Interleukin-15 compositions and uses thereof

• US 10,350,270 B2
• Filed: 10/12/2015
• Issued: 07/16/2019
• Est. Priority Date: 10/14/2014
• Status: Expired due to Fees

• Current Assignee: Armo BioSciences Inc. (Eli Lilly and Company)
• Original Assignee: Armo BioSciences Inc. (Eli Lilly and Company)
• Inventors: McCauley, Scott
• Primary Examiner(s): Bunner, Bridget E
• Application Number:
  US15/513,820
• Publication Number:
  US 20170246253A1
• Time in Patent Office: 1,373 Days
• Field of Search: None
• CPC Class Codes: A61K 38/2086 IL-13 to IL-16
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: C07K 14/5443 : IL-15
• CPC Class Codes: C07K 16/244 : Interleukins [IL]
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/31 : fusions, other than Fc, for prolonged plasma life, e.g. albumin
• CPC Class Codes: C08G 2650/02 : characterized by the type of post-polymerisation functionalisation
• CPC Class Codes: C08G 65/3348 : containing nitrogen in addition to sulfur
• CPC Class Codes: G01N 2500/10 : involving cells
• CPC Class Codes: G01N 33/5011 : for testing antineoplastic activity

Abstract

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.

Claims

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.