Analogues of hepcidin mimetics with improved in vivo half lives
Inventors
Bourne, Gregory Thomas • Smythe, Mark Leslie • Frederick, Brian Troy • Bhandari, Ashok
Assignees
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Publication Number
US-11472842-B2
Publication Date
2022-10-18
Expiration Date
Abstract
The present invention provides hepcidin analogues with improved in vivo half lives, and related pharmaceutical compositions and methods of use thereof.
Core Innovation
The disclosure relates to hepcidin analogue peptide conjugates in which a hepcidin analogue is modified to provide half-life extension. The analogues are provided as monomers and disulfide-linked peptide dimers, and may be provided as a pharmaceutically acceptable salt or solvate thereof.
The modification uses lipophilic substituents and polymeric moieties conjugated to amino-acid side chains, including Lys side-chain conjugation. The half-life extension moieties include PEG architectures such as PEG2, PEG3, PEG8, PEG11, and PEG25, as well as lipophilic groups and related derivatives such as palmitoyl, lauric, stearic, isovaleric acid, biotin, IsoGlu, OEG, Ahx, and disulfide bridges or linker moieties.
The disclosed analogues are described in a functional context involving ferroportin binding/internalization and ferroportin degradation leading to reduced serum iron. The disclosure further describes treatment embodiments for diseases of iron metabolism, including hemochromatosis, iron overload, hereditary hemochromatosis, hepcidin deficiency, transfusional iron overload, iron-loading anemias, and thalassemia, including thalassemia intermedia, alpha thalassemia, and β-thalassemia.
Claims Coverage
The independent claims define two inventive features. Across the independent claims, the inventive subject matter centers on selected hepcidin analogue polypeptide sequences or structures with half-life extension moieties, and on a pharmaceutical composition comprising the hepcidin analogue.
Selected hepcidin analogue polypeptide sequence or structure with half-life extension moiety
A hepcidin analogue comprising a polypeptide sequence or structure selected from specified hepcidin analogue constructs, including Lys-linked moieties such as isoGlu-Palm, isoGlu-biotin, isoGlu-Isovaleric acid, PEG2-Palm, PEG11-Palm, PEG11-Lauric acid, PEG11-Myristic acid, Ahx-Palm, isoGlu-Ahx-Palm, OEG-OEG-isoGlu-(C18-diacid), and related monomeric, dimeric, or linker-containing forms, or a pharmaceutically acceptable salt or solvate thereof.
Pharmaceutical composition comprising the selected hepcidin analogue
A pharmaceutical composition comprising the hepcidin analogue or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable carrier, excipient, or vehicle.
Claim coverage focuses on hepcidin analogues defined by selected polypeptide sequence or structure variants with half-life extension moieties and linker architectures, together with their use in a pharmaceutical composition.
Stated Advantages
Extended in vivo half-life.
Reduced clearance.
Albumin binding.
Reduction of serum iron via ferroportin binding/internalization and ferroportin degradation.
Documented Applications
Treatment of diseases of iron metabolism.
Treatment of hereditary hemochromatosis, hemochromatosis, iron overload, hepcidin deficiency, transfusional iron overload, iron-loading anemias, and thalassemia, including thalassemia intermedia, alpha thalassemia, and β-thalassemia.
Administration embodiments include oral and subcutaneous routes.
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