Granted Patent
B2
US 12,186,375 · App. 17/112,280 · Granted Jan 7, 2025
Factor VIII chimeric and hybrid polypeptides, and methods of use thereof
Inventors:
Jennifer A. Dumont (Groton, MA); Susan Low (Pepperill, MA); Alan J. Bitonti (Acton, MA); Glenn Pierce (Rancho Santa Fe, CA); Alvin Luk (Boston, MA); Haiyan Jiang (Belmont, MA); Byron McKinney (San Diego, CA); Matt Ottmer (Newton, MA); Jurg Sommer (Wayland, MA); Karen Nugent (Owlswick, GB); Lian Li (Lexington, MA); Robert T. Peters (Needham, MA)
Assignee:
BIOVERATIV THERAPEUTICS INC.
View Patent ↗
Loading inventors, assignments & file history…
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 (19)
1. A method for treating a subject in need of surgical prophylaxis, peri-operative management, or treatment for surgery, comprising administering to the subject a therapeutic dose of a chimeric polypeptide, the chimeric polypeptide comprising a Factor VIII portion and a second portion, wherein said Factor VIII portion comprises processed Factor VIII and single chain Factor VIII, wherein about 10% to about 40% of the Factor VIII portion is single chain Factor VIII; wherein the chimeric polypeptide is administered at a dosing interval of between about 12 hours and 24 hours; wherein the subject has hemophilia A.
2. The method of claim 1 , wherein the therapeutic dose is 10-100 IU/kg.
3. The method of claim 2 , wherein the therapeutic dose is 25-40 IU/kg.
4. The method of claim 2 , wherein the therapeutic dose is 40-60 IU/kg.
5. The method of claim 2 , wherein the therapeutic dose is 40-50 IU/kg.
6. The method of claim 1 , wherein the chimeric polypeptide is a FVIIIFc monomer dimer hybrid.
7. The method of claim 1 , wherein said Factor VIII portion has a full or partial deletion of the B domain.
8. The method of claim 1 , wherein about 10% of the Factor VIII portion is single chain Factor VIII, and wherein about 90% of the Factor VIII portion is processed Factor VIII.
9. The method of claim 1 , wherein about 15% of the Factor VIII portion is single chain Factor VIII, and wherein about 85% of the Factor VIII portion is processed Factor VIII.
10. The method of claim 1 , wherein about 20% of the Factor VIII portion is single chain Factor VIII, and wherein about 80% of the Factor VIII portion is processed Factor VIII.
11. The method of claim 1 , wherein about 25% of the Factor VIII portion is single chain Factor VIII, and wherein about 75% of the Factor VIII portion is processed Factor VIII.
12. The method of claim 1 , wherein about 30% of the Factor VIII portion is single chain Factor VIII, and wherein about 70% of the Factor VIII portion is processed Factor VIII.
13. The method of claim 1 , wherein about 35% of the Factor VIII portion is single chain Factor VIII, and wherein about 65% of the Factor VIII portion is processed Factor VIII.
14. The method of claim 1 , wherein about 40% of the Factor VIII portion is single chain Factor VIII, and wherein about 60% of the Factor VIII portion is processed Factor VIII.
15. The method of claim 1 , wherein about 40% of the Factor VIII portion is single chain Factor VIII, and wherein about 60% of the Factor VIII portion is processed Factor VIII.
16. The method of claim 1 , wherein the single chain Factor VIII comprises an amino acid sequence at least 95% identical to amino acids 20 to 1457 of SEQ ID NO: 2.
17. The method of claim 1 , wherein the single chain Factor VIII comprises an amino acid sequence identical to amino acids 20 to 1457 of SEQ ID NO: 2.
18. The method of claim 1 , wherein the second portion comprises an amino acid sequence at least 95% identical to amino acids 21 to 247 of SEQ ID NO: 4.
19. The method of claim 18 , wherein the second portion comprises an amino acid sequence identical to amino acids 21 to 246 of SEQ ID NO: 4.
Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 27, 2024
From: DUMONT, JENNIFER A.; LOW, SUSAN; BITONTI, ALAN J.; PIERCE, GLENN; LUK, ALVIN; JIANG, HAIYAN; MCKINNEY, BYRON; OTTMER, MATT; SOMMER, JURG; NUGENT, KAREN; LI, LIAN; PETERS, ROBERT
To: BIOGEN IDEC HEMOPHILIA INC.
Reel/Frame 069423/0371 →
CHANGE OF NAME
Recorded Nov 27, 2024
From: BIOGEN HEMOPHILIA INC.
