Long acting peptide tyrosine tyrosine (PYY) analogs and methods of use
Inventors
Blackwell, William • Srivastava, Ved P. • Way, James M.
Assignees
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Publication Number
US-12122816-B2
Publication Date
2024-10-22
Expiration Date
Abstract
This invention relates to isolated polypeptides that are long acting analogs of human PYY. The disclosed PYY analog polypeptides have beneficial physicochemical properties relative to endogenous PYY and known synthetic PYY analog polypeptides, such as longer (i.e., “long-acting”) elimination half-lives (t1/2), and improved solubility and thermal stability. This invention also relates to methods of using presently disclosed PYY analog polypeptides in a variety of therapeutic indications, as well as methods of producing the same. The disclosed PYY analog polypeptides are particularly useful in methods of treating metabolic diseases or disorders, such as type 2 diabetes, treating obesity, and providing weight loss, and in methods of treating nonalcoholic fatty liver disease (NAFLD) and/or nonalcoholic steatohepatitis (NASH).
Core Innovation
The invention relates to a pharmaceutical composition comprising an isolated polypeptide having the amino acid sequence of SEQ ID NO: 90, or a pharmaceutically acceptable salt thereof, with multiple residue positions defined by allowed alternatives. The polypeptide optionally comprises at least one residue covalently bound to a lipophilic substituent, optionally via a spacer, and the composition is formulated for injection, oral administration, or for administration via an implantable delivery device.
The polypeptide further optionally comprises a lactam bridge formed via an amide bond between side chains of a lysine and an aspartic acid or between side chains of a lysine and a glutamic acid, with the residues forming the lactam bridge located at defined positions. When specified positions are set such that X8 or X20 are k, a D-lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer.
The structural embodiments define lipophilic substituents connected to the polypeptide through a spacer using multiple spacer-lipophilic group formulae and bivalent bridging spacer moieties. The spacer definitions use selected values for Y and Z and defined linker-length parameters, and the bridging spacer moieties are described as forming covalent bridges between amino groups on the polypeptide and carbonyl groups on the lipophilic substituent.
Claims Coverage
1 independent claim is explicitly provided. The claim includes multiple inventive features: an isolated polypeptide of SEQ ID NO: 90 with defined residue-position allowances, optional covalent lipophilic substitution optionally via a spacer including a D-lysine option, an optional lysine–aspartic/glutamic lactam bridge at defined positions, and formulation for injection, oral administration, or administration via an implantable delivery device.
Pharmaceutical composition with isolated SEQ ID NO: 90 polypeptide for multiple administration routes
A pharmaceutical composition formulated for injection, oral administration, or via an implantable delivery device comprising an isolated polypeptide comprising the amino acid sequence of SEQ ID NO: 90, or a pharmaceutically acceptable salt thereof, with multiple specified residue position rules.
Optional covalent lipophilic substitution at lysine or D-lysine residues
When specified positions are set as lysine, or when X8 or X20 are k for the D-lysine case, a lysine residue or a D-lysine residue is optionally covalently bound to a lipophilic substituent, optionally via a spacer, with the proviso that the polypeptide comprises at least one residue covalently bound to a lipophilic substituent.
Optional lysine–aspartic/glutamic lactam bridge at defined positions
The polypeptide optionally further comprises a lactam bridge formed via an amide bond between the side chains of a lysine and an aspartic acid or between the side chains of a lysine and a glutamic acid, wherein the residues that form the lactam bridge are located at positions X9 and X13 or at positions X16 and X20 or at positions X22 and X26.
Spacer defined by formula II with Y and Z options
A lipophilic substituent is covalently bound through a spacer defined by Formula II, with specific allowable choices for spacer components Y and Z and defined linker parameters.
The independent claim covers pharmaceutical compositions containing an isolated SEQ ID NO: 90 polypeptide with defined residue-position allowances, optional covalent lipophilic substitution optionally via a spacer, and an optional lysine–aspartic/glutamic lactam bridge at specified positions, with delivery by injection, oral administration, or an implantable delivery device.
Stated Advantages
Longer elimination half-lives.
Improved solubility.
Improved thermal stability.
Therapeutic activity as PYY receptor agonists on NPY1R, NPY2R, NPY4R, and NPY5R.
Provides weight loss or suppresses appetite.
Lipophilic conjugation prolongs action by promoting albumin binding and delayed renal clearance.
Documented Applications
Metabolic indications including type 2 diabetes, obesity/weight loss, and NAFLD and/or NASH.
Evaluation contexts including weight loss, HbA1c, food intake/body weight, and combination effects with long-acting GLP-1 analogs.
Administration via osmotic mini-pumps or an implantable delivery device for long duration dosing.
Treatment of obesity, diabetes, NAFLD, or NASH using the pharmaceutical composition.
Combination therapy with GLP-1 receptor agonists.
Administration via an implantable osmotic delivery device for steady-state continuous delivery.
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