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An HGF–MSP chimera disassociates the trophic properties of scatter factors from their pro-invasive activity

Nature Biotechnology volume 20, pages 488–495 (2002)Cite this article

Abstract

Hepatocyte growth factor (HGF) and macrophage-stimulating protein (MSP) have an intrinsic dual nature: they are trophic cytokines preventing apoptosis on one side and scatter factors promoting invasion on the other. For therapeutic use, their anti-apoptotic activity must be separated from their pro-invasive activity. To this end, we engineered chimeric factors containing selected functional domains of HGF and/or MSP in different combinations, and tested their biological activity. Here we present a chimeric cytokine derived from the α-chains of HGF and MSP, named Metron factor 1 for its ability to concomitantly activate the HGF receptor (Met) and the MSP receptor (Ron). We provide evidence that Metron factor 1 prevents apoptosis and stimulates cell proliferation at nanomolar concentrations, but is devoid of any pro-invasive activity. In an in vivo murine model of drug-induced nephrotoxicity, intravenous injection of recombinant Metron factor 1 prevented renal damage and preserved tubular integrity.

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Figure 1: Engineering and purification of MF-1.
Figure 2: MF-1 binds independently to the Met and Ron receptors.
Figure 3: Ligand cross-linking and receptor activation analysis.
Figure 4: MF-1 elicits a reduced signal downstream of Met and Ron.
Figure 5: Biological activity of MF-1.
Figure 6: MF-1 is a non-invasive cytokine.
Figure 7: MF-1 prevents drug-induced acute renal failure.

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Acknowledgements

This work was supported in part by the contracts “Programma Nazionale di Ricerca e Formazione sui Farmaci” (Phase 2, Theme 4) and “Programma Nazionale di Ricerca e Formazione in Oncologia” (Theme 16) granted by the Italian Ministry of University and Scientific and Technological Research (MURST). We are grateful to Sergio Dompé and Gaetano Clavenna for continuous support, Livio Trusolino, Enzo Medico, Luigi Naldini, Antonia Follenzi, and Elisa Vigna for helpful discussion, Francesco Galimi and Erika Cottone for pioneer work, and Laura Palmas, Giovanna Petruccelli, and Raffaella Albano for skilled technical assistance.

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Authors and Affiliations

  1. Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo (Torino), I-10060, Italy

    Paolo Michieli, Silvia Cavassa, Cristina Basilico, Annarita De Luca, Massimiliano Mazzone & Paolo M. Comoglio

  2. Section of Preclinical Pharmacology, Dompé S.p.A. Research Center, L'Aquila, I-67100, Italy

    Cinzia Asti, Riccardo Chiusaroli, Mario Guglielmi, Paola Bossù, Francesco Colotta & Gianfranco Caselli

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Correspondence to Paolo Michieli.

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C.A., R.C., M.G., P.B., F.C., and G.C. are employed by Dompé S.p.A., which is the assignee of European Patent Applications PCT/EP99/00478 (WO99/38967) and PCT/EP99/00502 (WO99/38968), both entitled “Recombinant proteins derived from HGF and MSP”. However, the authors have no financial participation in the company and will not receive patent royalties.

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Michieli, P., Cavassa, S., Basilico, C. et al. An HGF–MSP chimera disassociates the trophic properties of scatter factors from their pro-invasive activity. Nat Biotechnol 20, 488–495 (2002). https://doi.org/10.1038/nbt0502-488

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