To: BIOGEN HEMOPHILIA INC.
Reel/Frame 069460/0634 →
CHANGE OF NAME
Recorded Nov 27, 2024
From: BIOGEN HEMOPHILIA INC.
To: BIOVERATIV THERAPEUTICS INC.
Reel/Frame 069461/0096 →
Continuity (10)
Division
14131600
Provisional Application
61657641
· Jun 8, 2012
Provisional Application
61622789
· Apr 11, 2012
Provisional Application
61586443
· Jan 13, 2012
Provisional Application
61569158
· Dec 9, 2011
Provisional Application
61541561
· Sep 30, 2011
Provisional Application
61522647
· Aug 11, 2011
Provisional Application
61506015
· Jul 8, 2011
References Cited (197)
US 4757006A
· Toole, Jr. et al.
· 1988
[cited by applicant]
US 4868112A
· Toole, Jr. et al.
· 1989
[cited by applicant]
US 4965199A
· Capon et al.
· 1990
[cited by applicant]
US 4994371A
· Davie et al.
· 1991
[cited by applicant]
US 5004803A
· Kaufman et al.
· 1991
[cited by applicant]
US 5112950A
· Meulien et al.
· 1992
[cited by applicant]
US 5171544A
· Lang
· 1992
[cited by applicant]
US 5171844A
· Van Ooyen et al.
· 1992
[cited by applicant]
US 5364771A
· Lollar et al.
· 1994
[cited by applicant]
US 5543502A
· Nordfang et al.
· 1996
[cited by applicant]
US 5563045A
· Pittman
· 1996
[cited by examiner]
US 5595886A
· Chapman et al.
· 1997
[cited by applicant]
US 5610278A
· Nordfang et al.
· 1997
[cited by applicant]
US 5712122A
· Boime et al.
· 1998
[cited by applicant]
US 5789203A
· Chapman et al.
· 1998
[cited by applicant]
US 5859204A
· Lollar
· 1999
[cited by applicant]
US 5972885A
· Spira et al.
· 1999
[cited by applicant]
US 6048720A
· Dalborg et al.
· 2000
[cited by applicant]
US 6060447A
· Chapman et al.
· 2000
[cited by applicant]
US 6200560B1
· Cuoto et al.
· 2001
[cited by applicant]
US 6228620B1
· Chapman et al.
· 2001
[cited by applicant]
US 6251632B1
· Lillicrap et al.
· 2001
[cited by applicant]
US 6316226B1
· Van Ooyen et al.
· 2001
[cited by applicant]
US 6346513B1
· Van Ooyen et al.
· 2002
[cited by applicant]
US 6376463B1
· Lollar
· 2002
[cited by applicant]
US 6458563B1
· Lollar
· 2002
[cited by applicant]
US 6686179B2
· Fleer et al.
· 2004
[cited by applicant]
US 7041635B2
· Kim et al.
· 2006
[cited by applicant]
US 7348004B2
· Peters et al.
· 2008
[cited by applicant]
US 7404956B2
· Peters et al.
· 2008
[cited by applicant]
US 7592010B2
· Rosen et al.
· 2009
[cited by applicant]
US 7632921B2
· Pan et al.
· 2009
[cited by applicant]
US 7862820B2
· Peters et al.
· 2011
[cited by applicant]
US 8329182B2
· Peters et al.
· 2012
[cited by applicant]
US 8815250B2
· Rivera et al.
· 2014
[cited by applicant]
US 9611310B2
· Low et al.
· 2017
[cited by applicant]
US 20050100990A1
· Saenko et al.
· 2005
[cited by applicant]
US 20050118684A1
· Lollar
· 2005
[cited by applicant]
US 20090087411A1
· Fares et al.
· 2009
[cited by applicant]
US 20090163699A1
· Chamberlain et al.
· 2009
[cited by applicant]
US 20090264627A1
· Gillies et al.
· 2009
[cited by applicant]
US 20100189682A1
· Schellenberger et al.
· 2010
[cited by applicant]
US 20100292130A1
· Skerra et al.
