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Publication Number
US-10030059-B2
Publication Date
2018-07-24
Expiration Date
Abstract
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. The disclosed peptides exhibit Simul-Block activity, inhibiting the activity of multiple γc-cytokine family members.
Core Innovation
The invention relates to composite peptides, or derivatives thereof, that comprise amino acid sequences of at least two interleukin (IL) protein gamma-c-box D helix regions. 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), and derivatives share at least 90% identity with SEQ ID NO: 3.
The composite peptide or the derivative inhibits the activity of at least IL-15 and IL-21. The peptide designs are described as composite peptide and peptide derivative constructs intended to target the common gamma-c subunit binding site (the "γc-box" in the cytokine D-helix) to inhibit multiple γc-family cytokines.
Stated implementations include "Simul-Block" activity directed to the shared γc-box/D-helix region, and peptide variants that include signal peptide and conjugation/stabilization options. Conjugation or stabilization is described using additional moieties at N-terminus, C-terminus, or side residues, and stabilizing/carrier proteins or moieties such as BSA/albumin, KLH, IgG Fc, scaffold proteins, metal ions, and PEG.
The document provides experimental evidence that BNZ-γc inhibits IL-15 and IL-9 signaling, including effects on proliferation and decreased STAT5 tyrosine phosphorylation. It also describes ex vivo efficacy in HAM/TSP cultures and broader disease-treatment contexts including GvHD, celiac disease, ATL, and LGL leukemia.
Claims Coverage
The document includes two independent claims. Across these independent claims, the coverage focuses on a defined composite peptide (SEQ ID NO: 3 and identity threshold) that inhibits IL-15 and IL-21 activity, and a pharmaceutical composition comprising a peptide conjugate of the same sequence (or a derivative) that similarly inhibits IL-15 and IL-21 activity.
Composite peptide from at least two IL gamma-c-box D helix regions that inhibits IL-15 and IL-21
A composite peptide, or a derivative thereof, comprising amino acid sequences of at least two interleukin (IL) gamma-c-box D helix regions, wherein the composite peptide comprises 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 a peptide sequence sharing at least 90% identity with SEQ ID NO: 3, and wherein the composite peptide or the derivative thereof inhibits the activity of at least IL-15 and IL-21.
Pharmaceutical composition with a peptide conjugate inhibiting IL-15 and IL-21
A pharmaceutical composition comprising a peptide conjugate, or a derivative thereof, wherein the peptide conjugate comprises 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 a peptide sequence sharing at least 90% identity with the amino acid sequence of SEQ ID NO: 3, and wherein the peptide conjugate or the derivative thereof inhibits the activity of at least IL-15 and IL-21.
Overall, claim coverage centers on SEQ ID NO: 3-based composite peptide or peptide conjugate/derivative constructs that share at least 90% identity and are defined to inhibit IL-15 and IL-21 activity, with optional composite enhancement features described in dependent claims.
Stated Advantages
Inhibits the activity of at least IL-15 and IL-21.
Targets the common gamma-c (γc) subunit binding site ("γc-box" in the cytokine D-helix) to inhibit multiple γc-family cytokines.
Decreases STAT5 tyrosine phosphorylation in the described evidence.
Reduces proliferation in the described evidence.
Documented Applications
Ex vivo efficacy in HAM/TSP cultures, including HAM/TSP ex vivo T-cell proliferation.
Therapeutic or treatment contexts described include GvHD, celiac disease, ATL, and LGL leukemia.
BNZ-γc is described in relation to inhibiting IL-15 and IL-9 signaling in the provided evidence context.
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