Presentation Title
Presentation Type
Oral Presentation
Abstract
Blood coagulation factor VIII (FVIII), is a non-enzymatic cofactor which plays a crucial role in the formation of a stable blood clot. Absence or deficiency of FVIII results in the blood disorder hemophilia A; with symptoms including internal hemorrhaging and the inability to stop bleeding from open wounds. Treatment of hemophilia A relies on infusions of blood, plasma, or protein concentrates to replace FVIII. Unfortunately, approximately 30% of patients receiving replacement FVIII generate pathologic anti-FVIII inhibitory antibodies, which both reduce the effectiveness of the FVIII therapeutic and increase the severity of hemophilia A symptoms.
We have determined the molecular structure of the novel human/porcine chimeric FVIII protein “HP47”, a next-generation hemophilia A replacement FVIII therapeutic. At 3.2 Å resolution with a Rworkof 0.2146 and Rfree of 0.2879, this will be the highest resolution structure of FVIII to date and will be of substantial interest to the hematological community. Furthermore, we have constructed an improved model of human FVIII with more robust geometry and amino acid register assignment based on previous 3.7 Å data, with an Rwork of 0.2655, and Rfree of 0.2895. Lastly, progress has been made towards the structural determination of the inhibitory antibodies M6143, 2A9, and B136 in complex with the C1 domain of human FVIII. Details of these interactions could inform the development of future hemophilia A protein therapeutics with reduced immunogenicity.
Start Date
10-5-2018 9:15 AM
Genre/Form
presentations (communicative events)
Subjects - Topical (LCSH)
Hemophilia--Treatment; Blood coagulation factor VIII
Type
Event
Format
application/pdf
Language
English
Included in
Biochemistry Commons, Hematology Commons, Structural Biology Commons, Therapeutics Commons
Structure Determination of a Bioengineered Human/Porcine Factor VIII for Hemophilia A Treatment, and Improvements to the Human Factor VIII Model
Blood coagulation factor VIII (FVIII), is a non-enzymatic cofactor which plays a crucial role in the formation of a stable blood clot. Absence or deficiency of FVIII results in the blood disorder hemophilia A; with symptoms including internal hemorrhaging and the inability to stop bleeding from open wounds. Treatment of hemophilia A relies on infusions of blood, plasma, or protein concentrates to replace FVIII. Unfortunately, approximately 30% of patients receiving replacement FVIII generate pathologic anti-FVIII inhibitory antibodies, which both reduce the effectiveness of the FVIII therapeutic and increase the severity of hemophilia A symptoms.
We have determined the molecular structure of the novel human/porcine chimeric FVIII protein “HP47”, a next-generation hemophilia A replacement FVIII therapeutic. At 3.2 Å resolution with a Rworkof 0.2146 and Rfree of 0.2879, this will be the highest resolution structure of FVIII to date and will be of substantial interest to the hematological community. Furthermore, we have constructed an improved model of human FVIII with more robust geometry and amino acid register assignment based on previous 3.7 Å data, with an Rwork of 0.2655, and Rfree of 0.2895. Lastly, progress has been made towards the structural determination of the inhibitory antibodies M6143, 2A9, and B136 in complex with the C1 domain of human FVIII. Details of these interactions could inform the development of future hemophilia A protein therapeutics with reduced immunogenicity.