· 2010
[cited by applicant]
BR PI0410345A
· 2006
[cited by applicant]
CL 201201463
· 2011
[cited by applicant]
EP 0154316A2
· 1985
[cited by applicant]
EP 0295597A2
· 1988
[cited by applicant]
EP 0401384A1
· 1990
[cited by applicant]
EP 2173890A1
· 2010
[cited by applicant]
EP 2729161A4
· 2015
[cited by applicant]
EP 3513804A1
· 2019
[cited by applicant]
JP 2013512678A
· 2013
[cited by applicant]
WO WO1987004187A1
· 1987
[cited by applicant]
WO WO1988000831A1
· 1988
[cited by applicant]
WO WO1988003558A1
· 1988
[cited by applicant]
WO WO1988008035A1
· 1988
[cited by applicant]
WO WO1991009122A1
· 1991
[cited by applicant]
WO WO1992016221A1
· 1992
[cited by applicant]
WO WO1993020093A1
· 1993
[cited by applicant]
WO WO1994011503A2
· 1994
[cited by applicant]
WO WO1995034326A1
· 1995
[cited by applicant]
WO WO2004101740A2
· 2004
[cited by applicant]
WO WO2005001025A2
· 2005
[cited by applicant]
WO WO2006074199A1
· 2006
[cited by applicant]
WO WO2007103515A2
· 2007
[cited by applicant]
WO WO2008155134A1
· 2008
[cited by applicant]
WO WO2009023270A2
· 2009
[cited by applicant]
WO WO2010091122A1
· 2010
[cited by applicant]
WO WO2011069164A2
· 2011
[cited by examiner]
WO WO2012006623A1
· 2012
[cited by applicant]
WO WO2012006635A1
· 2012
[cited by examiner]
WO WO2013009627A2
· 2013
[cited by applicant]
Peng, HT., Mil Med Res. Mar. 25, 2020;7(1):13. doi: 10.1186/s40779-020-00241-z. PMID: 32209132.
[cited by examiner]
Guo et al., Theranostics. 2023; 13(1): 161-196. Published online Jan. 1, 2023. doi: 10.7150/thno.79639 PMCID: PMC9800728 PMID: 36593953.
[cited by examiner]
Smith et al., Haemophilia. Sep. 2005;11(5):444-51. doi: 10.1111/j.1365-2516.2005.01131.x. PMID: 16128886.
[cited by examiner]
U.S. Appl. No. 15/991,629 2018/0360982 U.S. Pat. No. 10,881,742. filed May 29, 2018 Dec. 20, 2018 Jan. 5, 2021, Jennifer A. Dumont.
[cited by applicant]
U.S. Appl. No. 14/131,600 2014/0294821 U.S. Pat. No. 10,010,622, filed Jun. 13, 2014 Oct. 2, 2014 Jul. 3, 2018, Jennifer A. Dumont.
[cited by applicant]
Aledort, et al., A longitudinal study of orthopaedic outcomes for severe factor-VIII-Deficient haemophiliacs, Journal of Internal Medicine, vol. 236, No. 4, pp. 391-399, 1994.
[cited by applicant]
Armour, et al., Recombinant Human IgG Molecules Lacking Fc gamma Receptor I Binding and Monocyte Triggering Activities, European Journal of Immunology, vol. 29, No. 8, pp. 2613-2624, Aug. 1999.
[cited by applicant]
Aznar, et al., The Orthopaedic Status of Severe Haemophiliacs in Spain, Haemophilia, vol. 6, No. 3, pp. 170-176, May 2000.
[cited by applicant]
Bai, et al., Recombinant Granulocyte Colony-Stimulating Factor-Transferrin Fusion Protein as an Oral Myelopoietic Agent, Proceedings of the National Academy of Sciences of the United States of America, vol. 102, No. 20,…
[cited by applicant]
Brandsma, et al., Recombinant Human Transferrin: Beyond Iron Binding and Transport, Biotechnology Advances, vol. 29, No. 2, pp. 230-238, Mar.-Apr. 2011.
[cited by applicant]
Brutlag, et al., Improved Sensitivity of Biological Sequence Database Searches, Computer Applications in the Biosciences: CABIOS, vol. 6, No. 3, pp. 237-245, Aug. 1990.
[cited by applicant]
Burmeister, et al., Crystal Structure of the Complex of Rat Neonatal Fc Receptor with Fc, Nature, vol. 372, No. 6504, pp. 379-383, Nov. 24, 1994.
[cited by applicant]
Cameron, et al., The Canine Factor VIII cDNA and 5′ Flanking Sequence, Journal of Thrombosis and Haemostasis, vol. 79, No. 2, pp. 317-322, Feb. 1998.
[cited by applicant]
Cheng, et al., Single-molecule measurement and bioinformatics analysis suggest a preferred orientation of human coagulation factor VIII on hydrophobic interfaces, Homo sapiens coagulation factor VIII (F8), transcript va…
[cited by applicant]
Coppola, et al., Primary prophylaxis in children with haemophilia, Blood Transfusion, vol. 6, Supplement 2, pp. S4-S11, Sep. 2008.
