Compositions and methods for modulating γ-c-cytokine activity
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Publication Number
US-11834519-B2
Publication Date
2023-12-05
Expiration Date
Abstract
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 and/or peptide derivative antagonists based on the consensus γc-subunit binding site to inhibit γc-cytokine activity are described. Also described are peptide and/or peptide derivative antagonists exhibiting Simul-Block activity, and inhibiting the activity of multiple γc-cytokine family members.
Core Innovation
The invention relates to γc-family cytokine (interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, IL-21) antagonist peptides/derivatives designed from a conserved γc-subunit-binding D-helix “γc-box” motif. The approach uses a consensus γc-subunit-binding site formed by a γc-box D-helix region and builds composite peptides comprising amino acid sequences from at least two IL protein γc-box D-helix regions.
The composite peptides are defined by an amino-acid sequence motif Xaa Phe Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gln (SEQ ID NO: 2), with positional constraints at specific residues. The document specifically identifies BNZ-γ (SEQ ID NO: 1) as an example composite peptide/derivative sequence, and describes nucleic-acid/genetic-construct embodiments encoding such composite peptides.
Inhibitory activity is reported for the γc-box composite peptide BNZ-γ, including suppression of IL-15 and IL-9 signaling/proliferation, including reduced STAT5 phosphorylation, and ex vivo inhibition of HAM/TSP patient T-cell spontaneous proliferation with effects on activation/proliferation markers. The disclosed concept is positioned as multi-cytokine blockade via γc-subunit binding competition (“Simul-Block”), aimed at γc-cytokine-mediated diseases and related indications.
Claims Coverage
Independent claims cover three main categories: a nucleotide sequence encoding a composite peptide with a defined γc-box D-helix-derived motif, a pharmaceutical composition including a nucleotide sequence encoding a peptide conjugate with the same motif and γc-cytokine inhibitory activity, and a genetic construct with regulatory elements controlling expression of the composite peptide inhibiting multiple γc-cytokines. Overall, the inventive features are centered on the γc-box D-helix-derived composite peptide motif (SEQ ID NO: 2), multi-γc-cytokine inhibition, and embodiments as nucleotide/genetic constructs and pharmaceutical compositions.
Composite peptide motif derived from γc-box D-helix regions
A nucleotide sequence encoding a composite peptide that comprises amino acid sequences of at least two interleukin (IL) protein γc-box D-helix regions, wherein the composite peptide comprises an amino acid sequence Xaa Phe Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gln (SEQ ID NO: 2) with position rules for Xaa at positions 1, 4, 5, 7, and 9.
Multi-γc-cytokine inhibition by the composite peptide
The nucleotide sequence encodes a composite peptide that 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, and IL-21.
Pharmaceutical composition with a nucleotide-encoded peptide conjugate
A pharmaceutical composition comprising a nucleotide sequence encoding a peptide conjugate and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof, wherein the peptide conjugate comprises an amino acid sequence Xaa Phe Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gln (SEQ ID NO: 2) with position rules for Xaa at positions 1, 4, 5, 7, and 9.
Genetic construct with regulated expression of the composite peptide
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 comprises an amino acid sequence Xaa Phe Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gln (SEQ ID NO: 2) with position rules for Xaa at positions 1, 4, 5, 7, and 9.
Inhibition of two or more γc-cytokines upon expression
When expressed, the composite peptide can inhibit the activity of two or more γc-cytokines selected from the group consisting of IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.
The independent claims jointly define a composite peptide/peptide conjugate motif based on γc-box D-helix regions (SEQ ID NO: 2), require inhibition of at least two selected γc-cytokines (IL-2/IL-4/IL-7/IL-9/IL-15/IL-21), and claim embodiments as a nucleotide sequence, a pharmaceutical composition with a pharmaceutically acceptable carrier, and a genetic construct with regulatory elements controlling expression.
Stated Advantages
Suppresses IL-15 and IL-9 signaling/proliferation, including reduced STAT5 phosphorylation.
Inhibits ex vivo HAM/TSP patient T-cell spontaneous proliferation.
Provides multi-cytokine blockade described as “Simul-Block” via γc-subunit binding competition.
Documented Applications
Therapeutic uses across γc-cytokine-mediated diseases, including HTLV-1-associated HAM/TSP-associated diseases and Adult T-cell leukemia.
Use in inflammatory respiratory diseases.
Cosmetic/skin-care applications, including acne, hair loss, sunburn, nail maintenance, and anti-aging.
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