Interleukin-15 compositions and uses thereof
Interleukin-15 muteins and other interleukin-15-related molecules are described, as well as methods of identifying interleukin-15 muteins and other interleukin-15-related molecules. Also described herein are modifications of the foregoing, which modifications may enhance a property (e.g., half-life) of the muteins or other molecules compared to human interleukin-15. Pharmaceutical compositions and methods of use are also described herein.
1. A peptide comprising an amino acid sequence of SEQ ID NO:3, wherein the peptide comprises:
a) a Helix A,
b) an A/B Inter-helix Junction,
c) a Helix B,
d) a B/C Inter-helix Junction,
e) a Helix C,
f) a C/D Inter-helix Junction and
g) a Helix D;
and wherein the peptide further comprises at least one amino acid substitution of the following positions: 1, 17-23, 60, 89-98, 113, or 114.
2. The peptide of claim 1 , wherein substitution of the at least one amino acid is a conservative substitution.
3. The peptide of claim 1 or 2 , wherein the peptide has a bioactivity at least equal to the bioactivity of SEQ ID NO:3, wherein the bioactivity is determined in an in vitro assay or an in vivo assay.
4. The peptide of claim 3 , wherein the bioactivity is determined in an in vitro assay selected from the group consisting of a TNFα production assay, a CTLL-2 cell proliferation assay, a M07e cell proliferation assay, or a T-cell IFNγ secretion assay.
5. The peptide of claim 1 , wherein the at least one amino acid substitution does not adversely affect immunogenicity.
6. The peptide of claim 5 , wherein the immunogenicity of the peptide is predicted by screening for at least one of T-cell epitopes or B-cell epitopes.
7. The peptide of claim 6 , wherein the screening is at least one of an in silico screening system or an ex vivo assay system.
8. The peptide of claim 1 , wherein the peptide comprises at least one modification to form a modified peptide;
wherein the modification does not alter the amino acid sequence of the peptide, and
wherein the modification improves at least one property of the peptide.
9. The peptide of claim 8 , wherein the modified peptide is pegylated with a PEG component.
10. The peptide of claim 9 , wherein the modified peptide comprises at least one PEG molecule covalently attached to the N-terminus of the peptide.
11. The peptide of claim 9 , wherein the PEG component of the modified peptide has a molecular mass from 5 kDa to 50 kDa.
12. The peptide of claim 9 , wherein the PEG component of the modified peptide has a molecular mass from 20 kDa to 40 kDa.
13. The peptide of claim 9 , wherein the PEG component of the modified peptide has a molecular mass greater than 20 kDa.
14. The peptide of claim 9 , wherein the PEG component of the modified peptide has a molecular mass of at least 30 kD.
15. The peptide of claim 9 , wherein the PEG component of the modified peptide has a molecular mass of at least 40 kD.
16. The peptide of claim 8 , wherein the modified peptide is glycosylated.
17. The peptide of claim 8 , wherein the modified peptide comprises an Fc fusion molecule.
18. The peptide of claim 8 , wherein the modified peptide comprises a serum albumin.
19. The peptide of claim 8 , wherein the modification is site-specific.
20. The peptide of claim 8 , wherein the modification comprises a linker.
21. The peptide of claim 8 , wherein the modification improves at least one physical property of the peptide.
22. The peptide of claim 21 , wherein the physical property is selected from the group consisting of solubility, bioavailability, serum half-life, and circulation time.
23. The peptide of claim 8 , wherein the modified peptide has activity at least comparable to the activity of mature human IL-15.
24. The peptide of claim 1 , wherein the peptide is produced recombinantly.
25. A pharmaceutical composition, comprising a peptide of claim 1 , and a pharmaceutically acceptable diluent, carrier or excipient.