Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases
Inventors
Sun, Chengzao • Frederick, Brian Troy • Somani, Sandeep • Bourne, Gregory Thomas • Patch, Raymond • Bhandari, Ashok
Assignees
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Publication Number
US-11845808-B2
Publication Date
2023-12-19
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-23R antagonist monocyclic peptides having an amino-acid sequence described by Formula (I) and related formulas, with position-dependent residue options and specific modified amino acids. The monocyclic peptide is cyclized to form a Pen-Pen disulfide bond, and the sequence definitions include residues such as Trp, 7-methyl tryptophan, 7 phenyl tryptophan, Lys(Ac), Phe(4-(2-aminoethoxy)), THP, and 3-pyridyl substituted alanine (3Pal).
The invention further specifies monocyclic peptides selected from SEQ ID NO:104, SEQ ID NO:158, and SEQ ID NO:247, again requiring cyclization via a Pen-Pen disulfide bond. These defined sequences include Pen residues and Lys(Ac), Phe(4-(2-aminoethoxy)), 2-Nal, THP, E, 3Pal, and Sarc, with SEQ ID NO:247 additionally incorporating (D)Arg.
The peptide inhibitor inhibits binding of IL-23 to its receptor (IL-23R). The disclosure also includes broader peptide inhibitor conjugation concepts with linkers and half-life extension moieties, including PEG based linkers, polyoxyethylene terminology, PEG-derived entities, and PEGylated isoGlu and βAla variants, in the context of IL-23/IL-23R targeting and treatment.
Claims Coverage
The independent claims cover monocyclic peptide inhibitors cyclized via a Pen-Pen disulfide bond, with one claim directed to a Formula (I) framework with defined residue options and another directed to specific monocyclic peptide sequences selected from SEQ ID NO:104, SEQ ID NO:158, and SEQ ID NO:247. Across the independent claims, there are two main inventive-feature groupings.
Formula (i) monocyclic peptide with Pen-pen disulfide cyclization
A monocyclic peptide comprising the amino acid sequence of Formula (I), with X7 being Trp, 7-methyl tryptophan, or 7 phenyl tryptophan; X10 being Phe(4-(2-aminoethoxy)); X12 being THP; and X15 being 3-pyridyl substituted alanine (3Pal), or a pharmaceutically acceptable salt thereof; wherein the monocyclic peptide is cyclized via a Pen-Pen disulfide bond.
Selected seq id monocyclic peptides with Pen-pen disulfide cyclization
A monocyclic peptide comprising the amino acid sequence selected from the group consisting of Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-(2-aminoethoxy))]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:104), Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-[Phe(4-(2-aminoethoxy))]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:158), and Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:247), or a pharmaceutically acceptable salt thereof; wherein the monocyclic peptide is cyclized via a Pen-Pen disulfide bond.
Overall, the inventive subject matter centers on IL-23R-targeting monocyclic peptide inhibitors defined either by a positionally specified Formula (I) or by selected explicit SEQ ID NO sequences, each cyclized via a Pen-Pen disulfide bond and including pharmaceutically acceptable salts.
Stated Advantages
Selectively inhibits IL-23/IL-23R signaling in the GI tract without blocking IL-6/IL-6R.
Does not antagonize IL-12 signaling.
Inhibits IL-23 binding to its receptor.
PEGylation is used for solubility, half-life, and reduced clearance.
Documented Applications
Treating an IL-23- or IL-23R-associated disease in a patient by administering an effective amount of the monocyclic peptide or a pharmaceutically acceptable salt, for conditions including inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, and psoriatic arthritis.
Treating or preventing IL-23 signaling-associated inflammatory diseases, including inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, and psoriatic arthritis.
Plaque psoriasis.
Ulcerative colitis.
Imaging or detection of intestinal inflammation using microPET with a labeled peptide.
Oral administration with higher GI exposure than blood.
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