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Enhancement of the antitumor activity of interleukin-12 by targeted delivery to neovasculature

Nature Biotechnology volume 20, pages 264–269 (2002)Cite this article

Abstract

Interleukin-12 (IL-12) is a heterodimeric cytokine with potent immunostimulatory activity and anti-angiogenic properties. Its clinical applications are limited, however, by severe side-effects. Here we report that an IL-12 fusion protein, consisting of IL-12 fused to a human antibody fragment specific to the oncofetal ED-B domain of fibronectin, markedly enhances the antitumor activity of this cytokine, as demonstrated in a mouse lung-metastasis model and in two models of mice bearing different aggressive murine tumors. The residual small tumor masses seen in the treated mice were infiltrated with lymphocytes, macrophages, and natural killer cells and had elevated interferon γ (IFN-γ). These results are of therapeutic relevance as the ED-B domain of fibronectin, a naturally occurring marker of angiogenesis identical in mouse and man, is expressed in the majority of aggressive solid tumors but is not detectable in normal vessels and tissues.

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Figure 1: IL–12 fusion proteins.
Figure 2: Effect of IL12–L19 on tumor growth studied in two syngenic murine tumor models.
Figure 3: Antibody response to IL–12 fusion proteins.
Figure 4: Effect of IL12–L19 versus IL-12 on tumor growth.
Figure 5: Antimetastatic activity of IL-12 and IL12–L19.

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Acknowledgements

This work was supported by grants from the Krebsforschung Schweiz, the Bundesamt für Bildung und Wissenschaft (EC Project) and ETH Zürich (D.N.), the Thüringer Ministerium für Wissenschaft, Forschung und Kultur (IZKF and HSPIII projects) (H.K.), and the Associazione Italiana Ricerca sul Cancro (A.I.R.C.) (L.Z.).

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Authors and Affiliations

  1. Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich, Winterthurerstrasse 190, Zurich, CH-8057, Switzerland

    C. Halin, S. Rondini & F. Nilsson

  2. Institute of Pathology, Friedrich Schiller University, Jena, Germany, D-07740

    A. Berndt & H. Kosmehl

  3. Laboratory of Cell Biology, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, Genoa, I-16132, Italy

    L. Zardi

  4. D. Neri

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  1. C. Halin
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Correspondence to D. Neri.

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Competing interests

D.N. and L.Z. are consultants and shareholders of Philogen, a biotechnology company that has acquired the rights to the L19 antibody from their academic institutions (the Swiss Federal Institute of Technology Zürich and the National Cancer Research Institute, Genoa, respectively).

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Halin, C., Rondini, S., Nilsson, F. et al. Enhancement of the antitumor activity of interleukin-12 by targeted delivery to neovasculature. Nat Biotechnol 20, 264–269 (2002). https://doi.org/10.1038/nbt0302-264

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