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Publication Number
US-10030058-B2
Publication Date
2018-07-24
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 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.
Core Innovation
The invention describes peptide antagonists that target the shared γc-subunit binding site (the γc-box) of γc-family cytokines. The disclosed approach inhibits multiple γc-family cytokines by blocking the γc-cytokine/γc-subunit interaction, including IL-15/IL-21 activity modulation. The peptide embodiments include a composite peptide corresponding to SEQ ID NO:3 and a derivative peptide referred to as BNZ-γc corresponding to SEQ ID NO:1, and the γc-box core motif is associated with SEQ ID NO:2.
The background problem addressed is that antibody strategies are described as poorly effective and impractical, motivating alternative strategies for γc-family cytokine inhibition. The disclosed rationale is that blocking γc-cytokine/γc-subunit interactions can suppress downstream signaling, including reduced STAT5 phosphorylation in the Jak3/STAT5 pathway. The concept is further supported by ex vivo/in vitro evidence showing inhibition of IL-15/IL-9-mediated proliferation and inhibition of HAM/TSP patient T-cell spontaneous proliferation.
The invention further provides kit and composition concepts for using a therapeutically effective amount of a peptide conjugate or derivative together with a pharmaceutically acceptable carrier, diluent, or excipient. The kit is described for treating γc cytokine-mediated disease categories, including HTLV-1-associated HAM/TSP, inflammatory respiratory diseases, and cosmetic conditions, and as combinations thereof. The peptide conjugates are configured to modulate the activity of two or more γc-cytokines selected from IL-15 and IL-21, including derivatives sharing at least 90% identity with SEQ ID NO:3.
Claims Coverage
Independent claim clm-00001 covers a treatment kit containing a peptide conjugate or derivative that modulates two or more γc-cytokines selected from IL-15 and IL-21, with defined peptide sequence requirements, for multiple disease categories. It includes core kit composition elements and specifies peptide identity and derivative scope anchored to SEQ ID NO:3.
Kit for treating γc cytokine-mediated disease with IL-15/IL-21 modulating peptide conjugate
A kit for treating a condition in a patient, where the condition is a γc cytokine-mediated disease, an HTLV-1-associated HAM/TSP-associated disease, an inflammatory respiratory disease, a cosmetic condition, or a combination thereof, the kit comprising a pharmaceutical composition with a therapeutically effective amount of a peptide conjugate or derivative and a pharmaceutically acceptable carrier, diluent, or excipient.
Peptide conjugate modulates IL-15 and IL-21 activities
The peptide conjugate or derivative modulates the activity of two or more γc-cytokines selected from the group consisting of interleukin (IL)-15 and IL-21.
Composite peptide sequence requirement for SEQ ID NO:3 and derivatives with at least 90% identity
The peptide conjugate 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 the derivative comprises a peptide sequence sharing at least 90% identity with the amino acid sequence of SEQ ID NO:3.
Overall, the claim coverage centers on a disease-treating kit using a peptide conjugate that modulates multiple γc-family cytokines by targeting IL-15 and IL-21, with a specified composite sequence (SEQ ID NO:3) and derivative sequence identity constraint (at least 90% identity to SEQ ID NO:3).
Stated Advantages
Antibody strategies are described as poorly effective and impractical.
Blocking γc-cytokine/γc-subunit interactions can suppress downstream signaling, including reduced STAT5 phosphorylation in the Jak3/STAT5 pathway.
Ex vivo/in vitro evidence shows inhibition of IL-15/IL-9-mediated proliferation and inhibition of HAM/TSP patient T-cell spontaneous proliferation.
Documented Applications
Treating γc cytokine-mediated disease.
Treating HTLV-1-associated HAM/TSP.
Treating inflammatory respiratory diseases.
Treating cosmetic conditions.
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