Modified therapeutic agents, stapled peptide lipid conjugates, and compositions thereof

• US 10,039,809 B2
• Filed: 12/17/2014
• Issued: 08/07/2018
• Est. Priority Date: 12/18/2013
• Status: Active Grant

• Current Assignee: The Scripps Research Institute
• Original Assignee: The California Institute For Biomedical Research, The Scripps Research Institute
• Inventors: Shen, Weijun, Yang, Pengyu, Zou, Huafei, Schultz, Peter G.
• Primary Examiner(s): Ha, Julie
• Assistant Examiner(s): Hellman, Kristina M
• Application Number:
  US15/104,807
• Publication Number:
  US 20160317623A1
• Time in Patent Office: 1,329 Days
• Field of Search: None
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/2278 Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/543 Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0021 Intradermal administration, e.g. through microneedle arrays, needleless injectors mechanical aspects A61M
• CPC Class Codes: A61K 9/703 characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system

Abstract

Methods and compositions are provided for extending the half-life of a therapeutic agent. A modified therapeutic agent (mTA) comprises a therapeutic agent, a staple, and a half-life extending molecule. The mTAs disclosed herein may be used to treat a disease or a condition in a subject in need thereof.

Claims

1. A modified therapeutic agent (mTA) comprising a therapeutic agent comprising the amino acid sequence selected from the group consisting of SEQ ID NOs:

30-32 and 35-53, a staple, and a half-life extending molecule, wherein the therapeutic agent is covalently attached to the staple via two amino acid residues in the therapeutic agent;

the half-life extending molecule is covalently attached to the staple; and

the half-life of the mTA is longer than the half-life of the therapeutic agent alone.

2. The mTA of claim 1, wherein the half-life extending molecule comprises a lipid, a polyglycol region selected from

3. The mTA of claim 2, wherein the lipid is selected from a group consisting of sterols, bile acids, vitamin E, fatty di-acids, fatty acids, fatty amides, fatty amines, fatty alcohols, and derivatives thereof.

4. The mTA of claim 1, wherein at least one of the two amino acid residues is an amino acid addition or substitution on the therapeutic agent.

5. The mTA of claim 1, wherein each of the two amino acid residues is cysteine.

6. The mTA of claim 1, wherein the staple comprises a group selected from:

7. The mTA of claim 6, wherein the half-life extending molecule comprises a lipid, a polyglycol region selected from

8. The mTA of claim 7, wherein the half-life extending molecule comprises a lipid and a polyglycol region selected from

9. The mTA of claim 8, wherein the lipid is selected from a group consisting of sterols, bile acids, vitamin E, fatty di-acids, fatty acids, fatty amides, fatty amines, fatty alcohols, and derivatives thereof.

10. The mTA of claim 1, wherein the half-life of the mTA is 5-fold longer than the half-life of the therapeutic agent alone.

11. A pharmaceutical composition comprising the mTA of claim 1 and a pharmaceutically acceptable excipient.

12. The mTA of claim 6, wherein the staple comprises:

13. The mTA of claim 1, wherein the staple covalently attached to the half-life extending molecule is selected from the group consisting of: