Modulating gamma-c-cytokine activity

Abstract

Embodiments relate to peptide antagonists of γc-family cytokines, which is 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. Traditional approaches to inhibiting γc-cytokine activity involve raising neutralizing antibodies against each individual γc-cytokine family member/receptor subunit. However, success has been limited and often multiple γc-cytokine family members co-operate to cause the disease state. Combinatorial use of neutralizing antibodies raised against each factor is impractical and poses an increased risk of adverse immune reactions. The present embodiments overcome these shortcomings by utilizing peptide antagonists based on the consensus γc-subunit binding site to inhibit γc-cytokine activity. Such approach allows for flexibility in antagonist design. In several embodiments, peptides exhibit Simul-Block activity, inhibiting the activity of multiple γc-cytokine family members.

What is claimed is: 
     
         1 . A composite peptide, or derivative thereof, that comprises amino acid sequences of at least two interleukin (IL) protein gamma-c-box D-helix regions, wherein the composite peptide comprises the amino acid sequence P-K-E-F-L-E-R-F-V-H-L-V-Q-M-F-I-H-Q-S-L-S (SEQ ID NO: 3), wherein the derivative thereof comprises an amino acid sequence sharing at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 3, wherein the composite peptide or the derivative thereof inhibits the activity of at least IL-15 and IL-21. 
     
     
         2 . The composite peptide or derivative thereof of  claim 1 , further comprising a signal peptide. 
     
     
         3 . The composite peptide or derivative thereof of  claim 1 , further comprising a linker element. 
     
     
         4 . The composite peptide or derivative thereof of  claim 1 , wherein the derivative thereof comprises amino acid residues that retain similar physico-chemical properties to the amino acids of SEQ ID NO:3. 
     
     
         5 . The composite peptide or derivative thereof of  claim 1 , wherein the composite peptide or derivative thereof is further conjugated to one or more additional moieties at the N-terminus, C-terminus, or side residue of the composite peptide. 
     
     
         6 . The composite peptide or derivative thereof of  claim 4 , wherein the one or more additional moieties are selected from the group consisting of bovine serum albumin (BSA), albumin, Keyhole Limpet Hemocyanin (KLH), Fc region of immunoglobulin G (IgG), a biological protein that functions as scaffold, an antibody against a cell-specific antigen, a receptor, a ligand, a metal ion, and Poly Ethylene Glycol (PEG). 
     
     
         7 . A pharmaceutical composition comprising:
 a peptide conjugate, or a derivative thereof; and   a pharmaceutically acceptable carrier, diluent, excipient or combination thereof;   wherein the peptide conjugate or the derivative thereof modulates the activity of IL-15 and IL-21;   wherein the peptide conjugate or the derivative thereof comprises an amino acid sequence sharing at least 70% sequence identity to P-K-E-F-L-E-R-F-V-H-L-V-Q-M-F-I-H-Q-S-L-S (SEQ ID NO: 3).   
     
     
         8 . The pharmaceutical composition of  claim 6 , wherein the peptide conjugate or derivative thereof further comprises a signal peptide. 
     
     
         9 . The pharmaceutical composition of  claim 6 , wherein the peptide conjugate or derivative thereof further comprises a linker element. 
     
     
         10 . The pharmaceutical composition of  claim 6 , wherein the derivative thereof comprises amino acid residues that retain similar physico-chemical properties to the amino acids of SEQ ID NO:3. 
     
     
         11 . The pharmaceutical composition of  claim 6 , wherein the peptide conjugate or derivative thereof consists of the amino acid sequence of SEQ ID NO: 3. 
     
     
         12 . The pharmaceutical composition of  claim 6 , wherein the peptide conjugate or derivative thereof is further conjugated to one or more additional moieties at the N-terminus, C-terminus or a side residue thereof. 
     
     
         13 . The pharmaceutical composition of  claim 10 , wherein the one or more additional moieties are selected from the group consisting of bovine serum albumin (BSA), albumin, Keyhole Limpet Hemocyanin (KLH), Fc region of immunoglobulin G (IgG), a biological protein that functions as scaffold, an antibody against a cell-specific antigen, a receptor, a ligand, a metal ion, and Poly Ethylene Glycol (PEG). 
     
     
         14 . A method for blocking signaling by two or more γc-cytokine family members, comprising contacting a cell with the pharmaceutical composition of  claim 6 . 
     
     
         15 . 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 6 . 
     
     
         16 . A method of treating a γc-cytokine-mediated disease, the method comprising administering the pharmaceutical composition of  claim 6  to a subject in need of treatment, wherein the γc-cytokine-mediated disease is selected from the group consisting of myasthenia gravis, inflammatory bowel disease, CD4-leukemia, CD8-leukemia, LGL-leukemia, systemic lupus erythematosus, Sjögren's syndrome, Wegener's granulomatosis, Celiac disease, Hashimoto's thyroiditis, rheumatoid arthritis, diabetes mellitus, psoriasis, multiple sclerosis, uveitis, inflammation of the eye, and graft-versus-host disease (GvHD). 
     
     
         17 . A method of treating uveitis, arthropathy, dermatitis, exocrinopathy, and myositis, the method comprising administering the pharmaceutical composition of  claim 6  to a subject in need of treatment. 
     
     
         18 . A method of treating Adult T-cell Leukemia (ATL) and HTLV-associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), the method comprising administering the pharmaceutical composition of  claim 6  to a subject in need of treatment. 
     
     
         19 . A method of treating an inflammatory respiratory disease, the method comprising administering the pharmaceutical composition of  claim 6  to a subject in need of treatment, wherein the inflammatory respiratory disease is selected from the group consisting of sinusitis, bronchitis, chronic obstructive pulmonary disease (COPD), and lung fibrosis. 
     
     
         20 . A method of treating intraepithelial lymphoma and leukemia in Refractory Celiac Disease, NK leukemia/lymphoma, and NK-T leukemia/lymphoma, the method comprising administering the pharmaceutical composition of  claim 6  to a subject in need of treatment.