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Publication Number
US-11400134-B2
Publication Date
2022-08-02
Expiration Date
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 yc-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.
Core Innovation
The invention relates to a composite peptide-based antagonist strategy targeting interleukin (IL) protein gamma-c-box D-helix regions of IL-15 and IL-21. The composite peptide comprises amino acid sequences of at least two IL protein gamma-c-box D-helix regions and inhibits the activity of IL-15 and IL-21.
The composite peptide is defined by sequence identity to an 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 composite peptide comprises an amino acid sequence having at least 70% sequence identity to SEQ ID NO: 3. Embodiments include a consensus composite peptide comprising at least two IL gamma-c-box D-helix regions.
The disclosure further provides pharmaceutical compositions comprising a nucleotide sequence encoding a peptide conjugate or derivative and a pharmaceutically acceptable carrier, where the peptide conjugate or derivative modulates IL-15 and IL-21 activity and includes an amino acid sequence having at least 70% sequence identity to SEQ ID NO: 3. The disclosure also includes genetic constructs comprising nucleotide sequences encoding the composite peptide with regulatory elements configured to regulate expression, enabling modulation of IL-15 and IL-21 activity.
Claims Coverage
The provided claims include three independent claims covering a nucleotide sequence encoding a composite peptide antagonist inhibiting IL-15 and IL-21, pharmaceutical compositions comprising nucleotide-encoded peptide conjugates or derivatives plus pharmaceutically acceptable carriers, and genetic constructs with regulatory elements that drive expression to modulate IL-15 and IL-21.
Composite peptide sequence identity with at least two IL gamma-c-box D-helix regions inhibiting IL-15 and IL-21
A nucleotide sequence encoding a composite peptide comprising amino acid sequences of at least two interleukin (IL) protein gamma-c-box D-helix regions, wherein the composite peptide comprises an amino acid sequence having 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), and the composite peptide inhibits the activity of IL-15 and IL-21.
Pharmaceutical composition with nucleotide-encoded peptide conjugate modulating IL-15 and IL-21
A pharmaceutical composition comprising a nucleotide sequence encoding 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, and wherein the peptide conjugate or the derivative thereof comprises an amino acid sequence having 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).
Genetic construct with regulatory elements for expression modulating IL-15 and IL-21
A genetic construct comprising a nucleotide sequence encoding a composite peptide; and at least one regulatory element configured to regulate expression of the composite peptide, wherein the composite peptide, when expressed, can modulate the activity of IL-15 and IL-21, and wherein the composite peptide comprises an amino acid sequence having 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).
Collectively, the claims cover a nucleotide-encoded composite peptide comprising at least two IL gamma-c-box D-helix regions and having at least 70% sequence identity to SEQ ID NO: 3 that inhibits or modulates IL-15 and IL-21 activity, implemented as a nucleotide sequence encoding the composite peptide, pharmaceutical compositions comprising nucleotide-encoded peptide conjugates or derivatives with a pharmaceutically acceptable carrier, and genetic constructs with regulatory elements configured to regulate expression.
Stated Advantages
Documented Applications
Treating an inflammatory respiratory disease by administering the pharmaceutical composition, where the inflammatory respiratory disease is selected from sinusitis, bronchitis, chronic obstructive pulmonary disease (COPD), and lung fibrosis.
Treating a gamma-cytokine-mediated disease by administering the pharmaceutical composition to a subject in need, where the gamma-cytokine-mediated disease is selected from 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, uvietis, inflammation of the eye, and graft-versus-host disease (GvHD).
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