Methods of treatment of cellulite

• US 9,775,889 B2
• Filed: 04/02/2014
• Issued: 10/03/2017
• Est. Priority Date: 03/06/2008
• Status: Active Grant

• Current Assignee: Halozyme, Inc. (Halozyme Therapeutics, Inc.)
• Original Assignee: Halozyme, Inc. (Halozyme Therapeutics, Inc.)
• Inventors: Keller, Gilbert, Frost, Gregory I.
• Primary Examiner(s): Swope, Sheridan
• Application Number:
  US14/243,805
• Publication Number:
  US 20140271609A1
• Time in Patent Office: 1,280 Days
• Field of Search: None
• CPC Class Codes: A61K 38/4813 Exopeptidases (3.4.11. to 3.4.19)
• CPC Class Codes: A61K 38/482 Serine endopeptidases (3.4.21)
• CPC Class Codes: A61K 38/4873 Cysteine endopeptidases (3.4.22), e.g. stem bromelain, papain, ficin, cathepsin H
• CPC Class Codes: A61K 38/488 Aspartic endopeptidases (3.4.23), e.g. pepsin, chymosin, renin, cathepsin E
• 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 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 9/6472 Cysteine endopeptidases (3.4.22)
• CPC Class Codes: C12N 9/6491 Matrix metalloproteases [MMP's], e.g. interstitial collagenase (3.4.24.7); Stromelysins (3.4.24.17; 3.2.1.22); Matrilysin (3.4.24.23)
• CPC Class Codes: C12Y 304/22015 Cathepsin L (3.4.22.15)
• CPC Class Codes: C12Y 304/24007 Interstitial collagenase (3.4.24.7), i.e. matrix metalloprotease 1 or MMP1

Abstract

Methods and combinations are provided for controlling the duration of action, in vivo, of matrix-degrading enzymes. The methods and combinations permit temporary in-vivo activation of matrix-degrading enzymes upon administration to the extra cellular matrix (or “ECM”). Matrix-degrading enzymes having a controlled duration of action can be used to treat ECM-mediated diseases or disorders characterized by increased deposition or accumulation of one or more ECM components.

Claims

1. A method for treating cellulite, comprising administering to a subject a composition comprising a cathepsin L enzyme, wherein:

the composition is administered by subcutaneous administration into the extracellular matrix (ECM) to effect treatment of the cellulite;

the pH of the composition containing the cathepsin L enzyme is 3 to 6.5, whereby the cathepsin L enzyme is active in the composition, and whereby, upon administration into the ECM, the cathepsin L enzyme is active for a limited time after administration to the subject, thereby treating the cellulite; and

the cathepsin L enzyme in the composition;

a) consists of the sequence of amino acid residues whose sequence is set forth in SEQ ID NO;

1;

or

b) consists of a sequence of amino acid residues that has at least 90% sequence identity with the sequence of amino acid residues set forth in SEQ ID NO;

1 and has cathepsin L activity to cleave type I collagen;

or

c) is a two-chain form of a) or b), and has cathepsin L activity to cleave type I collagen;

or

d) is a catalytically active fragment of the enzymes of any of a)-c) that has cathepsin L activity to cleave type I collagen.

2. The method of claim 1, wherein the pH of the composition is within a range of about 4.5 to 6.

3. The method of claim 1, wherein the pH of the composition is within a range of 4 to 6.

4. The method of claim 1, wherein the pH of the composition is within a range of about 5 to 6.

5. The method of claim 1, wherein the cathepsin L enzyme is a two-chain form.

6. The method of claim 1, wherein the cathepsin L enzyme comprises:

a heavy chain having the sequence of amino acids set forth as amino acids 1-175 of SEQ ID NO;

1 or a sequence that exhibits at least 90% sequence identity to the sequence of amino acids 1-175; and

a light chain having the sequence of amino acids set forth as amino acids 179-220 of SEQ ID NO;

1 or a sequence that exhibits at least 90% sequence identity to the sequence of amino acids 179-220.

7. The method of claim 1, wherein the cathepsin L enzyme consists of the sequence of amino acid residues set forth in SEQ ID NO:

1.

8. The method of claim 1, wherein the cathepsin L enzyme in the composition is a mature cathepsin L enzyme that is generated from a cathepsin L zymogen by activation cleavage to cleave the prosegment of the Cathepsin L zymogen, thereby producing the mature cathepsin L enzyme.

9. The method of claim 8, wherein the cleaved prosegment is removed from the composition.

10. The method of claim 8, wherein the cathepsin L zymogen comprises:

the sequence of amino acids set forth as amino acids 18-333 of SEQ ID NO;

62;

or

a sequence of amino acids that exhibits at least 90% sequence identity to the sequence of amino acids set forth as amino acids 18-333 of SEQ ID NO;

62.

11. The method of claim 8, wherein the cathepsin L zymogen consists of:

the sequence of amino acids set forth as amino acids 18-333 SEQ ID NO;

62;

or

a sequence of amino acids that exhibits at least 90% sequence identity to the sequence of amino acids set forth as amino acids 18-333 of SEQ ID NO;

62.

12. The method of claim 8, wherein the cathepsin L zymogen is produced by expression of a nucleic acid encoding the polypeptide set forth in SEQ ID NO:

62.

13. The method of claim 12, wherein the nucleic acid has the sequence of nucleotides set forth in SEQ ID NO:

61.

14. The method of claim 1, wherein the composition comprising the cathepsin L enzyme is prepared by a method comprising:

providing a lyophilized preparation containing the cathepsin L enzyme; and

adding an acidic buffered solution at the acidic pH to the lyophilized preparation, thereby generating an acidic pH composition containing the cathepsin L enzyme.

15. The method of claim 14, wherein the acidic buffered solution has a pH within a range of 4 to 6.

16. The method of claim 14, wherein the pH of the acidic buffered solution has a pH within a range of 3.5 to 6.

17. The method of claim 1, wherein administration is effected by injection.

18. The method of claim 1, wherein the composition comprises a buffer containing an acid selected from among 2-(N-morpholino)ethanesulfonic acid) (MES), acetic acid, citric acid, succinic acid, lactic acid, maleic acid, glycine-hydrochloric acid, citric phosphate and histidine.

19. The method of claim 1, wherein:

the composition comprises succinic acid; and

the pH of the composition is within a range of about 4 to 6.

20. The method of claim 1, wherein the composition is administered to deliver the cathepsin L enzyme in a dosage range amount of, or about, 100 μ

g to 50 mg.

21. The method of claim 20, wherein the composition is administered in a volume that is in a range of, or about, 1 mL to 50 mL.

22. The method of claim 1, wherein:

the composition is administered to deliver the cathepsin L enzyme in a dosage range amount of, or about, 500 μ

g to 10 mg; and

the composition is administered in a volume that is in a range of, or about, 1 mL to 10 mL.

23. The method of claim 1, wherein the pH of the composition comprising the cathepsin L is 4 to 6.