[cited by applicant]
Cutler, et al., The Identification and Classification of 41 Novel Mutations in The Factor VIII Gene (F8c), Human Mutation, vol. 19, No. 3, pp. 274-278, Mar. 2002.
[cited by applicant]
Dennis, et al., Albumin Binding as a General Strategy for Improving the Pharmacokinetics of Proteins, Journal of Biological Chemistry, vol. 277, No. 38, pp. 35035-35043, Sep. 20, 2002.
[cited by applicant]
Dobeli, et al., Role of the Carboxy-Terminal Sequence on the Biological Activity of Human Immune Interferon (IFN-y), Journal of Biotechnology, vol. 7, No. 3, pp. 199-216, 1988.
[cited by applicant]
Donath, et al., Characterization of Des-(741-1668)-Factor VIII, a Single-Chain Factor VIII Variant with a Fusion Site Susceptible to Proteolysis by Thrombin and Factor Xa, Biochemical Journal, vol. 312, Pt 1, pp. 49-55,…
[cited by applicant]
Dumont, et al., Factor VIII-Fc Fusion Protein Shows Extended Half-Life and Hemostatic Activity in Hemophilia A Dogs, Abstract 545, Blood, vol. 114, No. 22, 51st Annual Meeting of the American Society of Hematology, 1 Pa…
[cited by applicant]
Dumont, et al., Factor VIII-FcFusion Protein Shows Extended Half-Life and Hemostatic Activity in Hemostatic Activity in Hemophilia A Dogs, Blood, vol. 116, No. 21, 2009.
[cited by applicant]
Dumont, et al., Monomeric Fc Fusion Technology: An Approach to Create Long-Lasting Clotting Factors, Therapeutic Proteins: Strategies to Modulate Their Plasma Half-Lives, Chapter 10, Wiley VCH publisher, pp. 189-206, 20…
[cited by applicant]
Dumont, J A., Monomeric Fc Fusions: Impact on Pharmacokinetic and Biological Activity of Protein Therapeutics, BioDrugs, vol. 20, No. 3, pp. 151-160, May 1, 2006.
[cited by applicant]
Eaton, et al., Construction and Characterization of an Active Factor VIII Variant Lacking the Central One-Third of the Molecule, Biochemistry, vol. 25, No. 26, pp. 8343-8347, Dec. 1986.
[cited by applicant]
Extended European Search Report received for European Patent Application No. 18211156.7, mailed on Jun. 6, 2019, 7 Pages.
[cited by applicant]
Fatouros, et al., Recombinant factor VIII SQ-Influence of Oxygen , Metal Ions, pH and lonic Strength on its Stability in Aqueous Solution, International journal of Phamaceutics, vol. 155, No. 1, pp. 121-131, 1997.
[cited by applicant]
Feldman, et al., Tailored Prophylaxis in Severe Hemophilia A: Interim Results From the First 5 Years of the Canadian Hemophilia Primary Prophylaxis Study, Journal of Thrombosis and Haemostasis, vol. 4, No. 6, pp. 1228-1…
[cited by applicant]
Francis, G E., Protein Modification and Fusion Proteins, Focus on Growth Factors, vol. 3, No. 2, Mediscript, England, pp. 4-10, 1992.
[cited by applicant]
Friend, et al., Phase I Study of an Engineered Aglycosylated Humanized Cd3 Antibody in Renal Transplant Rejection1, Transplantation, vol. 68, Issue 11, pp. 1632-1637, Dec. 15, 1999.
[cited by applicant]
Gayle, et al., Identification of Regions in Interleukin-1 Alpha Important for Activity, Journal of Biological Chemistry, vol. 268, No. 29, pp. 22105-22111, Oct. 15, 1993.
[cited by applicant]
Genbank,
[cited by applicant]
Genbank,
[cited by applicant]
Genbank,
[cited by applicant]
Genbank,
[cited by applicant]
Genbank, Human Transferrin mRNA, Complete cds, Accession No. M12530, Retrieved From: «http://www.ncbi.nlm.nih.gov/nuccore/M12530» Retrieved on Jan. 15, 2015, 2 Pages, Jan. 14, 1995.
[cited by applicant]
Genbank, Transferrin [Human, Liver, mRNA, 2347 nt], Accession No. S95936, Retrieved From:«http://www.ncbi.nlm.nih.gov/nuccore/S95936», May 7, 1993.
