Methods for Use of a Specific Anti-Angiogenic Adenoviral Agent

Abstract

Anti-angiogenic adenovirus vectors, and therapeutic use thereof are provided, and more particularly, but not exclusively, clinical protocols for treatment of solid tumors in patients with an Ad5-PPE-1-3X-fas-chimera adenovirus vector.

1 . A method of treating a solid tumor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a non-replicating adenovirus vector, wherein said vector comprises a polynucleotide which comprises a fas-chimera transgene transcriptionally linked to a murine pre-proendothelin promoter, wherein said therapeutically effective amount is at least 1×10 8  virus particles. 
     
     
         2 . The method of  claim 1 , wherein said therapeutically effective amount is at least about 1×10 9  to about 1×10 16  virus particles or at least about 1×10 11  to about 1×10 13  virus particles. 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein said therapeutically effective amount is at least about 3×10 12  virus particles or at least about 1×10 13  virus particles. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein said fas-chimera transgene comprises the sequence as set forth in SEQ ID NO: 2. 
     
     
         7 . The method of  claim 1 , wherein said fas-chimera transgene comprises the sequence as set forth in SEQ ID NO: 3. 
     
     
         8 . The method of  claim 1 , wherein said fas-chimera transgene comprises the sequence as set forth in SEQ ID NO: 4. 
     
     
         9 . The method of  claim 1 , wherein said murine pre-pro endothelin promoter comprises an enhancer comprising the sequence as set forth in SEQ ID NO: 6 or the complements sequence thereof. 
     
     
         10 . The method of  claim 1 , wherein said murine pre-pro endothelin promoter comprises an enhancer comprising the sequence as set forth in SEQ ID NO: 8 or the complementary sequence thereof. 
     
     
         11 . The method of  claim 1 , wherein said murine pre-pro endothelin promoter comprises an enhancer comprising the sequence as set forth in SEQ ID NO: 7 or a complementary sequence thereof. 
     
     
         12 . The method of  claim 1 , wherein said murine pre-pro endothelin promoter comprises the sequence as set forth in SEQ ID NO: 13. 
     
     
         13 . The method of  claim 1 , wherein said murine prepro-endothelin promoter comprises the sequence as set forth in SEQ ID NO: 12. 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein said non-replicating adenovirus vector is an adenovirus 5 vector. 
     
     
         16 . The method of  claim 1 , wherein said adenovirus vector comprises the polynucleotide sequence as set forth in SEQ ID NO: 9 or 10. 
     
     
         17 . The method of  claim 1 , wherein said solid tumor is a cancer. 
     
     
         18 . The method of  claim 1 , wherein said solid tumor is a primary tumor or a metastatic tumor. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein said adenovirus vector is administered systemically. 
     
     
         21 . The method of  claim 20 , wherein said vector is administered systemically by a route selected from the group consisting of intra-articular administration, intravenous administration, intraperitoneal administration, subcutaneous administration, infusion, oral administration, rectal administration, nasal administration and inhalation. 
     
     
         22 . The method of  claim 1 , comprising administering said adenovirus vector in at least two separate systemic doses. 
     
     
         23 . The method of  claim 1 , wherein said adenovirus is detected in the blood of said subject at least about 4 days post administration. 
     
     
         24 . The method of  claim 1 , wherein an amount of serum anti-adenovirus antibodies is increased following said administering, and said adenovirus is detected in the blood of said subject at least about 21 days post administration. 
     
     
         25 - 37 . (canceled) 
     
     
         38 . The method of  claim 1 , wherein said non-replicating adenovirus vector is administered to said subject, in at least two separate doses, and wherein said administration does not induce a dose-dependent increase in antibodies against said adenovirus vector in said subject. 
     
     
         39 - 65 . (canceled) 
     
     
         66 . The method of  claim 1 , wherein said administering inhibits angiogenesis of said tumor or inhibits growth of said tumor. 
     
     
         67 . (canceled) 
     
     
         68 . (canceled) 
     
     
         69 . The method of  claim 1 , wherein said solid tumor is a thyroid cancer. 
     
     
         70 . The method of  claim 69 , wherein said therapeutically effective amount is at least about 1×10 13  virus particles. 
     
     
         71 . The method of  claim 1 , wherein said solid tumor is a neuroendocrine cancer. 
     
     
         72 . The method of  claim 71 , wherein said therapeutically effective amount is at least about 1×10 13  virus particles. 
     
     
         73 . A kit for treating a solid tumor in a subject in need thereof, comprising a unit dosage of virus particles of a non-replicating adenovirus vector comprising the polynucleotide sequence as set forth in SEQ ID NO: 9 or 10 wherein said non-replicating adenovirus vector is formulated for intravenous administration, and instructions for administration of said adenovirus. 
     
     
         74 . (canceled) 
     
     
         75 . (canceled) 
     
     
         76 . A method for administering a therapeutic composition comprising an adenoviral vector to a subject, comprising administering a therapeutically effective amount of the composition to the subject at least twice, wherein the administering does not induce a dose-dependent increase in anti-adenovirus antibodies against said adenoviral vector in the subject. 
     
     
         77 - 82 . (canceled) 
     
     
         83 . The method of  claim 1 , wherein said subject is further receiving a chemotherapeutic agent. 
     
     
         84 . The method of  claim 83 , wherein said chemotherapeutic agent is administered prior to treatment with said virus particles, concomitantly with treatment with said virus particles, or following treatment with said virus particles. 
     
     
         85 . (canceled) 
     
     
         86 . (canceled) 
     
     
         87 . The method of  claim 83 , wherein said chemotherapeutic agent is sunitinib. 
     
     
         88 . An adenovirus vector comprising the polynucleotide sequence as set forth in SEQ ID NO:9. 
     
     
         89 . An adenovirus vector comprising the polynucleotide sequence as set forth in SEQ ID NO: 10.