Compounds including a mutant KRAS sequence and a lipid and uses thereof
The invention features a compound including a mutant KRAS sequence and a lipid, where the mutant KRAS sequence is conjugated to the lipid by a linker, and (i) the linker includes one or more polyethylene glycol blocks, (ii) the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), and (iii) the mutant KRAS sequence comprises or consists of the amino acid sequence selected from the group consisting of SEQ ID NOs:1-7 and 22-30. The invention features a composition including one or more compounds of the invention and a pharmaceutically acceptable carrier. The invention also features a method of treating a cancer in a human patient, the method including administering the composition to the patient. Further, the invention features a kit comprising the compound.
1. A compound comprising a mutant KRAS sequence and a lipid, wherein the mutant KRAS sequence is conjugated to the lipid by a linker, and (i) the linker comprises one or more polyethylene glycol blocks, (ii) the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), and (iii) the mutant KRAS sequence consists of an amino acid sequence selected from the group consisting of CYKLVVVGADGVGKSALTI (SEQ ID NO:1), CYKLVVVGAVGVGKSALTI (SEQ ID NO:2), CYKLVVVGARGVGKSALTI (SEQ ID NO:3), CYKLVVVGAAGVGKSALTI (SEQ ID NO:4), CYKLVVVGASGVGKSALTI (SEQ ID NO:5), CYKLVVVGACGVGKSALTI (SEQ ID NO:6), CYKLVVVGAGDVGKSALTI (SEQ ID NO:7), CYKLVVVGATGVGKSALTI (SEQ ID NO:22), YKLVVVGADGVGKSALTI (SEQ ID NO:23), YKLVVVGAVGVGKSALTI (SEQ ID NO:24), YKLVVVGARGVGKSALTI (SEQ ID NO:25), YKLVVVGAAGVGKSALTI (SEQ ID NO:26), YKLVVVGASGVGKSALTI (SEQ ID NO:27), YKLVVVGACGVGKSALTI (SEQ ID NO:28), YKLVVVGATGVGKSALTI (SEQ ID NO:29), and YKLVVVGAGDVGKSALTI (SEQ ID NO:30).
2. The compound of claim 1 , wherein the mutant KRAS sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, and 22, at the N-terminus, is conjugated to the linker through a cysteine-maleimide linkage.
3. The compound of claim 1 or 2 , wherein the linker comprises 48 repeat units of polyethylene glycol.
4. The compound of claim 1 , wherein the mutant KRAS sequence, at the N-terminus, is conjugated to the following structure:
5. The compound of claim 1 , wherein the linker comprises 2 to 50 repeat units of polyethylene glycol.
6. A kit comprising the compound of claim 1 .
7. A composition comprising one or more compounds of claim 1 , and a pharmaceutically acceptable carrier.
8. The composition of claim 6 , wherein the composition comprises 700 μg of each compound.
9. A method of treating a cancer in a human patient, the method comprising administering the composition of claim 7 to the human patient.
10. The method of claim 9 , wherein the method further comprises administering an adjuvant.
11. The method of claim 10 , wherein the adjuvant comprises a CpG nucleotide sequence.
12. The method of claim 10 , wherein 0.1 mg, 0.5 mg, or 2.5 mg of the adjuvant is administered.
13. The mthod of claim 9 , wherein the cancer is a pancreatic cancer, a lung cancer, or a colorectal cancer.
14. A compound comprising a mutant KRAS sequence and a lipid, wherein the mutant KRAS sequence is conjugated to the lipid by a linker, and (i) the linker comprises one or more polyethylene glycol blocks, (ii) the lipid is 1 ,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), and (iii) the mutant KRAS sequence consists of the amino acid sequence CYKLVVVGADGVGKSALTI (SEQ ID NO: 1), wherein the mutant KRAS sequence is conjugated to the linker through a cysteine-maleimide linkage.
