Modified tumor necrosis factor
Modifying TNF with polyethyleneglycol (PEG) having an approximate weight average molecular weight in the range of about 10,000 to about 40,000, preferably in the range of about 20,000 to 30,000, significantly increases the circulating half-life of the TNF while not increasing its toxicity. As a result, lower doses of the TNF may be administered to effectively treat tumors with fewer, accompanying adverse side effects to the patient.
1. A method of enhancing the tumoricidal activity of isolated TNF comprising covalently bonding to the TNF PEG having an approximate weight average molecular weight in the range of 20,000 to 40,000.
2. The method of claim 1 wherein the PEG is covalently bound to primary amine groups on the TNF through a biocompatible linker.
3. The method of claim 2 wherein the biocompatible linker is succinimidyl succinate, succinimidyl proprionate, or N-hydroxy succinimidyl.
4. The method of claim 1 wherein the PEG has an approximate weight average molecular weight in the range of 20,000 to 30,000.
5. The method of claim 1 wherein the TNF is TNF-α.
6. The method of claim 1 wherein the TNF is isolated human TNF.
7. The method of claim 1 wherein the TNF is recombinant human TNF.
8. The method of claim 1 wherein the TNF is human TNF mutated by deleting amino acids 1 to 9 of the mature TNF protein.
9. A method of inhibiting tumor growth in a patient suffering from cancer comprising administering to the patient a therapeutically effective amount of isolated TNF covalently bound to PEG having an approximate weight average molecular weight in the range of 20,000 to 40,000.
10. The method of claim 9 wherein the tumor is a melanoma.
11. The method of claim 9 wherein the tumor is a colon cancer.
12. The method of claim 9 wherein the tumor is a kidney cancer.
13. The method of claim 9 wherein the tumor is a breast cancer.
14. The method of claim 9 wherein the PEG is covalently bound to primary amine groups on the TNF through a biocompatible linker.
15. The method of claim 14 wherein the biocompatible linker is succinimidyl succinate, succinimidyl proprionate, or N-hydroxy succinimidyl.
16. The method of claim 9 wherein the PEG has an approximate weight average molecular weight in the range of 20,000 to 30,000.
17. The method of claim 9 wherein the TNF is TNF-α.
18. The method of claim 9 wherein the TNF is isolated human TNF.
19. The method of claim 9 wherein the TNF is recombinant human TNF.
20. The method of claim 9 wherein the TNF is human TNF mutated by deleting amino acids 1 to 9 of the mature TNF protein.