FACTOR VIII-FC CHIMERIC AND HYBRID POLYPEPTIDES, AND METHODS OF USE THEREOF
The present invention provides methods of administering Factor VIII; 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.
1 . A method of administering Factor VIII to a human subject in need thereof, comprising
administering to the subject a therapeutic dose of a chimeric polypeptide comprising a Factor VIII portion and an Fc portion at a dosing interval at least about one and one-half times longer than the dosing interval required for an equivalent amount of a polypeptide consisting of said Factor VIII portion.
2 . (canceled)
3 . The method of claim 1 , where said dosing interval is at least about one and one-half to six times longer, one and one-half to five times longer, one and one-half to four times longer, one and one-half to three times longer, or one and one-half to two times longer, than the dosing interval required for an equivalent amount of a polypeptide consisting of said Factor VIII portion.
4 - 5 . (canceled)
6 . The method of claim 1 , wherein said subject is in need of prophylactic treatment, on-demand treatment, treatment for a bleeding episode, treatment for hemarthrosis, muscle bleed, oral bleed, hemorrhage, hemorrhage into muscles, oral hemorrhage, trauma, trauma capitis, 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, bleeding in the illiopsoas sheath, surgical prophylaxis, peri-operative management, or treatment for surgery.
7 . (canceled)
8 . The method of claim 1 , wherein said subject is in need of treatment for a bleeding episode.
9 . (canceled)
10 . The method of claim 1 , wherein said subject is in need of surgical prophylaxis, peri-operative management, or treatment for surgery.
11 . (canceled)
12 . The method of claim 1 , wherein said dosing interval of said chimeric polypeptide is about once every 24-36, 24-48, 24-72, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, or 72 hours or longer.
13 . The method of claim 1 , wherein said therapeutic dose is 10-100 IU/kg.
14 - 17 . (canceled)
18 . The method of claim 1 , wherein said Factor VIII has a full or partial deletion of the B domain.
19 - 24 . (canceled)
25 . The method of claim 1 , wherein said chimeric polypeptide is in the form of a hybrid comprising a second polypeptide in association with said chimeric polypeptide, wherein said second polypeptide consists essentially of an Fc.
26 - 29 . (canceled)
30 . The method of claim 1 , wherein said chimeric polypeptide is administered as part of a pharmaceutical composition comprising at least one excipient.
31 . A method of administering Factor VIII to a human subject in need thereof, comprising
administering to the subject a therapeutic dose of a chimeric polypeptide comprising a Factor VIII portion and a second portion to obtain an area under the plasma concentration versus time curve (AUC) at least about one and one-quarter times greater than the AUC obtained by an equivalent amount of a polypeptide consisting of said Factor VIII portion.
32 . (canceled)
33 . The method of claim 31 , wherein said subject is in need of prophylactic treatment.
34 . The method of claim 31 , wherein said subject is in need of on-demand treatment.
35 . The method of claim 31 , wherein said subject is in need of treatment for a bleeding episode.
36 - 57 . (canceled)
58 . A method of administering Factor VIII to a human subject in need thereof, comprising
administering to the subject a therapeutic dose of a polypeptide comprising a Factor VIII and an Fc at a dosing interval of about every five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen days or longer.
59 . The method of any of claim 58 , wherein said subject is in need of prophylactic treatment.
60 . The method of claim 58 , wherein said therapeutic dose is 10-100 IU/kg.
61 . The method of claim 60 , wherein said therapeutic dose is 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, or 90-100 IU/kg.
62 - 108 . (canceled)
109 . The method of claim 1 , wherein the therapeutic dose is about 10 to about 150, 100-110, 110-120, 120-130, 130-140, 140-150, 110, 115, 120, 125, 130, 135, 140, 145, or 150 IU/kg.
110 . The method of claim 1 , wherein the dosing interval is one and one-half to 5, one and one-half, 2, 3, 4, or 5 days or longer.