[cited by applicant]
Genbank, Variation in IgG1 heavy chain allotype does not contribute to differences in biological activity of two human anti-Rhesus (D) monoclonal antibodies,
[cited by applicant]
Geraghty, et al., Practice Patterns in Haemophilia A Therapy—Global Progress Towards Optimal Care, Haemophilia, vol. 12, No. 1, pp. 75-81, Jan. 2006.
[cited by applicant]
Gitschier, et al., Characterization of The Human Factor VIII Gene, Nature, vol. 312, No. 5992, pp. 326-330, Nov. 22-28, 1984.
[cited by applicant]
Gruppo, et al., Comparative Effectiveness of Full-Length and B-Domain Deleted Factor VIII for Prophylaxis-A Meta-Analysis, Haemophilia, vol. 9, No. 3, pp. 251-260, May 2003.
[cited by applicant]
Hacker, et al., Barriers to compliance With Prophylaxis therapy in Haemophilia, Haemophilia, vol. 4, No. 4, pp. 392-396, 2001.
[cited by applicant]
Healey, et al., The cDNA and Derived Amino Acid Sequence of Porcine Factor VIII, Blood, vol. 88, No. 11, pp. 4209-4214, Dec. 1, 1996.
[cited by applicant]
Hoeben, et al., Expression of Functional Factor VIII In Primary Human Skin Fibroblasts After Retrovirus-Mediated Gene Transfer, Journal of Biological Chemistry, vol. 265, No. 13, pp. 7318-7323, May 1990.
[cited by applicant]
Holt, et al., Anti-Serum Albumin Domain Antibodies for Extending The Half-Lives of Short Lived Drugs, Protein Engineering, Design and Selection, vol. 21, No. 5, pp. 283-288, May 2008.
[cited by applicant]
Huang, et al., Receptor-Fc Fusion Therapeutics, Traps, and Mimetibody Technology, Current Opinion in Biotechnology, vol. 20, Issue 6, Current Biology, England, pp. 692-699, Dec. 2009.
[cited by applicant]
International Search Report and Written Opinion received for PCT Patent Application No. PCT/US2010/059136, mailed on Jun. 2, 2011, 10 Pages.
[cited by applicant]
International Search Report and Written Opinion received for PCT Patent Application No. PCT/US12/45784, mailed on Dec. 21, 2012, 13 pages.
[cited by applicant]
Jefferis, Roy, Glycosylation as a Strategy to Improve Antibody-Based Therapeutics, Nature Reviews: Drug Discovery, vol. 8, No. 3, pp. 226-234, Mar. 2009.
[cited by applicant]
Kim, et al., Transferrin Fusion Technology: A Novel Approach To Prolonging Biological Half-Life of Insulinotropic Peptides, Journal of Pharmacology and Experimental Therapeutics, vol. 334, No. 3, pp. 682-692, Sep. 2010.
[cited by applicant]
Koshihara Kimihito, et al., Properties of factor VIII in Immune-Affinity purified VIII concentrate, Japanese Journal of Transfusion Medicine, vol. 36, No. 3, pp. 406-410, 1990.
[cited by applicant]
Kraulis, et al., The Serum Albumin-Binding Domain of Streptococcal Protein G is A Three-Helical Bundle: A Heteronuclear NMR Study, FEBS Letters, vol. 378, Issue 2, pp. 190-194, Jan. 8, 1996.
[cited by applicant]
Kreuz, et al., When Should Prophylactic Treatment in Patients With Haemophilia A and B Start ?—The German Experience, Haemophilia, vol. 4, No. 4, pp. 413-417, Jul. 1998.
[cited by applicant]
Langner, et al., Synthesis of Biologically Active Deletion Mutants of Human Factor VIII:C, Behring Institute Mitteilungen, No. 82, pp. 16-25, Apr. 1988.
[cited by applicant]
Lee, et al., Pharmacokinetics of Recombinant Factor VIII (Recombinate) Using One-Stage Clotting and Chromogenic Factor VIII Assay, Journal of Thrombosis and Haemostasis, vol. 82, No. 6, pp. 1644-1647, Dec. 1999.
[cited by applicant]
Lencer, et al., A Passionate Kiss, Then Run: Exocytosis and Recycling of Igg by Forn, Trends in cell biology, vol. 15, No. 1, pp. 5-9, Jan. 2005.
[cited by applicant]
Lenting, et al., Clearance Mechanisms of von Willebrand Factor and Factor VIII, Journal of Thrombosis and Haemostasis, vol. 5, No. 7, pp. 1353-1360, Jul. 2007.
