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Coupling Tumor Necrosis Factor- with _V Integrin Ligands Improves Its Antineoplastic Activity

¹ Department of Biological and Technological Research and Cancer Immunotherapy and Gene Therapy Program, San Raffaele H. Scientific Institute, Milan, Italy, and
² Consiglio Nazionale delle Ricerche, Istituto di Chimica del Riconoscimento Molecolare, Milan, Italy

Despite the impressive results obtained in animal models, the clinical use of tumor necrosis factor- (TNF) as an anticancer drug is limited by severe toxicity. We have shown previously that targeted delivery of TNF to aminopeptidase N (CD13), a marker of angiogenic vessels, improved the therapeutic index of this cytokine in tumor-bearing mice. To assess whether the vascular-targeting approach could be extended to other markers of tumor blood vessels, in this work, we have fused TNF with the ACDCRGDCFCG peptide, a ligand of _V integrins by recombinant DNA technology. We have found that subnanogram doses of this conjugate are sufficient to induce antitumor effects in tumor-bearing mice when combined with melphalan, a chemotherapeutic drug. Cell adhesion assays and competitive binding experiments with anti-integrin antibodies showed that the Arg-Gly-Asp moiety interacts with cell adhesion receptors, including _Vß₃ integrin, as originally postulated. In addition, ACGDRGDCFCG-mouse TNF conjugate induced cytotoxic effects in standard cytolytic assays, implying that ACGDRGDCFCG-mouse TNF conjugate can also bind TNF receptors and trigger death signals. These results indicate that coupling TNF with _V integrin ligands improves its antineoplastic activity and supports the concept that vascular targeting is a strategy potentially applicable to different endothelial markers, not limited to CD13.

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