Method of treating cancer by administering conjugates comprising human IL-18 and substitution mutants thereof
Methods of treating cancer in patients in need thereof with human interleukin-18 (IL-18) polypeptides and substitution mutants thereof that are conjugated to water-soluble polymers at specific sites on the human IL-18 protein are disclosed.
1. A method of treating cancer in a patient in need thereof by administering a therapeutically effective dose of a composition comprising a polypeptide conjugated to a water-soluble polymer, wherein the polypeptide is a substitution mutant of human native IL-18, wherein the substitution mutant is selected from the group consisting of: SEQ ID NO: 4, 5, 6, 7, 8, 9, and 10, and wherein the administration results in treatment of the cancer in the patient.
2. The method as claimed in claim 1 , wherein the cancer comprises an immunosensitive tumor chosen from the group of: renal cell carcinoma, myeloma, lymphoma, and melanoma.
3. The method of treatment as claimed in claim 1 , wherein the human IL-18 substitution mutant has the amino acid sequence set forth in SEQ ID NO:4, and wherein the mutant is conjugated to the water-soluble polymer at the cysteine at residue 38.
4. The method as claimed in claim 1 , wherein the conjugation between the polypeptide and the polymer is covalent.
5. The method as claimed in claim 1 , wherein the water-soluble polymer is a member chosen from the group of: polyethylene glycol homopolymers, polyethylene glycol copolymers, polypropylene glycol homopolymers, poly(N-vinylpyrrolidone), poly(vinyl alcohol), poly(ethylene glycol-co-propylene glycol), poly(N-2-(hydroxypropyl)methacrylamide), poly(sialic acid), poly(N-acryloyl morpholine), and dextran.
6. The method as claimed in claim 5 , wherein the water-soluble polymer is unsubstituted.
7. The method as claimed in claim 5 , wherein the water-soluble polymer is substituted at one end with an alkyl group.
8. The method as claimed in claim 7 , wherein the water-soluble polymer is a polyethylene glycol homopolymer.
9. The method as claimed in claim 8 , wherein the polyethylene glycol homopolymer is monomethoxy-polyethylene glycol.
10. The method as claimed in claim 9 , wherein the monomethoxy-polyethylene glycol is chosen from the group of: linear monomethoxy-polyethylene glycol and branched monomethoxy-polyethylene glycol.
11. The method as claimed in claim 10 , wherein the polyethylene glycol homopolymer has a molecular weight of from about 20,000 daltons to about 40,000 daltons.
12. The method as claimed in claim 11 , wherein the polyethylene glycol homopolymer has a molecular weight of about 20,000 daltons.
13. The method as claimed in claim 10 , wherein the polyethylene glycol homopolymer has a molecular weight of about 30,000 daltons.
14. The method as claimed in claim 11 , wherein the polyethylene glycol homopolymer has a molecular weight of about 40,000 daltons.
15. The method as claimed in claim 11 , wherein the composition is PEGylated native human IL-18 (SEQ ID NO:1).
16. The method as claimed in claim 13 , wherein the human IL-18 substitution mutant has the amino acid sequence set forth in SEQ ID NO:5, and wherein the mutant is conjugated to the water-soluble polymer at the cysteine at residue 78.
17. The method as claimed in claim 13 , wherein the human IL-18 substitution mutant has the amino acid sequence set forth in SEQ ID NO:6, and wherein the mutant is conjugated to the water-soluble polymer at the cysteine at residue 121.
18. The method as claimed in claim 13 , wherein the human IL-18 substitution mutant has the amino acid sequence set forth in SEQ ID NO:7, and wherein the mutant is conjugated to the water-soluble polymer at the cysteine at residue 144.
19. The method as claimed in claim 13 , wherein the human IL-18 substitution mutant has the amino acid sequence set forth in SEQ ID NO:8, and wherein the mutant is conjugated to the water-soluble polymer at the cysteine at residue 157.
20. The method as claimed in claim 13 , wherein the human IL-18 substitution mutant has the amino acid sequence set forth in SEQ ID NO:9, and wherein the mutant is conjugated to the water-soluble polymer at the cysteine at residue 144.
21. The method as claimed in claim 20 , wherein the water-soluble polymer is chosen from the group of: linear polyethylene glycol homopolymer having a molecular weight of from about 20,000 to about 40,000 daltons and branched polyethylene glycol homopolymer having a molecular weight of from about 20,000 to about 40,000 daltons.
22. The method as claimed in claim 21 , wherein the linear polyethylene glycol homopolymer has a molecular weight of about 20,000 daltons.
23. The method as claimed in claim 13 , wherein the human IL-18 substitution mutant has the amino acid sequence set forth in SEQ ID NO:10, and wherein the mutant is conjugated to the water-soluble polymer at the cysteine at residue 157.
24. The method as claimed in claim 23 , wherein the water-soluble polymer is linear polyethylene glycol homopolymer having a molecular weight of from about 20,000 to about 40,000 daltons.
25. The method as claimed in claim 24 , wherein the linear polyethylene glycol homopolymer has a molecular weight of about 20,000 daltons.