[cited by applicant]
Li, et al., The Role of The Transferrin-Transferrin-Receptor System in Drug Delivery and Targeting, Trends in Pharmacological Sciences, vol. 23, No. 5, pp. 206-209, May 2002.
[cited by applicant]
Liesner, et al., The impact of prophylactic treatment on children with severe haemophilia, British journal of Haematology, vol. 92, No. 4, pp. 973-978, 1996.
[cited by applicant]
Lillicrap, David, Improvements in Factor Concentrates, Current Opinion in Haemotology, vol. 17, No. 5, pp. 393-397, Sep. 1, 2010.
[cited by applicant]
Linhult, et al., Mutational Analysis of The Interaction Between Albumin-Binding Domain From Streptococcal Protein G and Human Serum Albumin, Protein Science, vol. 11, No. 2, pp. 206-213, Feb. 2002.
[cited by applicant]
Liu, et al., Recombinant FVIII Fc Fusion Protein is Fully Active in Treating Acute Injury and Demonstrates Prolonged Prophylactic Efficacy in Hemophilia a Mice, Journal of Thrombosis and Haemostasis, vol. 9, Supplement …
[cited by applicant]
Ljung, et al., Prophylactic Treatment in Sweden-overtreatment or Optimal Model?, Haemophilia, vol. 4, No. 4, pp. 409-412, 1998.
[cited by applicant]
Löfqvist, et al., Haemophilia Prophylaxis in Young Patients ± A Long-Term Follow-Up, Journal of Internal Medicine, vol. 241, pp. 395-400, 1997.
[cited by applicant]
Lollar, et al., Coagulant Properties of Hybrid Human/Porcine Factor VIII Molecules, Journal of Biological chemistry, vol. 267, pp. 23652-23657, Nov. 25, 1992.
[cited by applicant]
Lollar, et al., Structural Basis for The Deceased Procoagulant Activity of Human Factor VIII Compared to The Porcine Homolog, Journal of biological chemistry, vol. 266, Number, pp. 12481-12486, Jul. 5, 1991.
[cited by applicant]
Malik, et al., Polyethylene Glycol (PEG)-Modified Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) With Conserved Biological Activity, Experimental Hematology, vol. 20, No. 8, pp. 1028-1035, Sep. 1992.
[cited by applicant]
Manco-Johnson, et al., Prophylaxis Versus Episodic Treatment to Prevent Joint Disease in Boys With Severe Hemophilia, The new England journal of medicine, vol. 357, No. 6, pp. 535-544, Aug. 9, 2007.
[cited by applicant]
Mannucci, et al., The Hemophilias—From Royal Genes to Gene Therapy, New England Journal of Medicine, vol. 344, No. 23, pp. 1773-1779, Jun. 1, 2001.
[cited by applicant]
McCue, et al., Application of a Novel Affinity Adsorbent for the Capture and Purification of Recombinant Factor VIII Compounds, Journal of Chromatography A, vol. 1216, No. 45, pp. 7824-7830, Nov. 6, 2009.
[cited by applicant]
Mei, et al., Rational Design of a Fully Active, Long-Acting PEGylated Factor VIII for Hemophilia A Treatment, Blood, vol. 116, No. 2, pp. 270-279, Jul. 15, 2010.
[cited by applicant]
Metzner, et al., Characterization of factor VIII/von Willebrand factor concentrates using a modified method of von Willebrand factor multimer analysis, Haemophilia, vol. 4, Supplement 3, pp. 25-32, 1998.
[cited by applicant]
Meulien, et al., A New Recombinant Procoagulant Protein Derived From The Cdna Encoding Human Factor VIII, Protein Engineering, Design and Selection, vol. 2, No. 4, pp. 301-306, Oct. 1, 1988.
[cited by applicant]
Mikaelsson, et al., Assaying the circulating Factor VIII Activity in Hemophilia A patients Treated with Recombinant Factor VIII Products, Seminars in Thrombosis And Hemostasis, vol. 28, No. 3, pp. 257-264, 2002.
[cited by applicant]
Molho, et al., Epidemiological Survey of The Orthopaedic Status of Severe Haemophilia A and B Patients in France. The French Study Group, Haemophilia, vol. 6, No. 1, pp. 23-32, Jan. 2000.
[cited by applicant]
Mols, et al., Recombinant interferon-gamma secreted by Chinese hamster ovary—320 cells cultivated in suspension in protein-free media is protected against extracellular proteolysis by the expression of natural protease …
[cited by applicant]
Morfini, M, Pharmacokinetics of Factor VIII and Factor IX, Haemophilia, vol. 9, No. 1, pp. 94-99, May 2003.
