title: Copper-67 radioimmunotherapy and growth inhibition by anti-L1-cell adhesion molecule monoclonal antibodies in a therapy model of ovarian cancer metastasis.
abstract: OBJECTIVE
  We examined the tumor-targeting and therapeutic effects of (67)Cu-labeled single amino acid mutant forms of anti-L1 monoclonal antibody chCE7 in nude mice with orthotopically implanted SKOV3ip human ovarian carcinoma cells.
  
  
  METHODS
  For radioimmunotherapy, chCE7 antibodies with a mutation of histidine 310 to alanine (chCE7H310A) and a mutation of asparagine 297 to glutamine (chCE7agl) were generated to achieve more rapid blood clearance. Biodistributions of (67)Cu-4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl benzoic acid tetrachloride (CPTA)-labeled mutant antibodies were measured in nude mice bearing SKOV3ip human ovarian cancer metastases. The effects of single i.v. injections of (67)Cu-chCE7agl alone on tumor reduction and survival were investigated. In addition, a combination of low-dose (67)Cu-radioimmunotherapy with unlabeled anti-L1 antibody L1-11A on survival was investigated.
  
  
  RESULTS
  (67)Cu-CPTA-chCE7agl showed high (up to 49% ID/g) and persistent (up to 168 h) uptake in SKOV3ip metastases, with low levels in normal tissues. (67)Cu-CPTA-chCE7H310A revealed a shorter half-life in the blood and a lower tumor uptake and retention. A single low dose of 4 MBq of (67)Cu-chCE7agl reduced tumor growth but did not prolong survival significantly, whereas a single 10.5 MBq dose of (67)Cu-chCE7agl reduced tumor growth and prolonged survival significantly. The combination of unlabeled monoclonal antibody L1-11A with a subtherapeutic dose of (67)Cu-radioimmunotherapy also prolonged survival significantly.
  
  
  CONCLUSIONS
  The results show improved pharmacokinetics and biodistributions as well as the therapeutic effect of the (67)Cu-labeled single amino acid mutant chCE7agl. Therapeutic data indicate, for the first time, the feasibility of combining anti-L1-directed growth inhibition and (67)Cu-radioimmunotherapy, thereby increasing the efficiency of antibody treatment of metastatic ovarian carcinoma.
authors.affiliation: Center for Radiopharmaceutical Science, ETH-PSI-USZ, Paul Scherrer Institute, CH-5232 Villigen, Switzerland.
authors.forename: Karin
authors.initials: K
authors.lastname: Knogler
authors.forename: Jürgen
authors.initials: J
authors.lastname: Grünberg
authors.forename: Kurt
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Susan
authors.initials: S
authors.lastname: Cohrs
authors.forename: Michael
authors.initials: M
authors.lastname: Honer
authors.forename: Simon
authors.initials: S
authors.lastname: Ametamey
authors.forename: Peter
authors.initials: P
authors.lastname: Altevogt
authors.forename: Mina
authors.initials: M
authors.lastname: Fogel
authors.forename: P August
authors.initials: PA
authors.lastname: Schubiger
authors.forename: Ilse
authors.initials: I
authors.lastname: Novak-Hofer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009362:Neoplasm Metastasis; D039842:Neural Cell Adhesion Molecule L1 / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology* / Q000628:therapy*; D010957:Plasmids / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D016499:Radioimmunotherapy / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D003301:Copper Radioisotopes; D039842:Neural Cell Adhesion Molecule L1