FACTOR VIII CHIMERIC AND HYBRID POLYPEPTIDES, AND METHODS OF USE THEREOF

• US 20140294821A1
• Filed: 07/06/2012
• Published: 10/02/2014
• Est. Priority Date: 07/08/2011
• Status: Active Grant

• Current Assignee: Bioverativ Therapeutics Inc. (Sanofi )
• Original Assignee: Biogen Idec Hemophilia Inc (Sanofi )
• Inventors: Dumont, Jennifer A., Low, Susan, Bitonti, Alan J., Pierce, Glenn, Luk, Alvin, Jiang, Haiyan, Ottmer, Matt, Sommer, Jurg, Li, Lian, Peters, Robert, Mckinney, Byron, Nugent, Karen
• Granted Patent: US 10,010,622 B2
• Time in Patent Office: Days
• US Class Current: 424/134.1
• CPC Class Codes: A61K 38/37 Factors VIII
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/68 the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: C07K 14/755 Factors VIII , e.g. factor VIII C (AHF), factor VIII Ag (VWF)
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/31 fusions, other than Fc, for prolonged plasma life, e.g. albumin
• CPC Class Codes: G01N 33/86 involving blood coagulating time or factors, or their receptors

Abstract

The present invention provides methods of administering Factor VIII (processed FVIII, single chain FVIII, or a combination thereof); methods of administering chimeric and hybrid polypeptides comprising Factor VIII; chimeric and hybrid polypeptides comprising Factor VIII; polynucleotides encoding such chimeric and hybrid polypeptides; cells comprising such polynucleotides; and methods of producing such chimeric and hybrid polypeptides using such cells

Claims

1-264. -264. (canceled)

265. A pharmaceutical composition comprising (i) a chimeric polypeptide, which comprises a Factor VIII (FVIII) portion and a second portion, and (ii) at least one pharmaceutically acceptable excipient, wherein at least about 1%, about 5%, about 10%, about 15%, about 20%, or about 25% of the chimeric polypeptide comprises single chain FVIII in the FVIII portion.

266. The pharmaceutical composition of claim 265, wherein about 1%-about 10%, about 5%-about 15%, about 10%-about 20%, about 15%-about 25%, about 20%-about 30%, about 25%-about 35%, or about 30%-about 40% of the chimeric polypeptide is single chain FVIII in the FVIII portion.

267. The pharmaceutical composition of claim 265, wherein at least 75% of the chimeric polypeptide comprises processed FVIII in the FVIII portion.

268. The pharmaceutical composition of claim 265, wherein about 15% to about 25% of the chimeric polypeptide comprises single chain FVIII in the FVIII portion and about 75% to about 85% of the chimeric polypeptide comprises processed FVIII in the FVIII portion.

269. The pharmaceutical composition of claim 265, (i) wherein about 25% of the chimeric polypeptide comprises single chain FVIII in the FVIII portion and about 75% of the chimeric polypeptide comprises processed FVIII in the FVIII portion, (ii) wherein about 20% of the chimeric polypeptide comprises single chain FVIII in the FVIII portion and about 80% of the chimeric polypeptide comprises processed FVIII in the FVIII portion, or (iii) wherein about 15% of the chimeric polypeptide comprises single chain FVIII in the FVIII portion and about 85% of the chimeric polypeptide comprises processed FVIII in the FVIII portion.

270. The pharmaceutical composition of claim 265, wherein the single chain FVIII comprises a heavy chain and a light chain connected by a peptide bond.

271. The pharmaceutical composition of claim 267, wherein the processed FVIII comprises two chains, a first chain comprising a heavy chain of FVIII and a second chain comprising a light chain of FVIII, wherein the first chain and the second chain are associated by a metal bond.

272. The pharmaceutical composition of claim 265, wherein the chimeric polypeptide is a long-acting FVIII polypeptide.

273. The pharmaceutical composition of claim 265, wherein the second portion comprises an Fc region, albumin, a PAS sequence, transferrin, CTP (28 amino acid C-terminal peptide (CTP) of hCG with its 4 O-glycans), polyethylene glycol (PEG), hydroxyethyl starch (HES), albumin binding polypeptide, albumin-binding small molecules, or two or more combinations thereof.

