title: Selecting an intervention time for intravascular enzymatic cleavage of peptide linkers to clear radioisotope from normal tissues.
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.
authors.affiliation: Glenn T. Seaborg Institute, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA. chs@llnl.gov
authors.forename: Christine L Hartmann
authors.initials: CL
authors.lastname: Siantar
authors.forename: Gerald L
authors.initials: GL
authors.lastname: DeNardo
authors.forename: Kit
authors.initials: K
authors.lastname: Lam
authors.forename: Aina
authors.initials: A
authors.lastname: Yuan
authors.forename: Thomas
authors.initials: T
authors.lastname: Daly
authors.forename: Sally J
authors.initials: SJ
authors.lastname: DeNardo
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000201:enzymology*; D045744:Cell Line, Tumor; D006801:Humans; D007205:Indium Radioisotopes / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051379:Mice; D023421:Models, Animal; D008954:Models, Biological; D010455:Peptides / Q000378:metabolism*; D012189:Retrospective Studies; D013997:Time Factors; D015021:Yttrium Radioisotopes / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use