Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases
Inventors
Sun, Chengzao • Frederick, Brian Troy • Somani, Sandeep • Bhandari, Ashok • Patch, Raymond • Barros, Stephanie • Ingenito, Raffaele • Costante, Roberto • Branca, Danila • Bianchi, Elisabetta
Assignees
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Publication Number
US-12018057-B2
Publication Date
2024-06-25
Expiration Date
Abstract
The present invention provides novel peptide inhibitors of the interleukin-23 receptor, and related compositions and methods of using these peptide inhibitors to treat or prevent a variety of diseases and disorders, including inflammatory bowel diseases.
Core Innovation
The invention relates to IL-23 receptor (IL-23R) antagonist peptides that inhibit IL-23 binding to IL-23R. The disclosed peptides are cyclized via a Pen–Pen disulfide bond and are defined by specific amino-acid sequence formulas and multiple SEQ ID NO variants. The peptides include defined amino-acid building blocks, optional substitutions and analogs, and pharmaceutically acceptable salts.
The core peptide structure is presented in multiple cyclized variants, including sequences defined by SEQ ID NOs 33–37, 38–39, 10, 13–15, 18, 26, 33, 51–61, 105–106, and 125–137 as listed. The scope also describes N-terminal capping moieties, side-chain modifications, and residue-level changes such as different carboxylic-acid termini, lysine substitutions, and other variable positions within the peptide frameworks.
The disclosure further describes peptide monomers and peptide dimers with structural formulas, including Pen–Pen disulfide bonds and Abu–Cys thioether bonds, as well as linker moieties such as cysteine/lysine/PEG linker moieties and DIG and PEG linkers. The invention is framed in pharmaceutical and therapeutic context for IL-23 signaling-associated inflammatory diseases, with reference to inflammatory bowel disease, Crohn’s disease, ulcerative colitis, and psoriasis.
Claims Coverage
The partial content provides independent claim coverage directed to cyclized IL-23R antagonist peptides. The inventive features center on Pen–Pen disulfide-cyclized peptide sequences defined by listed SEQ ID NO variants, with pharmaceutically acceptable salts, and related structural scope for peptide monomers and dimers.
Pen–Pen disulfide cyclized IL-23R antagonist peptide sequences
A cyclized peptide is cyclized via a Pen–Pen disulfide bond, wherein the peptide is defined by the listed sequence formulas for the specified SEQ ID NOs and includes a pharmaceutically acceptable salt thereof.
Pharmaceutically acceptable salts of cyclized peptides
A pharmaceutically acceptable salt thereof is included for the cyclized peptide defined by the Pen–Pen disulfide cyclized sequence.
The claim coverage is centered on Pen–Pen disulfide cyclized IL-23R antagonist peptide sequences with explicit SEQ ID NO variants and includes pharmaceutically acceptable salts. The broader structural descriptions also mention peptide dimers, linkers, and additional sequence variants within the same peptide framework.
Stated Advantages
Inhibits IL-23 binding to IL-23R.
Improved solubility.
Extended in vivo half-life.
Reduced renal clearance.
Improved bioavailability.
Half-life is increased, qualitatively stated as ≥100% to ≥500%.
Improved epithelial permeability and lamina propria retention.
Documented Applications
Treating inflammatory bowel disease, including Crohn’s disease and ulcerative colitis.
Treating psoriasis.
Treating psoriatic arthritis.
Treating a subject with an effective amount of the cyclized peptide or a pharmaceutically acceptable salt for a broad set of enumerated diseases.
IL-23R antagonism via competitive binding assays to human and rat IL-23R.
Functional inhibition of IL-23 signaling assessed by pSTAT3 assays in DB cells and PBMCs.
NK cell inhibition assay activity testing for cyclized peptides.
Treating other enumerated inflammatory, immune, gastrointestinal, and related conditions.
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