title: The antibody-based targeted delivery of TNF in combination with doxorubicin eradicates sarcomas in mice and confers protective immunity.
abstract: BACKGROUND
  Soft-tissue sarcomas are a group of malignancies of mesenchymal origin, which typically have a dismal prognosis if they reach the metastatic stage. The observation of rare spontaneous remissions in patients suffering from concomitant bacterial infections had triggered the clinical investigation of the use of heat-killed bacteria as therapeutic agents (Coley's toxin), which induced complete responses in patients in the pre-chemotherapy era and is now known to mediate substantial elevations in serum TNF levels.
  
  
  METHODS
  We designed and developed a novel immunocytokine based on murine TNF sequentially fused to the antibody fragment F8 (specific to extra-domain A of fibronectin). The antitumor activity was studied in two syngeneic murine sarcoma models.
  
  
  RESULTS
  The L19 antibody (specific to extra-domain B of fibronectin) has shown by SPECT imaging procedures to selectively localise on sarcoma in a patient with a peripheral nerve sheath tumour, and immunohistochemical analysis of human soft-tissue sarcoma samples showed comparable antigen expression of EDA and EDB. The antibody-based pharmacodelivery of TNF by the fusion protein 'F8-TNF' to oncofetal fibronectin in sarcoma-bearing mice leads to complete and long-lasting tumour eradications when administered in combination with doxorubicin, the first-line drug for the treatment of sarcomas in humans. Doxorubicin alone did not display any therapeutic effect in both tested models of this study. The cured mice had acquired protective immunity against the tumour, as they rejected subsequent challenges with sarcoma cells.
  
  
  CONCLUSIONS
  The findings of this study provide a rationale for the clinical study of the fully human immunocytokine L19-TNF in combination with doxorubicin in patients with soft-tissue sarcoma.
authors.affiliation: Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Wolfgang-Pauli-Strasse 10, CH-8093 Zürich, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Hemmerle
authors.forename: P
authors.initials: P
authors.lastname: Probst
authors.forename: L
authors.initials: L
authors.lastname: Giovannoni
authors.forename: A J
authors.initials: AJ
authors.lastname: Green
authors.forename: T
authors.initials: T
authors.lastname: Meyer
authors.forename: D
authors.initials: D
authors.lastname: Neri
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D016466:CHO Cells; D045744:Cell Line, Tumor; D003412:Cricetulus; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D012509:Sarcoma / Q000188:drug therapy*; D048069:Tumor Necrosis Factors / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C528643:F8 monoclonal antibody; D011993:Recombinant Fusion Proteins; D048069:Tumor Necrosis Factors; D004317:Doxorubicin