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 an endoglin 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 endoglin or immunogenic fragment thereof or against a tumor antigen expressed by said tumor growth or cancer, and wherein said immune response against said tumor antigen occurs via epitope spreading.
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 or cancer in said subject.
3. The recombinant Listeria strain of claim 1 , wherein said endoglin 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 sequence.
4. The recombinant Listeria strain of claim 1 , wherein said endoglin fragment is selected from SEQ ID NO: 52-53.
5. The recombinant Listeria strain of claim 1 , wherein said endoglin or immunogenic fragment thereof is expressed from an hly promoter, a prfA promoter, an actA promoter, or a p60 promoter.
6. The recombinant Listeria strain of claim 1 , wherein said endoglin or immunogenic fragment thereof is expressed from an episomal vector or from the Listeria chromosome.
7. The recombinant Listeria strain of claim 3 , wherein said additional polypeptide enhances the immunogenicity of said fragment or factor.
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.
12. A vaccine comprising the recombinant Listeria strain of claim 1 and an adjuvant.
13. The recombinant Listeria strain of claim 1 , wherein said tumor or cancer is a breast tumor or cancer, a gastric tumor or cancer, an ovarian tumor or cancer, a brain tumor or cancer or metastasis thereof, or an Her-2/neu-expressing tumor or cancer.
14. A method of targeting a tumor vasculature of a tumor growth or cancer in a subject, the method comprising the step of administering to said subject a recombinant Listeria strain expressing an endoglin or immunogenic fragment thereof for targeting said tumor vasculature of a tumor growth or cancer in said subject, wherein said subject mounts an immune response against said endoglin factor or immunogenic fragment thereof or against a tumor antigen expressed by said tumor growth or cancer, and wherein said immune response against said tumor antigen occurs via epitope spreading.
15. The method of claim 14 , wherein said immune response is a therapeutic immune response useful in treating, inhibiting or suppressing said tumor growth or cancer in said subject.
16. The method of claim 14 , wherein said endoglin 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 sequence.
17. The method of claim 14 , wherein said endoglin fragment is selected from SEQ ID NO: 52-53.
18. The method of claim 14 , wherein said endoglin is expressed from an hly promoter, a prfA promoter, an actA promoter, or a p60 promoter.
19. The method of claim 14 , wherein said endoglin is expressed from an episomal vector or from the Listeria chromosome.
20. The method of claim 16 , wherein said additional polypeptide enhances the immunogenicity of said fragment or factor.
21. The method of claim 14 , wherein said recombinant Listeria strain is a recombinant Listeria monocytogenes strain.
22. The method of claim 14 , wherein said recombinant Listeria strain has been passaged through an animal host.
23. The method of claim 14 , wherein said recombinant Listeria strain induces the release of one or more anti-angiogenic factors.
24. The method of claim 23 , wherein said anti-angiogenic factor is interferon-gamma.
25. The method of claim 14 , wherein said tumor growth or cancer is a breast tumor or cancer, a gastric tumor or cancer, an ovarian tumor or cancer, a brain tumor or cancer or metastases, or an Her-2/neu-expressing tumor or cancer.
26. The method of claim 14 , wherein the method enables inhibiting or suppressing the recurrence of a tumor or of inhibiting metastases of a tumor or cancer in a subject.
27. The method of claim 26 , wherein said tumor or cancer is a breast tumor or cancer, a brain metastasis or an Her-2/neu-expressing tumor or cancer.
28. The method of claim 14 , wherein said subject mounts an immune response against a tumor antigen expressed by said tumor or cancer, and wherein said immune response against said tumor antigen occurs via epitope spreading.