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Antiangiogenic activity of a neutralizing human single-chain antibody fragment against fibroblast growth factor
Roberto Ronca1, Patrizia Benzoni, Daria Leali
1Unit of General Pathology and Immunology, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
Abstract:
Fibroblast growth factor receptor-1 (FGFR-1) transduces proangiogenic and proliferative signals in human cancers. Thus, FGFR-1 may represent a target for the development of antiangiogenic/antineoplastic therapies. We screened a human single-chain fragment variable (scFv) antibody phage display library against the extracellular domain of the FGFR-1-IIIc isoform that harbors the FGF binding site. Several phages were isolated and tested for specificity and sensitivity, and the most promising antibody fragment RR-C2 was characterized for its biochemical and biological properties. ScFv RR-C2 specifically recognizes FGFR-1α and FGFR-1β isoforms in ELISA, Western blotting, and surface plasmon resonance analysis with a K(d) value of 300 and 144 nmol/L for the 2 receptor isoforms, respectively. The antibody fragment also recognizes FGFR-1 when the receptor is exposed on the cell surface, thus preventing the formation of the ternary complex among FGFR-1, its ligand FGF2, and cell surface heparan sulfate proteoglycans. Accordingly, scFv RR-C2 specifically inhibits FGF2-mediated mitogenic activity in endothelial cells of human, bovine, and murine origin in a nanomolar range of concentrations. Also, the antibody fragment prevents FGF2-triggered sprouting of both human umbilical vein endothelial cell spheroids and of murine endothelium from aortic rings. Finally, the antibody fragment hampers the angiogenic activity exerted both by FGF2 in the chick embryo chorioallantoic membrane assay and by S115 mouse mammary tumor cells in the Matrigel plug assay. Taken together, the data show that scFv RR-C2 recognizes and neutralizes FGFR-1 activity in different animal species, including humans, thus representing a novel tool for the development of antiangiogenic/antineoplastic therapies.
Insights
Researchers developed a novel antibody fragment, scFv RR-C2, that targets Fibroblast Growth Factor Receptor-1 (FGFR-1). This antibody neutralizes FGFR-1 activity, showing potential for anti-cancer therapies by inhibiting angiogenesis and proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Fibroblast Growth Factor Receptor-1 (FGFR-1) signaling promotes angiogenesis and proliferation in human cancers.
- Targeting FGFR-1 is a potential strategy for developing anti-cancer therapies.
Purpose of the Study:
- To develop and characterize a novel antibody fragment targeting the extracellular domain of FGFR-1.
- To evaluate the efficacy of the antibody fragment in inhibiting FGFR-1-mediated signaling and angiogenesis.
Main Methods:
- Screening a single-chain fragment variable (scFv) antibody phage display library against FGFR-1.
- Characterizing the antibody fragment (RR-C2) using ELISA, Western blotting, and surface plasmon resonance.
- Assessing the biological activity of scFv RR-C2 in vitro and in vivo models of angiogenesis.
Main Results:
- ScFv RR-C2 specifically recognizes FGFR-1 isoforms with high affinity.
- The antibody fragment inhibits FGF2-mediated endothelial cell proliferation and sprouting.
- ScFv RR-C2 effectively hampers angiogenic activity in multiple animal models.
Conclusions:
- ScFv RR-C2 is a potent inhibitor of FGFR-1 activity across different species.
- This novel antibody fragment represents a promising therapeutic tool for anti-angiogenic and anti-neoplastic strategies.
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