Oral peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory bowel diseases
Inventors
Bhandari, Ashok • Bourne, Gregory Thomas • Cheng, Xiaoli • Frederick, Brian Troy • Zhang, Jie • Patel, Dinesh V. • Liu, David
Assignees
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Publication Number
US-11884748-B2
Publication Date
2024-01-30
Expiration Date
Abstract
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 disease, are disclosed.
Core Innovation
The invention relates to a pharmaceutical composition comprising a peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent. The peptide inhibitor is selected from defined cyclized peptide sequences represented by SEQ ID NO examples, and the peptides are described as inhibiting IL-23 binding to IL-23R.
A central structural feature is cyclization via a thioether bond between an Abu residue and a C residue. The disclosure further describes oral peptide inhibitor monomers and peptide dimers, including homodimers and heterodimers, and also describes intramolecular cyclization via a thioether bond and/or disulfide bond, together with linker moiety concepts for dimerization and conjugation.
The description further characterizes peptide IL-23R inhibitor constructs in terms of linker and moiety components that support dimerization and/or conjugation, including amino acid linkers such as amino diacetic acid/iminodiacetic acid (IDA) and N-acetyl-IDA/β-Ala-IDA, PEG-based linkers, and biotin-containing conjugates such as PEG4-biotin, IDA-biotin, and Lys-biotin variants. The partial content also describes IL-23/IL-23R-binding peptide inhibitors associated with inhibitory activity, including IC50 data and cellular signaling inhibition readouts.
Claims Coverage
The independent claim coverage includes one claim family member and centers on a pharmaceutical composition comprising an IL-23 receptor peptide inhibitor selected from a defined group of cyclized peptide sequences, with a pharmaceutically acceptable carrier, excipient, or diluent. The inventive features are the composition, the defined peptide selection, and cyclization via a thioether bond between Abu and C.
Pharmaceutical composition with IL-23R peptide inhibitor
A pharmaceutical composition comprising a peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
Peptide inhibitor selected from defined cyclized sequences
The peptide inhibitor is selected from a group consisting of defined cyclized peptide sequences identified by SEQ ID NO examples.
Thioether cyclization between Abu and C
The peptide inhibitor is cyclized via a thioether bond between Abu and C.
The claim coverage focuses on pharmaceutical compositions containing IL-23R peptide inhibitors selected from specific cyclized sequence examples, together with pharmaceutically acceptable carrier/excipient/diluent, and explicitly requiring cyclization via a thioether bond between Abu and C.
Stated Advantages
Inhibiting IL-23 binding to IL-23R.
Selective IL-23R antagonism without blocking the IL-6/IL-6R pathway.
Does not block the IL-12 pathway.
GI stability with reduced proteolysis.
Reduced redox susceptibility.
Luminal targeting via GI-restricted delivery (oral GI-restricted localization).
In vivo efficacy in a TNBS rat colitis model comparable to anti-IL-23p19 mAb.
Enhanced half-life based on albumin binding and reduced clearance.
Enhanced permeability.
Documented Applications
Pharmaceutical compositions comprising an IL-23 receptor peptide inhibitor for use as IL-23 binding inhibitors.
Treating or preventing IL-23-associated inflammatory diseases, especially inflammatory bowel disease, including ulcerative colitis and Crohn’s disease.
Assessment in a TNBS-induced colitis (rat model) for IL-23-associated inflammation.
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