Claims
- 1. A targeting molecule comprising a soluble adenoviral receptor domain, a trimerization domain, and a targeting ligand domain.
- 2. The targeting molecule according to claim 1 wherein the soluble adenoviral receptor domain is sCAR.
- 3. The targeting molecule according to claim 1 wherein the trimerization domain is derived from a leucine zipper molecule.
- 4. The targeting molecule according to claim 1 wherein the trimerization domain is the isoleucine variant of the yeast GCN4 leucine zipper molecule.
- 5. The targeting molecule according to claim 1 wherein the trimerization domain is fused with the soluble adenoviral receptor domain.
- 6. The targeting molecule according to claim 5 wherein the trimerization domain is fused at the carboxy-terminal end of the soluble adenoviral receptor domain.
- 7. The targeting molecule according to claim 1 further comprising a linker element which is localized between the carboxy-terminal end of the soluble adenoviral receptor domain and the trimerization domain.
- 8. The targeting molecule according to claim 7 wherein the linker element consists of alternating glycine and serine residues.
- 9. The targeting molecule according to claim 1 wherein the targeting ligand domain is cyclic RGD.
- 10. The targeting molecule according to claim 1 wherein the targeting ligand domain includes at least 15 amino acids derived from an apoE protein.
- 11. The targeting molecule according to claim 10 wherein the targeting ligand domain includes two tandem copies of amino acids 141-155 derived from apoE protein.
- 12. The targeting molecule according to claim 1 wherein the targeting ligand domain is conjugated to the carboxy-terminus of the soluble adenoviral receptor domain.
- 13. The targeting molecule according to claim 1 further comprising a linker element which is localized between the carboxy-terminal end of the trimerization domain and the targeting ligand domain.
- 14. The targeting molecule according to claim 1 wherein the soluble adenoviral receptor domain is sCAR and the trimerization domain is derived from a leucine zipper molecule.
- 15. A trimeric targeting molecule comprising the targeting molecule according to claim 1.
- 16. A complex comprising an adenoviral particle and the targeting molecule according to claim 1.
- 17. The complex according to claim 16 wherein the soluble adenoviral receptor domain is sCAR.
- 18. The complex according to claim 16 wherein the trimerization domain is derived from a leucine zipper molecule.
- 19. The complex according to claim 16 further comprising a linker element which is localized between the carboxy-terminal end of the soluble adenoviral receptor domain and the trimerization domain.
- 20. The complex according to claim 16 wherein the soluble adenoviral receptor domain is sCAR and the trimerization domain is derived from a leucine zipper molecule.
- 21. The complex according to claim 16 wherein the adenoviral particle further comprises a heterologous gene.
- 22. The complex according to claim 16 wherein the adenoviral particle is an oncolytic adenoviral particle.
- 23. A polynucleotide encoding the targeting molecule according to claim 1.
- 24. An expression vector comprising a polynucleotide according to claim 23.
- 25. A method of targeting an adenoviral particle to a cell which expresses a cell surface molecule comprising the steps of (a) contacting an adenoviral particle with the targeting molecule of claim 1 to form a complex comprising said adenoviral particle and said targeting molecule and (b) contacting said cell with said complex.
- 26. The method of claim 25 wherein the adenoviral particle is an oncolytic adenoviral particle.
- 27. A method of delivering a heterologous gene selectively to a cell which expresses a cell surface molecule comprising the steps of (a) contacting an adenoviral particle which comprises said heterologous gene with the targeting molecule of claim 1 to form a complex suitable to target said cell surface molecule and (b) contacting said cell with said complex.
- 28. A method for identifying, either or both, a cell surface molecule that is suitable for mediating cell entry of an adenoviral particle to a specific cell or tissue expressing said cell surface molecule, or a ligand that is suitable for targeting an adenoviral particle to a specific cell or tissue, comprising the steps of, 1) combining a ligand molecule for a cell surface molecule with a soluble adenoviral receptor molecule and a trimerization domain to form a targeting molecule, 2) contacting an adenoviral particle which comprises a marker gene with the targeting molecule to form a complex, 3) contacting a cell or tissue expressing said cell surface molecule with said complex, and 4) selecting a complex able to transduce efficiently said cell or tissue as reported by the marker gene.
- 29. The targeting molecule according to claim 1, wherein the targeting ligand domain comprises a single chain antibody (scFv).
- 30. The complex of claim 16 for use as a medicament.
- 31. Use of the complex of claim 16 for the preparation of a medicament for the treatment of a disease in a mammal including a human.
- 32. The use of claim 31 wherein the disease is cancer.
- 33. The use of claim 32 wherein the cancer is an adenocarcinoma of the prostate.
- 34. A method for the treatment of a disease with adenoviral gene therapy comprising contacting a trimeric targeting molecule of claim 15 with an adenoviral gene therapy vector to form a complex, and administering said complex in a therapeutically effective amount to a patient in need thereof.
- 35. The method of claim 34 wherein the disease is cancer.
- 36. The method of claim 35, wherein said cancer is lung, colon, breast, prostate, or liver cancer.
- 37. The method of claim 35 wherein the cancer is an adenocarcinoma of the prostate.
- 38. The method of claim 34 wherein the side effects of the gene therapy are reduced.
- 39. The method of claim 34 wherein the side effect of adenoviral liver toxicity is reduced.
Parent Case Info
[0001] This application claims the benefit under 35 USC §119(e) of the following United States provisional patent application: Provisional Application No. to be assigned, filed on Oct. 6, 2000, as application Ser. No. 09/684,552, for “Targeting Molecules.” The disclosure of that application is incorporated hereby by reference in its entirety.
Provisional Applications (1)
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Number |
Date |
Country |
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60327562 |
Oct 2000 |
US |