biotherapy and Radiopharmaceuticals
Volume22
Issue number4
DOIs
StatePublished - Aug 2007

Keywords

  • Antibodies
  • Linkers
  • Radiation dose
  • Radioimmunotherapy
  • Targeted radioisotope therapy

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

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