Peptides and compounds that bind to the IL-5 receptor

• US 20060014680A1
• Filed: 07/13/2004
• Published: 01/19/2006
• Est. Priority Date: 07/13/2004
• Status: Abandoned Application

• Current Assignee: Ashok Bhandari, Caiding Xu, Chris Holmes, Lydie Yang, Min-Jia Chen, Palani Balu, Peter Schatz
• Original Assignee: Ashok Bhandari, Caiding Xu, Chris Holmes, Lydie Yang, Min-Jia Chen, Palani Balu, Peter Schatz
• Inventors: Balu, Palani, Bhandari, Ashok, Schatz, Peter, Holmes, Chris, Xu, Caiding, Chen, Min-Jia, Yang, Lydie
• Application Number:
  US10/890,546
• Publication Number:
  US 20060014680A1
• Time in Patent Office: Days
• US Class Current: 514/1.700
• CPC Class Codes: A61K 38/00 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 Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

New IL-5 receptor antagonists and methods of use are described, e.g., in the treatment of IL-5 receptor mediated disorders. The compounds include both monomers and dimers that were identified using one or more of alanine scans, lysine scans, other residue substitutions, and C- and N-terminal truncations and additions vis a vis the core sequence Val Asp Glu Cys Trp Arg Ile Ile Ala Ser His Thr Trp Phe Cys Ala Glu Glu-AF17121 (SEQ ID NO: 1) and shorter sequences and derivatives thereof.

Claims

1. A compound comprising a peptide sequence 12 to 40 amino acid residues in length, or pharmaceutically acceptable salt or ester thereof, said peptide sequence or pharmaceutically acceptable salt or ester thereof comprising a variation of sequence Ac-Val Asp Glu Cys Trp Arg Ile Ile Ala Ser His Thr Trp Phe Cys Ala Glu Glu-NH2 (SEQ ID NO:

1) wherein said variation comprises one or more of;

an alanine substitution at one or more of residues 1, 2, 3, 10, and 13;

a core sequence comprising residues 3-17 of SEQ ID NO;

1 and having a lysine substitution at one or more of residues 3, 10, 12, 15, and 16;

a substitution, truncation or addition to within 3 residues of the C- or N-terminus and having a C- or N-terminal lysine or AHX residue;

a core sequence comprising residues 3-17 of SEQ ID NO;

1, a C-terminal lysine residue substituted for residue 17 and a proline, aspartic acid, or D form of glutamic acid (e) substituted for residue 3;

the C-terminus is deamidated;

the N-terminus is deacylated;

an intramolecular cysteine-cysteine disulfide bridge;

an intermolecular cysteine-cysteine disulfide bridge that is present as part of a dimer; and

a Lys-Lys or AHX-AHX bridge is present as part of a dimer.

2. The compound of claim 1 that comprises an intramolecular disulfide bridge and that is selected from the following group of compounds:

3. The compound of claim 2 wherein said compound is a monomer.

4. The compound of claim 2 wherein said compound is a dimer.

5. The compound of claim 4 wherein said dimer is a homodimer.

6. The compound of claim 4 wherein said dimer is fashioned using a bifunctional linker, optionally one selected from the group consisting of:

7. A pharmaceutical composition comprising one or more compounds or pharmaceutically acceptable salts according to any one of claims 1-6, further comprising one or more pharmaceutically acceptable excipients, optionally further comprising one or more antihistamines, and optionally further still comprising one or more anti-IL9 receptor antibodies or antagonists.

8. A method of ameliorating or preventing an IL-5 receptor mediated disorder comprising administering to a patient in need thereof a pharmaceutically effective amount of one or more compounds according to any one of claims 1-6;

and optionally further comprising administering one or more members selected from the group of antihistamines and anti-IL9 receptor antibodies or antagonists.

9. The method of claim 8 wherein said compound is accompanied by one or more pharmaceutically acceptable excipients.

10. The method of claim 8 wherein said affliction is asthma.

11. The method of claim 8 wherein said patient is human.

12. The method of claim 8 wherein said one or more compounds is administered in tandem or sequentially with a beta-adrenergic agonist compound.

13. The method of claim 12 wherein said beta-adrenergic agonist compound is selected from the group consisting of albuterol, terbutaline, formoterol, fenoterol, and prenaline.

14. The method of claim 8 or 12 wherein said compound is administered in conjunction with an anti-inflammatory corticosteroid.

15. The method of claim 14 wherein said anti-inflammatory corticosteroid is selected from the group consisting of beclomethasome, triamcinolone, flurisolide, and dexamethasone.

16. The method of claim 8 wherein the compound is administered in conjunction with ipratropium bromide.