title: Evaluation of a cathepsin-cleavable peptide linked radioimmunoconjugate of a panadenocarcinoma MAb, m170, in mice and patients.
abstract: OBJECTIVE
  Radioimmunotherapy (RIT) delivered by radiometal immunoconjugates (RICs) is dose limited by deposition and retention of radioactivity in normal tissues. In order to increase elimination of radioactivity from the liver and body, a peptide having a specific cathepsin B cleavage site was placed between the radiometal chelate, 111In-DOTA, and the panadenocarcinoma monoclonal antibody (MAb), m170.
  
  
  METHODS
  Indium-111 (111In)-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)-2-iminothiolane (2IT)-m170 and 111In-DOTA-peptide-m170, representing the same MAb and chelate without and with a cleavable linkage, were studied in athymic mice and patients with breast or prostate cancer. Pharmacokinetics, cumulated activities and therapeutic indices (TI), were evaluated. Cumulated activities in the liver and tumors were calculated and used as a surrogate for radiation dose.
  
  
  RESULTS
  Except for liver, the pharmacokinetics of 111In-DOTA-peptide-m170 were similar to those of the 111In-2IT-2-[p(bromoacetamido)benzyl]-1,4,7,10-tetraazocyclododecane-N,N',N",N"'-tetraacetic acid-m170 (111In-2IT-BAD-m170) in mice and patients. Liver cumulated activities for 111In-DOTA-peptide-m170 were consistently decreased when compared to those for 111In-2IT-BAD-m170, reductions varying between 22-30%. Cumulated activities for 111In-DOTA-peptide-m170 in the malignant tumors of the patients were as great as those for 111In-2IT-BAD-m170, so that the tumor-to-liver cumulated activity ratios (therapeutic indices) were better for 111In-DOTA-peptide-m170.
  
  
  CONCLUSIONS
  A cathepsin-B-cleavable peptide used to link chelated 111In to MAb, m170, reduced liver cumulated activity (radiation dose) and improved the TI. This novel linker illustrates the importance of linker technology in the development of safer RICs for cancer therapy.
authors.affiliation: Department of Internal Medicine, University of California Davis, School of Medicine, Sacramento, CA, USA. gldenardo@ucdavis.edu
authors.forename: Gerald L
authors.initials: GL
authors.lastname: DeNardo
authors.forename: Sally J
authors.initials: SJ
authors.lastname: DeNardo
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000378:metabolism / Q000532:radiotherapy; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy; D002403:Cathepsins / Q000378:metabolism*; D002614:Chelating Agents / Q000032:analysis / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D018796:Immunoconjugates / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007205:Indium Radioisotopes / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy
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