Long-acting coagulation factors and methods of producing same
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Publication Number
US-9458444-B2
Publication Date
2016-10-04
Expiration Date
Abstract
Polypeptides comprising at least one carboxy-terminal peptide (CTP) of chorionic gonadotrophin attached to the carboxy terminus but not to the amino terminus of a coagulation factor and polynucleotides encoding the same are disclosed. Pharmaceutical compositions comprising the polypeptides and polynucleotides of the invention and methods of using and producing same are also disclosed.
Core Innovation
The disclosure describes CTP-modified polypeptides in which a coagulation factor has chorionic gonadotropin carboxy terminal peptides (CTPs) attached to the carboxy terminus. In particular, a CTP-modified polypeptide consisting of a coagulation factor and three CTPs attached to the carboxy terminus is provided, where at least one CTP is optionally attached via a linker. The coagulation factor is selected from Factor VII (FVII) and activated Factor VII (FVIIa).
The disclosure also relates to engineered forms of the CTP-modified coagulation factor using optionally glycosylated and/or truncated CTPs and specifying attachment features such as a linker. The disclosure includes full CTP-modified factor sequences defined by SEQ ID numbers, and purification and characterization are described in the context of the engineered constructs and their modified forms.
The disclosure further describes methods for extending the biological half-life of a coagulation factor, improving the area under the curve (AUC), and reducing the dosing frequency. Each method includes attaching three CTPs to the carboxy terminus of a coagulation factor selected from FVII and activated FVIIa, with at least one CTP optionally attached via a linker. The disclosure additionally includes pharmaceutical compositions and administration-related embodiments for the CTP-modified coagulation factors, including formulation components and dosage form options.
Claims Coverage
The independent claims include a CTP-modified polypeptide and three methods directed to the same three-CTP modification. Across the independent claims, inventive features focus on attachment of three chorionic gonadotropin carboxy terminal peptides to the carboxy terminus of Factor VII (FVII) or activated Factor VII (FVIIa), with optional linker attachment of at least one CTP, and outcomes of extending biological half-life, improving AUC, or reducing dosing frequency.
Three-CTP-modified FVII or FVIIa polypeptide
A CTP-modified polypeptide consisting of a coagulation factor and three chorionic gonadotropin carboxy terminal peptides (CTPs) attached to the carboxy terminus of the coagulation factor, wherein at least one CTP is optionally attached via a linker, and wherein the coagulation factor is selected from Factor VII (FVII) and activated Factor VII (FVIIa).
Extending biological half-life by three-CTP attachment to FVII or FVIIa
A method of extending the biological half-life of a coagulation factor by attaching three chorionic gonadotropin carboxy terminal peptides (CTPs) to the carboxy terminus of the coagulation factor, wherein at least one CTP is optionally attached via a linker, and wherein the coagulation factor is selected from Factor VII (FVII) and activated Factor VII (FVIIa).
Improving AUC by three-CTP attachment to FVII or FVIIa
A method of improving the area under the curve (AUC) of a coagulation factor by attaching three chorionic gonadotropin carboxy terminal peptides (CTPs) to the carboxy terminus of the coagulation factor, wherein at least one CTP is optionally attached via a linker, and wherein the coagulation factor is selected from Factor VII (FVII) and activated Factor VII (FVIIa).
Reducing dosing frequency by three-CTP attachment to FVII or FVIIa
A method of reducing the dosing frequency of a coagulation factor by attaching three chorionic gonadotropin carboxy terminal peptides (CTPs) to the carboxy terminus of the coagulation factor, wherein at least one CTP is optionally attached via a linker, and wherein the coagulation factor is selected from Factor VII (FVII) and activated Factor VII (FVIIa).
Claim coverage spans product and method claims focused on three-CTP modification of Factor VII (FVII) or activated Factor VII (FVIIa), including optional linker attachment of at least one CTP. The independent claims specify extending biological half-life, improving AUC, and reducing dosing frequency by the same carboxy-terminal three-CTP attachment.
Stated Advantages
Extends the biological half-life of a coagulation factor.
Improves the area under the curve (AUC) of a coagulation factor.
Reduces the dosing frequency of a coagulation factor.
Protects against degradation/clearance and extends half-life and pharmacokinetic measures.
Maintains or improves activity.
Documented Applications
Comparative in vitro and in vivo performance evaluation of CTP-fused Factor VII/Factor VIIa variants (including FVII-CTP3/4/5 and FVIIa-CTP3) versus NovoSeven® using clotting activity and pharmacokinetic measurements.
FVIII-deficient mouse studies evaluating FVIIa-CTP3 activity and pharmacokinetics and tail-vein transection survival to assess prolonged hemostatic efficacy.
Sprague Dawley rat pharmacokinetic studies comparing CTP copy number variants of CTP-fused Factor VII/Factor VIIa.
Treatment of coagulation disorders by coagulation factor replacement therapy using CTP-modified coagulation factors, notably hemophilia B.
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