Stabilized insulinotropic peptides and methods of use

Patent metadata

Field	Value
Publication number	US-9695224-B2
Application number	US-201615019678-A
Country	US
Kind code	B2
Filing date	Feb 9, 2016
Priority date	Jun 18, 2009
Publication date	Jul 4, 2017
Grant date	Jul 4, 2017

Abstract

The present invention provides stably crosslinked insulinotropic polypeptides having superior and unexpected benefits in the treatment of conditions involving abnormal glucose homeostasis, e.g., type 2 diabetes and conditions relating to type 2 diabetes. Such benefits include, but are not limited to, extended polypeptide half-life, enhanced alpha-helicity, improved thermal stability and protease resistance, increased functional activity and pharmacologic properties, improved bioavailability when administered by any route, and improved bioavailability and gastrointestinal absorption when delivered orally, as compared to the corresponding unmodified polypeptides. The invention also provides compositions for administering the polypeptides of the invention, as well as methods for preparing and evaluating the polypeptides of the invention.

First claim

What is claimed is:

1. A method for treating diabetes comprising administering a therapeutically effective amount of a cross-linked polypeptide comprising an alpha helix and one or more hydrocarbon staples, wherein each hydrocarbon staple covalently couples two non-natural amino acids within the alpha helix of said polypeptide, and wherein the cross-linked polypeptide comprises exenatide, gastric inhibitory polypeptide preprotein (GIPP), gastric inhibitory peptide (GIP), glucagon-like peptide-1 precursor (GLP-1P), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), GLP-1 (7-37), GLP-1-(7-36), liraglutide, taspoglutide, albiglutide or LY2189265.

2. The method of claim 1 , wherein the cross-linked polypeptide is exenatide.

3. The method of claim 1 , wherein the cross-linked polypeptide is administered via an oral delivery route.

4. The method of claim 1 , wherein the cross-linked polypeptide is administered via an injection-based route.

5. The method of claim 1 , wherein the cross-linked polypeptide is administered via an oral delivery route and wherein the level of bioavailable polypeptide delivered orally is about equivalent to the level of bioavailable polypeptide delivered intravenously.

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Walensky Loren D
• Bird Gregory

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K14/575

  Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695) · CPC title

• C07K14/605 Primary

  Glucagons · CPC title

• C07K14/57563

  Vasoactive intestinal peptide [VIP]; Related peptides · CPC title