title: Antitumor effects of a human dimeric antibody fragment 131I-AFRA-DFM5.3 in a mouse model for ovarian cancer.
abstract: AFRA-DMF5.3 is a human antibody fragment that, as a dimer, specifically binds to the α-folate receptor (FR) on ovary cancer cells. Pharmacokinetic and biodistribution parameters of (131)I-AFRA-DFM5.3 after intravenous administration in animal models support its potential therapeutic use. We evaluated its preclinical specificity and therapeutic efficacy in tumor models.
  
  
  METHODS
  A negative control, AFRA-DFM6.1, was obtained by protein engineering. The activity and specificity of (131)I-AFRA-DFMs were evaluated by systemic administration (intravenous) in subcutaneous tumor xenograft-bearing nude mice. Pharmacokinetics, biodistribution, and efficacy were assessed by intraperitoneal administration of (131)I-AFRA-DFM5.3 in nude mice bearing 2 different intraperitoneal ovarian carcinoma xenografts. Treatments were tested at different doses and as single or double administrations 1 wk apart.
  
  
  RESULTS
  In subcutaneous models, (131)I-AFRA-DFM5.3, but not the negative control, was found to reside on FR-positive tumor masses and significantly reduced tumor growth. In intraperitoneal models, early accumulation on free-floating clumps of ovarian cancer cells and solid peritoneal masses was evident after 1 h, and tumor uptake was stable for up to 3 h. The high tumor uptake determined the efficacy of (131)I-AFRA-DFM5.3. The best antitumor activity, with more than 50% of treated animals cured, was achieved with 2 locoregional treatments of intraperitoneally growing tumors on days 2 and 9.
  
  
  CONCLUSIONS
  These results suggest that radioimmunotherapy with (131)I-AFRA-DFM5.3 is feasible and leads to significantly prolonged survival. These preclinical data provide the basis for the rationale design of therapeutic treatments of ovarian cancer patients with a radiolabeled anti-FR antibody fragment.
authors: Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Alberto
authors: A
authors: Zacchetti
authors: Franck
authors: F
authors: Martin
authors: Elena
authors: E
authors: Luison
authors: Angela
authors: A
authors: Coliva
authors: Emilio
authors: E
authors: Bombardieri
authors: Marcello
authors: M
authors: Allegretti
authors: Mariangela
authors: M
authors: Figini
authors: Silvana
authors: S
authors: Canevari
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D058975:Folate Receptor 1 / Q000276:immunology; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D016499:Radioimmunotherapy
chemical_list: D000970:Antineoplastic Agents; D058975:Folate Receptor 1; D007128:Immunoglobulin Fragments