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Publication Number
US-10808009-B2
Publication Date
2020-10-20
Expiration Date
Abstract
Methods and compositions related to the selective, specific disruption of multiple ligand-receptor signaling interactions, such as ligand-receptor interactions implicated in disease, are disclosed. These interactions may involve multiple cytokines in a single receptor family or multiple ligand receptor interactions from at least two distinct ligand-receptor families. The compositions may comprise polypeptides having composite sequences that comprise sequence fragments of two or more ligand binding sites. The methods and compositions may involve sequence fragments of two or more ligand binding sites that are arranged to conserve the secondary structure of each of the ligands from which the sequence fragments were taken.
Core Innovation
The invention relates to therapeutic composite peptide conjugates that inhibit an activity of at least two cytokines selected from a family of cytokines that bind to a common receptor. The therapeutic composite peptide conjugate comprises a therapeutic composite peptide conjugated to a moiety, where the therapeutic peptide is 11-50 amino acids in length and includes a region 1-20 amino acids in length that aligns with a corresponding region of a single target ligand or receptor selected from specified SEQ ID NOs.
The disclosed peptide-antagonist designs emphasize composite polypeptides built from fragments of cytokine receptor-binding sites and conserved motifs derived from cytokine binding regions. The invention introduces γc-box-based peptide antagonists designed from conserved D-helix motifs of γc-family cytokines, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, with inhibition aimed at shared γc receptor-mediated signaling while avoiding off-target family members.
The disclosure extends γc-box-based concepts to other cytokine families, including IL-6 family cytokines and IL-17 family cytokines. It further describes cross-family and PEG-conjugated dual antagonists, including BNZ132-PEG-130, and reports selective inhibition of cytokine-induced proliferation and downstream signaling such as STAT5 phosphorylation.
Claims Coverage
The claims coverage centers on one independent claim directed to a therapeutic composite peptide conjugate that inhibits the activity of at least two cytokines sharing a common receptor, with the peptide constrained by length and alignment region features. Dependent claims refine conjugation moieties, conjugation locations, cytokine-family selections, named family members, and cosmetic-use framing.
Therapeutic composite peptide conjugate for inhibiting two cytokines binding a common receptor
A therapeutic composite peptide conjugate inhibits an activity of at least two cytokines selected from a family of cytokines that bind to a common receptor, and the therapeutic composite peptide is conjugated to a moiety.
Length-limited therapeutic composite peptide with aligned region
The therapeutic peptide is 11-50 amino acids in length and comprises a region 1-20 amino acids in length that aligns with a corresponding region of a single target ligand or receptor selected from specified SEQ ID NOs.
Conjugation moiety options for the therapeutic composite peptide conjugate
The conjugated moiety is selected from BSA/albumin, immunoglobulin/antibody fragment, Fc region of IgG, scaffold proteins, carbohydrates, and polyethylene glycol.
Where the peptide is conjugated on the moiety
The therapeutic composite peptide is conjugated at the N-terminus, C-terminus, and/or a side residue.
Cytokine-family selection for the composite peptide conjugate
The cytokine family is selected from the γc-family, IL-6 family, or IL-17 family of cytokines.
Specific cytokine member sets in γc, IL-6, and IL-17 families
The cytokine family includes the γc-family (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21), the IL-6 family (IL-6, IL-11, CNTF, CT-1, OSM, LIF, IL-27), and the IL-17 family (IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25), IL-17F).
Cosmetic use framing for the conjugate
The therapeutic composite peptide conjugate is used for cosmetic purposes.
The claims center on therapeutic composite peptide conjugates that inhibit multiple cytokines from a cytokine family sharing a common receptor, while constraining peptide size and requiring a defined 1-20 amino-acid alignment to a single target ligand or receptor from specified SEQ ID NOs. Dependent features further specify conjugation moieties, conjugation locations, selected cytokine-family members, and cosmetic-use framing.
Stated Advantages
Selectively inhibits cytokine-induced activity and downstream signaling such as STAT5 phosphorylation.
Documented Applications
Cosmetic use.
[procedural detail omitted for safety] Documented disease indications are listed for γc-cytokine blockade, including Adult T-cell Leukemia (ATL), Celiac Disease (CD)/refractory CD, Inflammatory Bowel Disease (IBD), Rheumatoid Arthritis (RA), and Asthma/COPD.
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