Compositions and methods for modulating gamma-C-cytokine activity
The γc-family cytokines, Interleukin-2 (IL-2), Interleukin-4 (IL-4), Interleukin-7 (IL-7), Interleukin-9 (IL-9), Interleukin-15 (IL-15), and Interleukin-21 (IL-21), are associated with important human diseases, such as leukemia, autoimmune diseases, collagen diseases, diabetes mellitus, skin diseases, degenerative neuronal diseases and graft-versus-host disease (GvHD). Thus, inhibitors of γc-cytokine activity are valuable therapeutic and cosmetic agents as well as research tools. Peptide antagonists based on the consensus γc-subunit binding site to inhibit γc-cytokine activity are described. Also described are peptide antagonists exhibiting Simul-Block activity, and inhibiting the activity of multiple γc-cytokine family members.
1. A pharmaceutical composition comprising:
a therapeutically effective amount of a peptide conjugate, or a derivative thereof; and
a pharmaceutically acceptable carrier, diluent, excipient or combination thereof;
wherein the peptide conjugate or derivative thereof comprises amino acid sequences of at least two interleukin (IL) protein gamma-c-box D-helix regions;
wherein the peptide conjugate or derivative thereof inhibits the activity of two or more γc-cytokines selected from the group consisting of: IL-2, IL-4, IL-7, IL-9, IL-15 or IL-21;
wherein the peptide conjugate comprises the amino acid sequence D/E-F-L-E/Q/N-S/R-X-I/K-X-L/I-X-Q (SEQ ID NO: 2), X representing any amino acid;
wherein the derivative comprises a peptide sequence sharing at least 90% identity with the amino acid sequence of SEQ ID NO: 2.
2. The pharmaceutical composition of claim 1 , wherein said peptide conjugate further comprises a signal peptide.
3. The pharmaceutical composition of claim 1 , wherein said peptide conjugate inhibits the activity of IL-2, IL-15 and IL-9.
4. The pharmaceutical composition of claim 1 , further comprising a protein that stabilizes the structure of the peptide conjugate and improves its biological activity, said protein is selected from the group consisting of bovine serum albumin (BSA), albumin, Fc region of immunoglobulin G (IgG), biological proteins that function as scaffold, and Poly Ethylene Glycol (PEG) or derivatives thereof.
5. The pharmaceutical composition of claim 1 , wherein said derivative comprises a peptide sequence sharing at least 95% identity with the amino acid sequence of SEQ ID NO: 2.
6. A method for blocking signaling by two or more γc-cytokine family members, comprising contacting a cell with the pharmaceutical composition of claim 1 .
7. A method of inhibiting γc-cytokine binding to a γc-subunit comprising contacting a γc-subunit of a cell with the pharmaceutical composition of claim 1 .
8. A method of treating a γc-cytokine-mediated disease, the method comprising administering the pharmaceutical composition of claim 1 to a subject in need thereof, wherein the γc-cytokine-mediated disease is selected from the group consisting of: CD4-leukemia, CD8-leukemia, LGL-leukemia, systemic lupus erythematosis, Sjoegren's syndrome, Wegener's granulomatosis, Celiac disease, Hashimoto's thyroiditis, rheumatoid arthritis, diabetes mellitus, psoriasis, multiple sclerosis, uvietis, inflammation of the eye, and graft-versus-host disease (GvHD).
9. A method of treating a HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) associated disease, the method comprising administering the pharmaceutical composition of claim 1 to a subject in need thereof, wherein the HAM/TSP associated disease is selected from the group consisting of: Adult T-cell Leukemia (ATL), HTLV-associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), and other non-neeoplastic inflammatory diseases associated with HTLV such as uveitis (HU), arthropathy, pneumopathy, dermatitis, exocrinopathy and myositis.
10. A method of treating an inflammatory respiratory disease, the method comprising administering the pharmaceutical composition of claim 1 to a subject in need thereof, wherein the inflammatory respiratory disease is selected from the group consisting of: asthma, sinusitis, hay fever, bronchitis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, acute and chronic otitis, and lung fibrosis.
11. A method of treating a cosmetic condition selected from the group consisting of acne, hair loss, sunburn, nail maintenance, and appearance of aging, the method comprising administering the pharmaceutical composition of claim 1 to a subject in need thereof.