Long-acting coagulation factors and methods of producing same
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Publication Number
US-10538755-B2
Publication Date
2020-01-21
Expiration Date
Abstract
Polypeptides comprising at least one carboxy-terminal peptide (CTP) of chorionic gonadotropin 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 invention relates to a CTP-modified polypeptide comprising a Factor IX coagulation factor and three chorionic gonadotropin carboxy terminal peptides (CTPs). The CTPs are attached to the carboxy terminus of the Factor IX coagulation factor, and the polypeptide does not include an N-terminal propeptide. An activated disulfide-linked two-chain heterodimer form is described for the CTP-modified Factor IX.
The invention further defines methods that attach three CTPs to the carboxy terminus of a Factor IX coagulation factor to modify its in vivo properties. In particular, the biological half-life is extended by the attachment of the three CTPs, with the same exclusion of an N-terminal propeptide. The disclosed subject matter also includes methods focused on improving pharmacokinetic exposure and dosing convenience.
An area under the curve (AUC) of a Factor IX coagulation factor is improved by attaching three CTPs to the carboxy terminus, under the condition that the Factor IX does not include an N-terminal propeptide. In addition, the dosing frequency is reduced by attaching three CTPs to the carboxy terminus under the same N-terminal propeptide exclusion. The documented content describes improved pharmacokinetic and pharmacodynamic behavior relative to reference forms, including prolonged clotting activity, and includes administration of CTP-modified coagulation factors for hemophilia.
Claims Coverage
The independent claims cover four related inventive themes: a CTP-modified Factor IX polypeptide without an N-terminal propeptide, a method of extending FIX biological half-life, a method of improving FIX AUC, and a method of reducing FIX dosing frequency. Across these independent claims, the core inventive concept is the attachment of three chorionic gonadotropin carboxy terminal peptides to the carboxy terminus of Factor IX while omitting an N-terminal propeptide.
Three CTPs at the Factor IX carboxy terminus without an N-terminal propeptide
A CTP-modified polypeptide consisting of a Factor IX coagulation factor and three chorionic gonadotropin carboxy terminal peptides attached to the carboxy terminus, wherein the polypeptide does not include an N-terminal propeptide.
Extending FIX biological half-life by attaching three CTPs to the carboxy terminus without an N-terminal propeptide
A method of extending the biological half-life of a Factor IX coagulation factor comprising attaching three chorionic gonadotropin carboxy terminal peptides to the carboxy terminus, wherein the coagulation factor does not include an N-terminal propeptide.
Improving FIX AUC by attaching three CTPs to the carboxy terminus without an N-terminal propeptide
A method of improving the area under the curve (AUC) of a Factor IX coagulation factor comprising attaching three chorionic gonadotropin carboxy terminal peptides to the carboxy terminus, wherein the coagulation factor does not include an N-terminal propeptide.
Reducing FIX dosing frequency by attaching three CTPs to the carboxy terminus without an N-terminal propeptide
A method of reducing the dosing frequency of a Factor IX coagulation factor comprising attaching three chorionic gonadotropin carboxy terminal peptides to the carboxy terminus, wherein the coagulation factor does not include an N-terminal propeptide.
Overall, the claim set focuses on three-CTP modification of Factor IX at the carboxy terminus as the defining inventive element, while explicitly excluding an N-terminal propeptide. The independent claims then assign specific functional outcomes to that same structural change, namely extending biological half-life, improving AUC, and reducing dosing frequency.
Stated Advantages
Extends biological half-life of a Factor IX coagulation factor.
Improves area under the curve (AUC) of a Factor IX coagulation factor.
Reduces dosing frequency of a Factor IX coagulation factor.
Prolongs clotting activity in pharmacokinetic and pharmacodynamic studies.
Improved pharmacokinetic and pharmacodynamic behavior relative to reference forms.
Maintaining biological activity while producing longer-acting pharmacokinetics/pharmacodynamics performance, including longer elimination half-life and prolonged procoagulatory effect.
Documented Applications
Preventing or treating hemophilia by administering CTP-modified coagulation factors, including CTP-modified Factor IX and Factor VII/Factor VIIa embodiments, with subcutaneous and/or intravenous administration routes.
Treating hemophilia B by administering the CTP-modified Factor IX polypeptide.
Treatment of hemophilia B by administering the CTP-modified polypeptide, including inhibitor-related cases.
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