[cited by applicant]
Muller, et al., Recombinant Bispecific Antibodies for Cellular Cancer Immunotherapy, Current opinion in molecular therapeutics, vol. 9, No. 4, pp. 319-326, Aug. 2007.
[cited by applicant]
Nilsson, et al., Twenty-Five Years Experience of Prophylactic Treatment i Severe Haemophilia A and B, Journal of internal medicine, vol. 235, Issue 1, pp. 25-32, Jul. 1992.
[cited by applicant]
Oganesyan, et al., Structural Characterization of a Human Fc Fragment Engineered for Extended Serum Half-Life, Molecular Immunology, vol. 46, No. 8-9, pp. 1750-1755, May 2009.
[cited by applicant]
Petrini, et al., Prophylaxis With Factor Concentrates in Preventing Hemophilic Arthropathy, Am J Pediatr Hematology Oncology, vol. 13, No. 3, pp. 280-287, 1991.
[cited by applicant]
Peyvandi, et al., Genetic Diagnosis of Haemophilia and Other Inherited Bleeding Disorders, Haemophilia, vol. 12, Suppl 3, pp. 82-89, Jul. 2006.
[cited by applicant]
Pittman, et al., Post-Translational Requirements for Functional Factor V and Factor VIII Secretion in Mammalian Cells, Journal of Biological Chemistry, vol. 269, No. 25, pp. 17329-17337, Jun. 24, 1994.
[cited by applicant]
Risebrough, et al., Cost-Utility Analysis of Canadian Tailored Prophylaxis, Primary Prophylaxis and On-Demand Therapy in Young Children With Severe Haemophilia A, Haemophilia, vol. 14, No. 4, pp. 743-752, Jul. 8, 2008.
[cited by applicant]
Rodriguez-Merchan, Carlos E.., Management of Musculoskeletal Complications of Hemophilia, Seminars in Thrombosis and Hemostasis., vol. 29, No. 01, pp. 87-96, 2003.
[cited by applicant]
Ron, et al., Expression of Biologically Active Recombinant Keratinocyte Growth Factor. Structure/Function Analysis of Amino-Terminal Truncation Mutants, Journal of Biological Chemistry, vol. 268, No. 4, pp. 2984-2988, 1…
[cited by applicant]
Roopenian, et al., FcRn: The Neonatal Fc Receptor Comes of Age, Nature Reviews Immunology, vol. 7, No. 9, pp. 715-725, Sep. 2007.
[cited by applicant]
Roovers, et al., Efficient Inhibition of EGFR Signaling and of Tumour Growth by Antagonistic anti-EFGR Nanobodies, Cancer Immunology, Immunotherapy, vol. 56, No. 3, pp. 303-317, Mar. 2007.
[cited by applicant]
Rosen, S, Assay of Factor VIII:C with a chromogenic substrate, Scandinavian Journal of Haematology, vol. 33, Supplement 40, pp. 139-145, 1984.
[cited by applicant]
Routledge, et al., The Effect of Aglycosylation on The Immunogenicity of A Humanized Therapeutic CD3 Monoclonal Antibody, Transplantation, vol. 60, No. 8, pp. 847-853, Oct. 1, 1995.
[cited by applicant]
Sarver, et al., Stable Expression of Recombinant Factor VIII Molecules Using A Bovine Papillomavirus Vector, DNA, vol. 6, No. 6, pp. 553-564, Dec. 1987.
[cited by applicant]
Schellenberger, et al., A Recombinant Polypeptide Extends The In Vivo Half-Life of Peptides and Proteins in a Tunable Manner, Nature Biotechnology, vol. 27, No. 12, pp. 1186-1190, Dec. 2009.
[cited by applicant]
Schmidt, S R., Fusion Proteins as Biopharmaceuticals—Applications and Challenges, Current opinion in drug discovery and development, vol. 12, No. 2, pp. 284-295, Mar. 2009.
[cited by applicant]
Schulte, Stefan, Half-Life Extension Through Albumin Fusion Technologies, Thrombosis Research, vol. 124, Supplement 2, pp. S6-S8, Dec. 2009.
[cited by applicant]
Shields, et al., High Resolution Mapping of the Binding Site on Human IgG1 for Fc Gamma RI, Fc Gamma RII, Fc Gamma RIII, and FcRn and Design of IgG1 Variants with Improved Binding to the Fc Gamma R, Journal of Biologica…
[cited by applicant]
Siedlecki, et al., Shear-Dependent Changes In The Three-Dimensional Structure of Human Von Willebrand Factor, Blood, vol. 88, No. 8, pp. 2939-2950, Oct. 15, 1996.
