MODIFIED IL-4 MUTEIN RECEPTOR ANTAGONISTS

• US 20090010874A1
• Filed: 11/14/2007
• Published: 01/08/2009
• Est. Priority Date: 08/29/2003
• Status: Active Grant

• Current Assignee: Aerovance, Inc.
• Original Assignee: Aerovance, Inc.
• Inventors: Pan, Clark, Tomkinson, Adrian, Wong, Teresa Mo-Fun, Roczniak, Steve, Greve, Jeffrey Michael, Longphre, Malinda, Yung, Stephanie L.
• Granted Patent: US 7,785,580 B2
• Time in Patent Office: Days
• US Class Current: 424/85.200
• 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: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: C07K 14/5406 IL-4
• CPC Class Codes: C07K 14/7155 for interleukins [IL]

Abstract

This invention relates to modified IL-4 mutein receptor antagonists comprising an IL-4 mutein receptor antagonist coupled to polyethylene glycol. Related formulations and dosages and methods of administration thereof for therapeutic purposes are also provided. These modified IL-4 mutein receptor antagonists, compositions and methods provide a treatment option for those individuals afflicted with a respiratory disorder such as asthma by inhibiting IL-4 and IL-13-mediated airway hyperresponsiveness and eosinophilia. More particularly, these antagonists have an increased duration of effect versus unmodified IL-4RA by virtue of a greater plasma half-life.

Claims

1. A modified IL-4 mutein receptor antagonist coupled to a non-protein polymer at an amino acid residue at position 37, 38, or 104 of IL-4, wherein the amino acids at positions 13, 121 and 124 are aspartic acid, and wherein the non-protein polymer is polyethylene glycol, polypropylene glycol or a polyoxyalkylene.

2. The modified IL-4 mutein receptor antagonist of claim 1, comprising the amino acid sequence as set forth in SEQ ID NO:

32.

3. The modified IL-4 mutein receptor antagonist of claim 1, wherein the non-protein polymer is polyethylene glycol, polypropylene glycol or a polyoxyalkylene.

4. The modified IL-4 mutein receptor antagonist of claim 1, wherein the non-protein polymer is polyethylene glycol.

5. The modified IL-4 mutein receptor antagonist of claim 4, wherein the polyethylene glycol is linear.

6. The modified IL-4 mutein receptor antagonist of claim 4, wherein the polyethylene glycol is branched.

7. The modified IL-4 mutein receptor antagonist of claim 6, wherein the polyethylene glycol is about 3 kD to 50 kD.

8. The modified IL-4 mutein receptor antagonist of claim 7, wherein the polyethylene glycol is 40 kD.

9. A pharmaceutical composition comprising:

a) the modified IL-4 mutein receptor antagonist of claim 1; and

b) a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising:

a) the modified IL-4 mutein receptor antagonist of claim 8; and

b) a pharmaceutically acceptable carrier.

11. The modified IL-4 mutein receptor antagonist of claim 1, wherein the modified mutein receptor antagonist binds to the IL-4 receptor alpha chain with a K_d of about 0.1 nM to about 10 μ

M, about 0.5 nM to about 1 μ

M, or about 1.0 nM to about 100 nM.

12. The modified IL-4 mutein receptor antagonist of claim 1, wherein the modified IL-4 mutein receptor antagonist inhibits the proliferative response of TF-1 cells to IL-4 with an IC₅₀ of about 0.1 nM to about 10 μ

M, about 0.5 nM to about 1 μ

M, or about 1.0 nM to about 100 nM.

13. The modified IL-4 mutein receptor antagonist of claim 1, wherein the modified IL-4 mutein receptor antagonist inhibits the proliferative response of TF-1 cells to IL-13 with an IC₅₀ of about 0.1 nM to about 10 μ

M, about 0.5 nM to about 1 μ

M, or about 1.0 nM to about 100 nM.

14. The modified IL-4 mutein receptor antagonist of claim 1, wherein the modified IL-4 mutein receptor antagonist inhibits the proliferative response of human B cells to IL-4 with an IC₅₀ of about 0.1 nM to about 10 μ

M, about 0.5 nM to about 1 μ

M, or about 1.0 nM to about 100 nM.

15. The modified IL-4 mutein receptor antagonist of claim 1, wherein the modified IL-4 mutein receptor antagonist inhibits the proliferative response of human T cells to IL-4 with an IC₅₀ of about 0.1 nM to about 10 μ

M, about 0.5 nM to about 1 μ

M, or about 1.0 nM to about 100 nM.

16. The modified IL-4 mutein receptor antagonist of claim 1, wherein the modified IL-4 mutein receptor antagonist has a plasma half-life which is at least about 2-10 fold greater than that of an unmodified IL-4 receptor antagonist.

17. A purified polynucleotide encoding the polypeptide comprising the amino acid sequence set forth in SEQ ID NO:

32.