title: Antibody-based targeting of interferon-alpha to the tumor neovasculature: a critical evaluation.
abstract: The antibody-mediated targeted delivery of cytokines, growth factors and immunomodulators offers great potential for the therapy of cancer and other serious conditions. Interferon-alpha has long been used in the clinic for the treatment of patients with certain malignancies or with viral disease. Promising anticancer activity has recently been reported for two fusion proteins consisting of immunoglobulins bearing the interferon-alpha polypeptide at the C-terminal end of the molecule. Here we describe the design, production and characterization of a novel immunocytokine, in which murine interferon-alpha2 was sequentially fused with the tumor-targeting antibody fragment scFv(F8), specific to the alternatively-spliced EDA domain of fibronectin. The resulting fusion protein (F8-IFNa) could be produced to homogeneity and was shown to retain both antigen binding activity and interferon-alpha activity. Biodistribution studies in tumor-bearing mice with radioiodinated protein preparations confirmed the ability of F8-IFNa to selectively localize at the tumor site. However, using two different murine models of cancer (F9 teratocarcinomas and Cloudman S91 melanomas in immunocompetent mice), we could not detect a striking superiority for the therapeutic performance of F8-IFNa as compared to KSF-IFNa, a fusion protein of irrelevant specificity in the mouse which was used as negative control. In the paper, we present hypotheses why the antibody-based pharmacodelivery of interferon-alpha fails to eradicate tumors, in contrast to the situation observed by our group for other immunocytokines, which benefit from a selective localization at the tumor site.
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zurich, Wolfgang-Pauli-Str. 10, CH-8093 Zurich, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Frey
authors.forename: Andjelija
authors.initials: A
authors.lastname: Zivanovic
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schwager
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
mesh_terms: D000825:Animal Structures / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001808:Blood Vessels / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005353:Fibronectins / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000235:genetics / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D009113:Muramidase / Q000276:immunology; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology*; D018243:Teratocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D005353:Fibronectins; D018796:Immunoconjugates; D016898:Interferon-alpha; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D009113:Muramidase