[cited by applicant]
Smith, et al., Novel associations of multiple genetic loci with plasma level of factor VII, Factor VIII, and von willebrand factor: the charge consortium, Circulation, vol. 121, No. 12, pp. 1382-1392, 2010.
[cited by applicant]
Sommermeyer, et al., Klinisch verwendete Hydroxyethylstärke: physikalischchemische Charakterisierung, Krankenhauspharmazie, vol. 8, No. 8, pp. 271-278, 1987.
[cited by applicant]
Soucie, et al., Mortality Among Males With Hemophilia: Relations With Source of Medical Care. The Hemophilia Surveillance System Project Investigators, Blood, vol. 96, No. 2, pp. 437-442, Jul. 15, 2000.
[cited by applicant]
Story, et al., A Major Histocompatibility Complex Class I-like Fc Receptor Cloned from Human Placenta: Possible Role in Transfer of Immunoglobulin G from Mother to Fetus, Journal of Experimental Medicine, vol. 180, No. …
[cited by applicant]
Stroobants, et al., Differences Between one stage clotting and chromogenic Factor VIII assay result, Journal of thrombosis and Haemostasis, vol. 9, Supplement 2, p. 381, 2011.
[cited by applicant]
Toole, et al., A Large Region (Approximately Equal to 95 kDa) of Human Factor VIII is Dispensable for In Vitro Procoagulant Activity, Proceedings of the National Academy of Sciences, vol. 83, No. 16, pp. 5939-5942, Aug.…
[cited by applicant]
Toole, et al., Molecular Cloning of a cDNA Encoding Human Antihaemophilic Factor, Nature, vol. 312, No. 5992, pp. 342-347, Nov. 22-28, 1984.
[cited by applicant]
Trusselet, et al., New Strategy for The Extension of The Serum Half-Life of Antibody Fragments, Bioconjugate Chemistry, vol. 20, pp. 2286-2292, 2009.
[cited by applicant]
Vaccaro, et al., Engineering the Fc Region of Immunoglobulin G to Modulate in Vivo Antibody Levels, Nature Biotechnology, vol. 23, No. 10, pp. 1283-1288, Oct. 2005.
[cited by applicant]
Van Den Berg, et al., Comparing Outcomes of Different Treatment Regimens for Severe Haemophilia, Haemophilia, vol. 9, Supplement 1, pp. 27-31, May 2003.
[cited by applicant]
Van Den Berg, et al., Issues Surrounding Therapeutic Choices for Hemophilia Patients, Haematologica, vol. 89, pp. 645-650, 2004.
[cited by applicant]
Vehar, et al., Structure of Human Factor VIII, Nature, vol. 312, No. 5992, pp. 337-342, Nov. 1984.
[cited by applicant]
Wakabayashi, et al., Residues 110-126 in the A1 Domain of Factor VIII Contain a Ca2+ Binding Site Required for Cofactor Activity, The Journal of Biological Chemistry, vol. 279, pp. 12677-12684, Jan. 13, 2004.
[cited by applicant]
Wang, et al., Receptor-Mediated Activation of a Proinsulin-Transferrin Fusion Protein in Hepatoma Cells, Journal of Controlled Release, vol. 155, No. 3, pp. 386-392, Nov. 7, 2011.
[cited by applicant]
Ward, et al., The Effector Functions of Immunoglobulins: Implications for Therapy, Therapeutic immunology, vol. 2, No. 2, pp. 77-94, Apr. 1995.
[cited by applicant]
Weidler, et al., Pharmacokinetic Parameters as Criteria for Clinical Use of Hydroxyethyl Starch Preparations, Arzneimittelforschung/Drug Research, vol. 41, No. 5, pp. 494-498, May 1991.
[cited by applicant]
White, et al., A Multicenter Study of Recombinant Factor VIII (Recombinate) in Previously Treated Patients With Hemophilia A. The Recombinate Previously Treated Patient Study Group, Thrombosis and haemostasis, vol. 77, …
[cited by applicant]
White, et al., Recombinant Factor IX, Thrombosis and Haemostasis, vol. 78, No. 1, pp. 261-265, Jul. 1997.
[cited by applicant]
Wood, et al., Expression of Active Human Factor VIII From Recombinant DNA Clones, Nature, vol. 312, No. 5992, pp. 330-337, Nov. 22-28, 1984.
[cited by applicant]
Cited By (1)