Neutralizing Monoclonal Antibodies to Hepatocyte Growth Factor/Scatter Factor (HGF/SF) Display Antitumor Activity in Animal Models

The hepatocyte growth factor (HGF/SF) receptor, Met, regulates mitogenesis, motility, and morphogenesis in a cell type-dependent fashion. Activation of Met via autocrine, paracrine, or mutational mechanisms can lead to tumorigenesis and metastasis and numerous studies have linked inappropriate expre...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2001-06, Vol.98 (13), p.7443-7448
Main Authors: Cao, Brian, Su, Yanli, Oskarsson, Marianne, Zhao, Ping, Kort, Eric J., Fisher, Robert J., Wang, Ling-Mei, George F. Vande Woude
Format: Article
Language:English
Subjects:
Angiogenesis
Animals
Antibodies, Monoclonal - pharmacology
Antineoplastic Agents - pharmacology
Biological Sciences
Biology
Cell growth
Cell Line
Dogs
Epitopes
Female
Fibroblast growth factors
Glioblastoma - pathology
Glioblastoma - therapy
Hepatocyte Growth Factor - genetics
Hepatocyte Growth Factor - immunology
Hepatocytes
Humans
Immunology
Ligands
Met protein
Mice
Mice, Nude
Morphogenesis
Neutralization Tests
Proto-Oncogene Proteins c-met - genetics
Proto-Oncogene Proteins c-met - metabolism
Receptors
scatter factor
Transplantation, Heterologous
Tumor Cells, Cultured
Tumors
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Summary:The hepatocyte growth factor (HGF/SF) receptor, Met, regulates mitogenesis, motility, and morphogenesis in a cell type-dependent fashion. Activation of Met via autocrine, paracrine, or mutational mechanisms can lead to tumorigenesis and metastasis and numerous studies have linked inappropriate expression of this ligand-receptor pair to most types of human solid tumors. To prepare mAbs to human HGF/SF, mice were immunized with native and denatured preparations of the ligand. Recloned mAbs were tested in vitro for blocking activity against scattering and branching morphogenesis. Our results show that no single mAb was capable of neutralizing the in vitro activity of HGF/SF, and that the ligand possesses a minimum of three epitopes that must be blocked to prevent Met tyrosine kinase activation. In vivo, the neutralizing mAb combination inhibited s.c. growth in athymic nu/nu mice of tumors dependent on an autocrine Met-HGF/SF loop. Importantly, growth of human glioblastoma multiforme xenografts expressing Met and HGF/SF were markedly reduced in the presence of HGF/SF-neutralizing mAbs. These results suggest interrupting autocrine and/or paracrine Met-HGF/SF signaling in tumors dependent on this pathway is a possible intervention strategy.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.131200498