title: Selective targeted delivery of the TNF-alpha receptor p75 and uteroglobin to the vasculature of inflamed tissues: a preliminary report.
abstract: BACKGROUND
  Ligand-targeted approaches have proven successful in improving the therapeutic index of a number of drugs. We hypothesized that the specific targeting of TNF-alpha antagonists to inflamed tissues could increase drug efficacy and reduce side effects.
  
  
  RESULTS
  Using uteroglobin (UG), a potent anti-inflammatory protein, as a scaffold, we prepared a bispecific tetravalent molecule consisting of the extracellular ligand-binding portion of the human TNF-alpha receptor P75 (TNFRII) and the scFv L19. L19 binds to the ED-B containing fibronectin isoform (B-FN), which is expressed only during angiogenesis processes and during tissue remodeling. B-FN has also been demonstrated in the pannus in rheumatoid arthritis. L19-UG-TNFRII is a stable, soluble homodimeric protein that maintains the activities of both moieties: the immuno-reactivity of L19 and the capability of TNFRII to inhibit TNF-alpha. In vivo bio-distribution studies demonstrated that the molecule selectively accumulated on B-FN containing tissues, showing a very fast clearance from the blood but a very long residence time on B-FN containing tissues. Despite the very fast clearance from the blood, this fusion protein was able to significantly improve the severe symptomatology of arthritis in collagen antibody-induced arthritis (CAIA) mouse model.
  
  
  CONCLUSIONS
  The recombinant protein described here, able to selectively deliver the TNF-alpha antagonist TNFRII to inflamed tissues, could yield important contributions for the therapy of degenerative inflammatory diseases.
authors.affiliation: Laboratory of Therapeutic Recombinant Proteins, Centro Biotecnologie Avanzate, Largo Rosanna Benzi, 1016132 Genoa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Ventura
authors.forename: Enrica
authors.initials: E
authors.lastname: Balza
authors.forename: Laura
authors.initials: L
authors.lastname: Borsi
authors.forename: Giorgia
authors.initials: G
authors.lastname: Tutolo
authors.forename: Barbara
authors.initials: B
authors.lastname: Carnemolla
authors.forename: Patrizia
authors.initials: P
authors.lastname: Castellani
authors.forename: Luciano
authors.initials: L
authors.lastname: Zardi
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016466:CHO Cells; D006224:Cricetinae; D019281:Dimerization; D016503:Drug Delivery Systems / Q000379:methods*; D005353:Fibronectins / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007457:Iodine Radioisotopes / Q000032:analysis; D007596:Joints / Q000098:blood supply* / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000276:immunology; D010957:Plasmids; D011485:Protein Binding; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics*; D018243:Teratocarcinoma; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014598:Uteroglobin / Q000737:chemistry / Q000235:genetics
chemical_list: C067625:FN1 protein, human; D005353:Fibronectins; D007457:Iodine Radioisotopes; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D014598:Uteroglobin
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