Administration of a liposomal FGF-2 peptide vaccine leads to abrogation of FGF-2-mediated angiogenesis and tumor development.
Basic fibroblast growth factor (FGF-2) is an important stimulator of angiogenesis that has been implicated in neoplastic progression. Attempts to neutralize or modulate FGF-2 have met with some success in controlling neovascularity and tumor growth. In the present study, two peptides: one corresponding to the heparin binding domain and the other to the receptor binding domain of FGF-2, exerted dose-dependent inhibition of FGF-2-stimulated human umbilical vein endothelial cell proliferation (IC(50)=70 and 20 microg/ml, respectively). The identification of these functional regions suggested that targeting these domains might be an approach for the modulation of FGF-2 function. To investigate this possibility, we vaccinated mice with either the heparin binding domain peptide or the receptor binding domain peptide of FGF-2 in a liposome/adjuvant format, and analyzed the effect of vaccination on FGF-2-driven angiogenesis, tumor development and immune status. Mice vaccinated with the heparin binding domain peptide generated a specific antibody response to FGF-2, blocked neovascularization in a gelfoam sponge model of angiogenesis, and inhibited experimental metastasis by >90% in two tumor models: the B16BL6 melanoma and the Lewis lung carcinoma. These effects were not observed in mice treated with the receptor binding domain peptide conjugated to liposomes or liposomes lacking conjugated peptide. These data suggest that a heparin binding domain peptide of FGF-2, when presented to a host in a liposomal adjuvant formulation, can ultimately lead to inhibition of angiogenesis and tumor growth.
Plum
S M
SM
EntreMed, Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA. stacyp@entremed.com
Holaday
J W
JW
Ruiz
A
A
Madsen
J W
JW
Fogler
W E
WE
Fortier
A H
AH
D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D008081:Liposomes; D008297:Male; D008546:Melanoma, Experimental / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D014611:Vaccination
D008081:Liposomes; D016222:Fibroblast Growth Factor 2