274. The pharmaceutical composition of claim 265, wherein the second portion comprises an Fc region.

275. The pharmaceutical composition of claim 265, wherein the FVIII portion comprises B-domain deleted FVIII or full-length, mature FVIII.

276. The pharmaceutical composition of claim 265, wherein residue 1645 corresponding to full-length, mature FVIII, residue 1648 corresponding to full-length, mature FVIII, or both residues in the single chain FVIII is arginine.

277. The pharmaceutical composition of claim 265, wherein the chimeric polypeptide has a half-life longer than a polypeptide consisting of the FVIII portion.

278. The pharmaceutical composition of claim 265, which is more stable than a composition comprising processed FVIII without single chain FVIII.

279. The pharmaceutical composition of claim 265, which is suitable for administration to a human.

280. The pharmaceutical composition of claim 265, which is suitable for subcutaneous, intradermal, intravascular, intravenous, intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial or intraperitoneal injection to a human.

281. The pharmaceutical composition of claim 265, which is lyophilized.

282. A method of preventing, decreasing, or treating a bleeding episode in a subject comprising administering to the subject an effective amount of the pharmaceutical composition of claim 265.

283. A method of prophylactic treatment of a bleeding episode in a subject comprising administering to the subject an effective amount of the pharmaceutical composition of claim 265.

284. A method of on-demand treatment of a bleeding episode in a subject comprising administering to the subject an effective amount of the pharmaceutical composition of claim 265.

285. A method of tailored prophylactic treatment of a bleeding episode in a subject comprising administering to the subject an effective amount of the pharmaceutical composition of claim 265.

286. The method of claim 282, wherein the bleeding episode is associated with a disease or condition comprising hemarthrosis, muscle bleed, oral bleed, hemorrhage, hemorrhage into muscles, oral hemorrhage, trauma, trauma capitis (head trauma), gastrointestinal bleeding, intracranial hemorrhage, intra-abdominal hemorrhage, intrathoracic hemorrhage, bone fracture, central nervous system bleeding, bleeding in the retropharyngeal space, bleeding in the retroperitoneal space, or bleeding in the illiopsoas sheath.

287. The method of claim 283, wherein the bleeding episode is associated with a disease or condition comprising hemarthrosis, muscle bleed, oral bleed, hemorrhage, hemorrhage into muscles, oral hemorrhage, trauma, trauma capitis (head trauma), gastrointestinal bleeding, intracranial hemorrhage, intra-abdominal hemorrhage, intrathoracic hemorrhage, bone fracture, central nervous system bleeding, bleeding in the retropharyngeal space, bleeding in the retroperitoneal space, or bleeding in the illiopsoas sheath.

288. A method of maintaining homeostatis in a subject in need of a surgery comprising administering to the subject an effective amount of the pharmaceutical composition of claim 265.

289. A method of perioperative management of a subject before, after, or during a surgery comprising administering to the subject an effective amount of the pharmaceutical composition of claim 265.

290. The method of claim 289, wherein the surgery is minor surgery, major surgery, tooth extraction, tonsillectomy, inguinal herniotomy, synovectomy, total knee replacement, craniotomy, osteosynthesis, trauma surgery, intracranial surgery, intra-abdominal surgery, intrathoracic surgery, or joint replacement surgery.

291. The method of claim 282, wherein the effective amount of the pharmaceutical composition is 10 IU/kg-20 IU/kg, 20 IU/kg-30 IU/kg, 30 IU/kg-40 IU/kg, 40 IU/kg-50 IU/kg, 50 IU/kg-60 IU/kg, 60 IU/kg-70 IU/kg, 70 IU/kg-80 IU/kg, 80 IU/kg-90 IU/kg, 90 IU/kg-100 IU/kg, 100 IU/kg-110 IU/kg, 110 IU/kg-120 IU/kg, 120 IU/kg-130 IU/kg, 130 IU/kg-140 IU/kg, or 140 IU/kg-150 IU/kg.

292. The method of claim 282, wherein a dosing interval of the pharmaceutical composition is once every 24-36, 24-48, 24-72, 24-96, 24-120, 24-144, or 24-168 hours or longer.