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 method for treating a metastatic tumor or cancer in the brain of a subject, the method comprising the step of administering to said subject a recombinant Listeria strain expressing an immunogenic fragment of an angiogenic factor, wherein said angiogenic factor is associated with a vasculature of said tumor or cancer in said subject, wherein said angiogenic factor is a high molecular weight melanoma associated antigen (HMW-MAA)-C, wherein said immunogenic fragment is fused to an additional polypeptide, wherein said additional polypeptide is a non-hemolytic LLO, wherein said subject mounts an immune response against said angiogenic factor or against said vasculature, and wherein said treating reduces growth of said tumor or cancer, or reduces the size of said tumor or cancer.
2. The method of claim 1 , wherein said method elicits protection against metastasizing of a breast tumor or cancer, a gastric tumor or cancer, an ovarian tumor or cancer, a melanoma, or a Her-2/neu-expressing tumor or cancer to the brain.
3. The method of claim 1 , wherein said immune response comprises a therapeutic immune response useful in treating, inhibiting, or suppressing said tumor in said subject.
4. The method of claim 1 , wherein said HMW-MAA-C immunogenic fragment comprises the amino acid sequence at positions 2160-2258 of the HMW-MAA protein.
5. The method claim 1 , wherein said immunogenic fragment is expressed from an hly promoter, a prfA promoter, an actA promoter, or a p60 promoter.
6. The method of claim 1 , wherein said immunogenic fragment is expressed from an episomal vector or from the Listeria chromosome.
7. The method of claim 1 , wherein said additional polypeptide enhances the immunogenicity of said immunogenic fragment.
8. The method of claim 1 , wherein said recombinant Listeria strain is a recombinant Listeria monocytogenes strain.
9. The method of claim 1 , wherein said recombinant Listeria strain has been passaged through an animal host.
10. The method of claim 1 , wherein said recombinant Listeria strain induces the release of one or more anti-angiogenic factors.
11. The method of claim 10 , wherein said anti-angiogenic factor is interferon-gamma.
12. The method of claim 1 , wherein said metastatic tumor or cancer in the brain comprises a metastatic tumor or cancer of a breast tumor or cancer, a gastric tumor or cancer, an ovarian tumor or cancer, a melanoma, or a Her-2/neu-expressing tumor or cancer.
13. A method for reducing the incidence of a metastasis of a tumor or cancer to the brain of a subject diagnosed with a primary tumor or cancer, the method comprising the step of administering to said subject a recombinant Listeria strain expressing an immunogenic fragment of an angiogenic factor, wherein said angiogenic factor is associated with a vasculature of said tumor or cancer in said subject, wherein said angiogenic factor is a high molecular weight melanoma associated antigen (HMW-MAA)-C, wherein said immunogenic fragment is fused to an additional polypeptide, wherein said additional polypeptide is a non-hemolytic LLO, wherein said subject mounts an immune response against said angiogenic factor or against said vasculature, and wherein said reducing the incidence of a metastasis reduces the number of metastatic tumors or cancer in the brain or reduces growth or size of a metastatic tumor or cancer in the brain as compared with an untreated subject diagnosed with a primary tumor or cancer or a subject diagnosed with a primary tumor or cancer and treated with a control.
14. The method of claim 13 , wherein said method elicits protection against a metastasis of a breast tumor or cancer, a gastric tumor or cancer, an ovarian tumor or cancer, a melanoma, or a Her-2/neu-expressing tumor or cancer to the brain.
15. The method of claim 13 , wherein said method elicits protection against a metastasis of a melanoma to the brain.
16. A method for reducing the incidence of a metastasis of a tumor or cancer to the brain of a subject diagnosed with a primary tumor or cancer, the method comprising the step of administering to said subject a recombinant Listeria strain expressing an immunogenic fragment of an angiogenic factor, wherein said angiogenic factor is associated with a vasculature of said tumor or cancer in said subject, wherein said angiogenic factor is a high molecular weight melanoma associated antigen (HMW-MAA)-C, wherein said immunogenic fragment is fused to an additional polypeptide, wherein said additional polypeptide is a non-hemolytic LLO, wherein said subject mounts an immune response against said angiogenic factor or against said vasculature, wherein said metastatic tumor or cancer in the brain comprises a metastatic tumor or cancer of a melanoma, wherein said reducing the incidence of a metastasis reduces the number of metastatic tumors or cancer in the brain or reduces growth or size of a metastatic tumor or cancer in the brain as compared with an untreated subject diagnosed with a primary tumor or cancer or a subject diagnosed with a primary tumor or cancer and treated with a control.
17. The method of claim 16 , wherein said method elicits protection against a metastasis of a melanoma to the brain.
18. The method of claim 16 , wherein said immune response comprises a therapeutic immune response useful in treating, inhibiting, or suppressing said tumor in said subject.