COMPOSITIONS, METHODS AND USES FOR ALPHA-1 ANTITRYPSIN FUSION MOLECULES

• US 20180208681A1
• Filed: 03/14/2018
• Published: 07/26/2018
• Est. Priority Date: 06/24/2011
• Status: Active Grant

• Current Assignee: Konkuk University, The Board of Regents of the University of Colorado (University of Colorado System)
• Original Assignee: Advent Bio Holdings LLC, Konkuk University, The Board of Regents of the University of Colorado (University of Colorado System)
• Inventors: Dinarello, Charles A., Crapo, James D., Kim, Soohyun
• Granted Patent: US 10,450,384 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/57 from animals; from humans A61K38/553, A61K38/556 take precedence
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• 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
• CPC Class Codes: C07K 14/8125 Alpha-1-antitrypsin
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C12N 15/62 DNA sequences coding for fusion proteins

Abstract

Embodiments herein report compositions of alpha-1 antitrypsin fusion polypeptides or peptide derivatives thereof. In certain embodiments, compositions and methods relate to generating a construct of use in pharmaceutically acceptable compositions to treat a subject in need of alpha-1 antitrypsin therapy or treatment. In other embodiments, compositions and methods disclosed herein concern linking alpha-1 antitrypsin or derivative thereof to an immune fragment.

Claims

1. A fusion polypeptide comprising consecutive amino acids which, beginning at the amino terminus of the protein, correspond to consecutive amino acids present in (i) alpha-1 antitrypsin or carboxyterminal fragment thereof, (ii) a peptide linker, and (iii) an immune fragment, wherein the consecutive amino acids (i) remain bound to (iii) when purified.

2. The fusion protein of claim 1, wherein the immune fragment comprises an Fc fragment.

3. The fusion protein of claim 2, wherein the Fc fragment comprises IgG2.

9. The construct of claim 4, wherein the construct encodes the polypeptide of claim 2.

13. A recombinant cell clone comprising the nucleic acid construct of claim 4 or fusion polypeptide of claim 1.

14. A method for treating a condition in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition of a fusion polypeptide of claim 1;

and a pharmaceutically acceptable carrier or salt thereof, wherein the administration treats the condition in the subject.

15. The method of claim 14, wherein the condition is Type I or Type II diabetes.

16. The method of claim 14, wherein the subject is undergoing an organ or non-organ transplant and the treatment modulates transplant rejection in the subject.

17. The method of claim 14, wherein the condition is AAT deficiency in the subject and wherein the treatment provides AAT replacement therapy to the subject.

18. The method of claim 14, wherein the condition is gout, and wherein the administration of the composition modulates gout in the subject.

19. The method of claim 14, wherein the condition is a cardiac condition, and wherein the administration modulates the cardiac condition in the subject.

20. The method of claim 14, wherein the condition is an autoimmune condition and the composition treats the autoimmune condition in the subject.

4. A nucleic acid construct comprising:

a nucleic acid encoding alpha-1 antitrypsin (AAT) or fragment or peptide cleavage molecule thereof;

a linker; and

a nucleic acid encoding an immune fragment wherein the immune fragment is an immunoglobulin molecule.

5. The construct of claim 4, wherein the nucleic acid encoding AAT comprises a nucleic acid encoding naturally occurring AAT (SEQ ID NO:

1).

6. The construct of claim 4, wherein the nucleic acid encoding the AAT peptide cleavage molecule comprises a nucleic acid encoding one or more carboxyterminal fragments of naturally occurring AAT.

7. The construct of claim 4, wherein the carboxyterminal fragment comprises the last 80 amino acids of SEQ ID NO:

1, or 10 or more consecutive amino acids thereof.

8. The construct of claim 6, wherein the carboxyterminal fragment comprises the amino acid sequence of SEQ ID NO:

34.

10. The construct of claim 4, wherein the immune fragment comprises an IgG1, IgG2, IgG3, IgG4 or IgD fragment.

11. The construct of claim 4, wherein the construct is formed by linking AAT or a carboxyterminal fragment thereof through its N-terminal end to the immune fragment.

12. The construct of claim 4, wherein the construct encodes the polypeptide of SEQ ID NO:

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