Immunoglobulin chimeric monomer-dimer hybrids

• US 7,348,004 B2
• Filed: 01/05/2005
• Issued: 03/25/2008
• Est. Priority Date: 05/06/2003
• Status: Active Grant

• Current Assignee: Bioverativ Therapeutics Inc. (Sanofi )
• Original Assignee: Syntonix Pharmaceuticals, Inc.
• Inventors: Peters, Robert T., Mezo, Adam R., Low, Susan C., Bitonti, Alan J., Rivera, Daniel S., Stattel, James
• Primary Examiner(s): Campell; Bruce R.
• Assistant Examiner(s): HUMPHREY, LOUISE WANG ZHIYING
• Application Number:
  US11/029,003
• Publication Number:
  US 20050260194A1
• Time in Patent Office: 1,175 Days
• Field of Search: 424/130.1, 424/133.1, 424/134.1, 514/2
• US Class Current: 424/178.1
• 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 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/475 Growth factors; Growth regulators
• CPC Class Codes: C07K 14/505 Erythropoietin [EPO]
• CPC Class Codes: C07K 14/555 Interferons [IFN]
• CPC Class Codes: C07K 14/56 IFN-alpha
• CPC Class Codes: C07K 14/565 IFN-beta
• CPC Class Codes: C07K 14/57 IFN-gamma
• CPC Class Codes: C07K 14/745 Blood coagulation or fibrinolysis factors
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• 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: C07K 2319/43 containing a FLAG-tag
• CPC Class Codes: C07K 2319/73 containing coiled-coiled motif (leucine zippers)
• CPC Class Codes: C07K 5/0806 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/1013 the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: C12N 9/6437 Coagulation factor VIIa (3.4.21.21)
• CPC Class Codes: C12N 9/644 Coagulation factor IXa (3.4.21.22)
• CPC Class Codes: C12N 9/647 : Blood coagulation factors not provided for in a preceding group or according to more than one of the proceeding groups
• CPC Class Codes: C12Y 304/21021 : Coagulation factor VIIa (3.4.21.21)
• CPC Class Codes: C12Y 304/21022 : Coagulation factor IXa (3.4.21.22)

Abstract

The invention relates to a chimeric monomer-dimer hybrid protein wherein said protein comprises a first and a second polypeptide chain, said first polypeptide chain comprising at least a portion of an immunoglobulin constant region and a biologically active molecule, and said second polypeptide chain comprising at least a portion of an immunoglobulin constant region without the biologically active molecule of the first chain. The invention also relates to methods of using and methods of making the chimeric monomer-dimer hybrid protein of the invention.

Claims

1. A method of treating a subject with a disease or condition comprising administering a pharmaceutically effective amount of a monomer-dimer hybrid immunoconjugate to the subject, wherein the immunoconjugate comprises

X-L_a-F₁:

F₂ or F₂;

F₁-L_a-X,

wherein;

X is a single biologically active molecule capable of treating the disease or condition;

L is a linker;

a is any integer or zero;

;

represents a chemical association;

F₁ is at least a portion of an immunoglobulin constant region comprising an FcRn binding site and does not comprise a biologically active molecule,

F₂ is at least a portion of an immunoglobulin constant region comprising an FcRn binding site; and

does not comprise a biologically active molecule or immunoglobulin variable region.

2. The method of claim 1, wherein said monomer-dimer hybrid immunoconjugate is administered intravenously, subcutaneously, orally, buccally, sublingually, nasally, parenterally, rectally, vaginally or via a pulmonary route.

3. The method of claim 1, wherein said disease or condition is a viral infection.

4. The method of claim 1, wherein X is interferon.

5. The method of claim 4, wherein the interferon is interferon α

and L consists of 15-25 amino acids.

6. The method of claim 5, wherein L consists of 15-20 amino acids.

7. The method of claim 1, wherein said disease or condition is a hemostatic disorder.

8. The method of claim 1, wherein said disease or condition is hemophilia A.

9. The method of claim 1, wherein said disease or condition is hemophilia B.

10. The method of claim 1, wherein X is Factor VII or Factor VIIa.

11. The method of claim 1, wherein X is Factor IX.

12. The method of claim 1, wherein said disease or condition is anemia.

13. The method of claim 1, wherein X is erythropoietin.

14. The method of claim 4, wherein the interferon is interferon α

.

15. The method of claim 4, wherein the interferon is interferon β

.

16. The method of claim 1, wherein the disease or condition is a cardiovascular disease or condition.

17. The method of claim 16, wherein the cardiovascular disease or condition is chosen from stroke, brain ischemia, cerebral ischemia, myocardial ischemia, cardiac ischemia, isehemic heart disease, myocardial infarction, coronary artery disease, acute coronary syndrome, artheroselerosis, chronic heart failure, congestive heart failure, and reperfusion injury.

18. The method of claim 16, wherein X is erythropoietin.

19. A method of treating a subject with a disease or condition comprising administering a pharmaceutically effective amount of a monomer-dimer hybrid immunoconjugate to the subject, wherein the immunoconjugate consists of the formula

X-L_a-F₁:

F₂-T or T-F₂;

F₁-L_a-X,

wherein;

X is a single biologically active molecule capable of treating the disease or condition;

L is a linker, a is any integer or zero;

T is a molecule having a molecular weight less than 2 kD;

;

represents a chemical association;

F₁ is at least a portion of an immunoglobulin constant region comprising an FcRn binding site; and

F₂ is at least a portion of an immunoglobulin constant region comprising an FcRn binding site.

20. A method of providing improved delivery of a biologically active molecule comprising administering to a subject a monomer-dimer hybrid immunoconjugate comprising

X-L_a-F₁:

F₂ or F₂;

F₁-L_a-X,

wherein;

X is a single biologically active molecule capable of treating the disease or condition;

L is a linker;

a is any integer or zero;

;

represents a chemical association;

F₁ is at least a portion of an immunoglobulin constant region comprising an FcRn binding site and does not comprise a biologically active molecule; and

F₂ is at least a portion of an immunoglobulin constant region comprising an FcRn binding site and does not comprise a biologically active molecule or immunoglobulin variable region.