title: Preclinical evaluation of cathepsin-degradable peptide linkers for radioimmunoconjugates.
abstract: OBJECTIVE
  Immunoglobulins are catabolized in the hepatocytes, primarily by cathepsins. The liver becomes the likely dose-limiting tissue for radiometals, like (90)Y, 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.
  
  
  METHODS
  Four different cathepsin-degradable peptides used to link 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid-chelated (111)In 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.
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001943:Breast Neoplasms / Q000473:pathology; D002403:Cathepsins / Q000737:chemistry*; D002614:Chelating Agents / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry*; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D016014:Linear Models; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D008223:Lymphoma / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D010455:Peptides / Q000737:chemistry; D016499:Radioimmunotherapy / Q000379:methods; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D006573:Heterocyclic Compounds, 1-Ring; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D010455:Peptides; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D002403:Cathepsins