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Claims for Patent: 6,426,335

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Claims for Patent: 6,426,335

Title: Vascular endothelial growth factor (VEGF) nucleic acid ligand complexes
Abstract:This invention discloses a method for preparing a complex comprised of a VEGF Nucleic Acid Ligand and a Non-Immunogenic, High Molecular Weight Compound or Lipophilic Compound by identifying a VEGF Nucleic Acid Ligand by SELEX methodology and associating the VEGF Nucleic Acid Ligand with a Non-Immunogenic, High Molecular Weight Compound or Lipophilic Compound. The invention further discloses Complexes comprising one or more VEGF Nucleic Acid Ligands in association with a Non-Immunogenic, High Molecular Weight Compound or Lipophilic Compound. The invention further includes a Lipid construct comprising a VEGF Nucleic Acid Ligand or Complex and methods for making the same.
Inventor(s): Janjic; Nebojsa (Boulder, CO), Gold; Larry (Boulder, CO), Schmidt; Paul (Niwot, CO), Vargeese; Chandra (Thornton, CO), Willis; Michael (Louisville, CO)
Assignee: Gilead Sciences, Inc. (Foster City, CA)
Application Number:09/254,968
Patent Claims: 1. A method for treating a VEGF mediated disease or medical condition selected from the group consisting of cancer, psoriasis, ocular disorders characterized by excessive angiogenesis, collagen vascular diseases and rheumatoid arthritis comprising administering a pharmaceutically effective amount of a Complex comprised of a VEGF Nucleic Acid Ligand comprising 2'F-modified nucleotides and a Non-Immunogenic, High Molecular Weight Compound or a Lipophilic Compound to a patient in need of said Complex.

2. The method of claim 1 wherein said Non-Immunogenic, High Molecular Weight Compound is a Polyalkylene Glycol.

3. The method of claim 2 wherein said Polyalkylene Glycol is polyethylene glycol.

4. The method of claim 3 wherein said polyethylene glycol has a molecular weight of about between 10-80K.

5. The method of claim 3 wherein said polyethylene glycol has a molecular weight of about 20-45K.

6. The method of claim 5 wherein said Complex has the structure ##STR9##

Ligand Component=fCmGmGrArAfUfCmAmGfUmGmAmAfUmGfCfUfUmAfUmAfCmAfUfCfCmG-3'3'-dT (VEGF ligand).

7. The method of claim 1 wherein said Lipophilic Compound is a glycerol lipid.

8. The method of claim 7 wherein said Complex is further associated with a lipid construct.

9. The method of claim 8 wherein said Complex has the structure ##STR10##

Ligand Component=fCmGmGrArAfUfCmAmGfUmGmAmAfUmGfCfUfUmAfUmAfCmAfUfCfCmG-3'3'-dT (VEGF ligand).

10. A method for improving the pharmacokinetic properties of a VEGF Nucleic Acid Ligand comprising 2'F-modified nucleotides comprising: covalently linking said VEGF Nucleic Acid Ligand with a Non-Immunogenic, High Molecular Weight Compound or Lipophilic Compound to form a Complex comprised of a VEGF Nucleic Acid Ligand and a Non-Immunogenic, High Molecular Weight Compound or Lipophilic Compound; and administering said Complex to a patient, whereby the pharmacokinetic properties of said VEGF Nucleic Acid Ligand are improved.

11. A method for targeting a therapeutic or diagnostic agent to a specific predetermined biological target that is expressing VEGF in a patient comprising: covalently linking said therapeutic or diagnostic agent with a Complex comprised of a VEGF Nucleic Acid Ligand comprising 2'F-modified nucleotides and a Non-Immunogenic, High Molecular Weight Compound or Lipophilic Compound, and administering said Complex to said patient, whereby said therapeutic or diagnostic agent is targeted to a specific predetermined biological target that is expressing VEGF.

12. A method of inhibiting VEGF mediated angiogenesis in a patient comprising: covalently linking a VEGF Nucleic Acid Ligand comprising 2'F-modified nucleotides to a Non-Immunogenic, High Molecular Weight Compound or Lipophilic Compound to form a Complex, said Complex being capable of inhibiting VEGF mediated angiogenesis; and administering said Complex to said patient, whereby said VEGF mediated angiogenesis is inhibited.

13. A method of inhibiting the growth of tumors in a patient comprising: covalently linking a VEGF Nucleic Acid Ligand comprising 2'F-modified nucleotides to a Non-Immunogenic, High Molecular Weight Compound or Lipophilic Compound to form a Complex, said Complex being capable of inhibiting the growth of tumors; and administering said Complex to said patient, whereby said growth of tumors is inhibited.

14. The method of claim 13 wherein said tumors or cells or tissues surrounding said tumors are expressing VEGF.

15. The method of claim 13 wherein said tumors or cells or tissues surrounding said tumors are expressing VEGF receptors.

16. The method of claim 15 wherein said tumors are comprised of Kaposi's sarcoma cells.

17. A method of inhibiting macular degeneration in a patient comprising: covalently linking a VEGF Nucleic Acid Ligand comprising 2' F-modified nucleotides to a Non-Immunogenic, High Molecular Weight Compound or Lipophilic Compound to form a Complex, said Complex being capable of inhibiting macular degeneration; and administering said Complex to said patient, whereby said macular degeneration is inhibited.

18. The method of claim 17 wherein said Non-Immunogenic, High Molecular Weight Compound is a polyalkylene glycol.

19. The method of claim 18 wherein said polyalkylene glycol is polyethylene glycol.

20. The method of claim 19 wherein said polyethylene glycol has a molecular weight of about between 10-80k.

21. The method of claim 19 wherein said polyethylene glycol has a molecular weight of about between 20-45k.

22. The method of claim 21 wherein said complex has the structure ##STR11##

Ligand Component=fCmGmGrArAfUfCmAmGfUmGmAmAfUmGfCfUfUmAfUmAfCmAfUfCfCmG-3'3'-dT (VEGF ligand).

23. A method for prolonging the residence time of a Nucleic Acid Ligand in an ocular application comprising attaching a Non-Immunogenic, High Molecular Weight Compound to a Nucleic Acid Ligand to form a Complex, and administering said complex to the eye, whereby the residence time of said Nucleic Acid Ligand is prolonged.
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