Selective targeted delivery of TNFα to tumor blood vessels

Laura Borsi, Enrica Balza, Barbara Carnemolla, Francesca Sassi, Patrizia Castellani, Alexander Berndt, Hartwig Kosmehl, Attila Birò, Annalisa Siri, Paola Orecchia, Jessica Grassi, Dario Neri, Luciano Zardi

Research output: Contribution to journalArticlepeer-review

Abstract

We sought to enhance the selective toxicity of tumor necrosis factor α (TNFα) to permit its systemic use in cancer therapy. Because ligand-targeted therapeutics have proven successful in improving the selective toxicity of drugs, we prepared a fusion protein (L19mTNFα) composed of mouse TNFα and a high-affinity antibody fragment (L19scFv) to the extradomain B (ED-B) domain of fibronectin, a marker of angiogenesis. L19mTNFα was expressed in mammalian cells, purified, and characterized. L19mTNFα was an immunoreactive and biologically active homotrimer. Radiolabeled L19mTNFα selectively targeted tumor neovasculature in tumor-bearing mice, where it accumulated selectively and persistently (tumor-to-blood ratio of the percentage of injected dose per gram [%ID/g] of 700, 48 hours from injection). L19mTNFα showed a greater anticancer therapeutic activity than both mTNFα and TN11mTNFα, a control fusion protein in which an antibody fragment, irrelevant in the tumor model used, substituted for L19. This activity was further dramatically enhanced by its combination with melphalan or the recently reported fusion protein L19-IL2. In conclusion, L19mTNFα allows concentrating therapeutically active doses of TNFα at the tumor level, thus opening new possibilities for the systemic use of TNFα in cancer therapy.

Original languageEnglish
Pages (from-to)4384-4392
Number of pages9
JournalBlood
Volume102
Issue number13
DOIs
Publication statusPublished - Dec 15 2003

ASJC Scopus subject areas

  • Hematology

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