Compositions comprising glucagon analogs and methods of making and using the same
Inventors
Shandler, Scott • Gellman, Samuel H.
Assignees
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Publication Number
US-9790262-B2
Publication Date
2017-10-17
Expiration Date
Abstract
This invention relates to novel compositions comprising analogs of glucagon, wherein the analog comprises an α-amino acid and at least one β-amino acid. Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused by dysfunctional biochemical or biological pathways, including diabetes and other metabolic disorders. The compositions and methods of this invention are particularly useful to identify novel therapeutic modulators of in-vivo receptor activity with extended half-lives and relevant bioactivity as compared to the naturally translated polypeptides upon which the analogs are derived.
Core Innovation
The invention relates to peptides comprising the amino acid sequence YXEGTFTSDYSIYLDKQAAXEFVNWLLA (SEQ ID NO: 168) or a pharmaceutically acceptable salt thereof, where X is the amino acid α-aminoisobutyric acid (Aib). The peptide includes at least four α amino acids in the amino acid sequence that are replaced with cyclic β amino acids, and it comprises at least two contiguous patterns of α and β amino acids selected from the listed pattern sets.
A related peptide comprises an amino acid sequence that is at least 96% homologous to YXEGTFTSDYSIYLDKX1AAXX1FVX2WLLX1G (SEQ ID NO: 41) or a pharmaceutically acceptable salt thereof. In this framework, X is α-aminoisobutyric acid (Aib), X1 is a cyclic β amino acid ACPC, and X2 is a cyclic β amino acid APC.
The disclosure also describes glucagon/GIP/GLP-1 analog compositions and co-agonists, including glucagon/GIP co-agonists and GIP/GLP-1 co-agonists, as tri-agonists. It includes pharmaceutical compositions, kits, administration devices, pharmaceutically acceptable carriers and excipients, and manufacturing concepts for GIP and/or GLP-1 analogs using non-natural α/β amino acids with cyclic residues.
Claims Coverage
The provided independent claims cover two peptide scopes: one centered on SEQ ID NO: 168 with cyclic β amino acid substitution patterns, and one centered on a peptide at least 96% homologous to SEQ ID NO: 41 with defined cyclic β amino acids. Across the claims, the coverage emphasizes α/β peptide sequence constraints and the identity of key residues for the SEQ ID NO: 41 framework.
Cyclic β amino acid substituted α/β peptide sequence
A peptide comprising the amino acid sequence YXEGTFTSDYSIYLDKQAAXEFVNWLLA (SEQ ID NO: 168) or a pharmaceutically acceptable salt thereof, where X is α-aminoisobutyric acid (Aib), wherein at least four α amino acids in the amino acid sequence are replaced with cyclic β amino acids, and wherein the peptide comprises at least two contiguous patterns of α and β amino acids chosen from the listed pattern sets.
At least 96% homologous peptide with defined cyclic β amino acids ACPC and APC
A peptide that comprises an amino acid sequence that is at least 96% homologous to YXEGTFTSDYSIYLDKX1AAXX1FVX2WLLX1G (SEQ ID NO: 41) or a pharmaceutically acceptable salt thereof, wherein X is α-aminoisobutyric acid (Aib), X1 is the cyclic β amino acid ACPC, and X2 is the cyclic β amino acid APC.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the peptide of claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
Treatment of metabolic disorders by administering the peptide-containing pharmaceutical composition
A method of treating weight gain, obesity, elevated insulin levels, hyperglycemia, or metabolic disorders by administering the pharmaceutical composition to a subject in need.
Kit with separate container for peptide and vehicle
A kit including a first container containing the peptide and a second container containing a vehicle for administering the peptide.
Overall, the claim coverage is directed to peptides with defined α-to-cyclic β replacement and contiguous α/β patterning, and to closely related peptides defined by a 96% homology relationship to SEQ ID NO: 41 with Aib, ACPC, and APC substitutions. The dependent claims extend to pharmaceutical compositions, treatment methods, and kit embodiments.
Stated Advantages
Reduced DPP-IV degradation.
Enhanced selectivity relative to wild-type ligands.
An unexpected enhanced weight-reduction effect of GIP+GLP-1 versus GLP-1 alone is reported in the document.
Documented Applications
Treating conditions including weight gain, obesity, elevated insulin levels, hyperglycemia, or metabolic disorders by administering the pharmaceutical composition to a subject in need.
Therapeutic treatment of hyperglycemia and diabetes, including Type I/II and gestational diabetes.
Therapeutic treatment for weight loss and obesity.
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