15. The compound of claim 14 , wherein the linker comprises 2 to 50 repeat units of polyethylene glycol.
16. The compound of claim 14 , wherein the linker comprises 48 repeat units of polyethylene glycol.
17. A compound comprising a mutant KRAS sequence and a lipid, wherein the mutant KRAS sequence is conjugated to the lipid by a linker, and (i) the linker comprises one or more polyethylene glycol blocks, (ii) the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), and (iii) the mutant KRAS sequence consists of the amino acid sequence CYKLVVVGAVGVGKSALTI (SEQ ID NO: 2), wherein the mutant KRAS sequence is conjugated to the linker through a cysteine-maleimide linkage.
18. The compound of claim 17 , wherein the linker comprises 2 to 50 repeat units of polyethylene glycol.
19. The compound of claim 17 , wherein the linker comprises 48 repeat units of polyethylene glycol.
20. A compound comprising a mutant KRAS sequence and a lipid, wherein the mutant KRAS sequence is conjugated to the lipid by a linker, and (i) the linker comprises one or more polyethylene glycol blocks, (ii) the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), and (iii) the mutant KRAS sequence consists of the amino acid sequence CYKLVVVGARGVGKSALTI (SEQ ID NO: 3), wherein the mutant KRAS sequence is conjugated to the linker through a cysteine-maleimide linkage.
21. The compound of claim 20 , wherein the linker comprises 2 to 50 repeat units of polyethylene glycol.
22. The compound of claim 20 , wherein the linker comprises 48 repeat units of polyethylene glycol.
23. A compound comprising a mutant KRAS sequence and a lipid, wherein the mutant KRAS sequence is conjugated to the lipid by a linker, and (i) the linker comprises one or more polyethylene glycol blocks, (ii) the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), and (iii) the mutant KRAS sequence consists of the amino acid sequence CYKLVVVGAAGVGKSALTI (SEQ ID NO: 4), wherein the mutant KRAS sequence is conjugated to the linker through a cysteine-maleimide linkage.
24. The compound of claim 23 , wherein the linker comprises 2 to 50 repeat units of polyethylene glycol.
25. The compound of claim 23 , wherein the linker comprises 48 repeat units of polyethylene glycol.
26. A compound comprising a mutant KRAS sequence and a lipid, wherein the mutant KRAS sequence is conjugated to the lipid by a linker, and (i) the linker comprises one or more polyethylene glycol blocks, (ii) the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), and (iii) the mutant KRAS sequence consists of the amino acid sequence CYKLVVVGASGVGKSALTI (SEQ ID NO: 5), wherein the mutant KRAS sequence is conjugated to the linker through a cysteine-maleimide linkage.
27. The compound of claim 26 , wherein the linker comprises 2 to 50 repeat units of polyethylene glycol.
28. The compound of claim 26 , wherein the linker comprises 48 repeat units of polyethylene glycol.
29. A compound comprising a mutant KRAS sequence and a lipid, wherein the mutant KRAS sequence is conjugated to the lipid by a linker, and (i) the linker comprises one or more polyethylene glycol blocks, (ii) the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), and (iii) the mutant KRAS sequence consists of the amino acid sequence CYKLVVVGAGDVGKSALTI (SEQ ID NO: 7), wherein the mutant KRAS sequence is conjugated to the linker through a cysteine-maleimide linkage.
30. The compound of claim 29 , wherein the linker comprises 2 to 50 repeat units of polyethylene glycol.
31. The compound of claim 29 , wherein the linker comprises 48 repeat units of polyethylene glycol.
32. A compound comprising a mutant KRAS sequence and a lipid, wherein the mutant KRAS sequence is conjugated to the lipid by a linker, and (i) the linker comprises one or more polyethylene glycol blocks, (ii) the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), and (iii) the mutant KRAS sequence consists of the amino acid sequence YKLVVVGACGVGKSALTI (SEQ ID NO: 28), wherein the mutant KRAS sequence is conjugated to the linker through a cysteine-maleimide linkage.
33. The compound of claim 32 , wherein the linker comprises 2 to 50 repeat units of polyethylene glycol.
34. The compound of claim 32 , wherein the linker comprises 48 repeat units of polyethylene glycol.