Compositions comprising angiogenic factors and methods of use thereof
The present invention provides recombinant Listeria strains comprising an angiogenic factor, recombinant polypeptides comprising an angiogenic factor operatively linked to a polypeptide comprising a PEST-like sequence, recombinant nucleotide molecules encoding same, related vaccines, and immunogenic and therapeutic methods utilizing same.
1. A recombinant Listeria strain expressing a vascular endothelial growth factor receptor-2 (VEGFR2) or immunogenic fragment thereof, wherein said recombinant Listeria strain is useful for targeting the tumor vasculature of a tumor growth or cancer in a subject, wherein said subject mounts an immune response against said VEGFR2 or immunogenic fragment thereof or against a tumor antigen expressed by said tumor growth or cancer, and wherein said VEGFR2 fragment is fetal liver kinase1 (Flk1)-E1, Flk1-E2, Flk1-I1, or a combination thereof.
2. The recombinant Listeria strain of claim 1 , wherein said immune response is a therapeutic immune response useful in treating, inhibiting or suppressing said tumor growth in said subject.
3. The recombinant Listeria strain of claim 1 , wherein said VEGFR2 or immunogenic fragment thereof is fused to an additional polypeptide, wherein said additionally polypeptide is a) a non-hemolytic LLO, b) an N-terminal ActA, or c) a PEST amino acid sequence.
4. The recombinant Listeria strain of claim 3 , wherein said additional polypeptide enhances the immunogenicity of said VEGFR2 or immunogenic fragment thereof.
5. The recombinant Listeria strain of claim 1 , wherein said VEGFR2 fragment is selected from SEQ ID NO: 5-7.
6. The recombinant Listeria strain of claim 1 , wherein said VEGFR2 or immunogenic fragment thereof is expressed from an hly promoter, a prfA promoter, an actA promoter, or a p60 promoter.
7. The recombinant Listeria strain of claim 1 , wherein said VEGFR2 or immunogenic fragment thereof is expressed from an episomal vector or from the Listeria chromosome.
8. The recombinant Listeria strain of claim 1 , wherein said recombinant Listeria strain is a recombinant Listeria monocytogenes strain.
9. The recombinant Listeria strain of claim 1 , wherein said recombinant Listeria strain has been passaged through an animal host.
10. The recombinant Listeria strain of claim 1 , wherein said recombinant Listeria strain induces the release of one or more anti-angiogenic factors.
11. The recombinant Listeria strain of claim 10 , wherein said anti-angiogenic factor is interferon-gamma; pigment epithelium-derived factor (PEDF); angiostatin; endostatin; fms-like tyrosine kinase (sFlt)-1; or soluble endoglin (sEng).
12. The recombinant Listeria of claim 1 , wherein said tumor growth or cancer is a breast tumor or cancer, a brain tumor or cancer or metastasis thereof, a gastric tumor or cancer, an ovarian tumor or cancer, or an her-2/neu-expressing tumor or cancer.
13. The recombinant Listeria of claim 1 , wherein said immune response allows preventing the recurrence of said tumor or said cancer, or allows inhibiting metastases of said tumor or said cancer in a subject.
14. The recombinant Listeria of claim 1 , wherein said immune response against tumor antigen occurs via epitope spreading.
15. A vaccine comprising the recombinant Listeria strain of claim 1 and an adjuvant.
16. An immunogenic composition comprising the recombinant Listeria strain of claim 1 and an adjuvant.