Long-acting coagulation factors and methods of producing same
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Publication Number
US-11066658-B2
Publication Date
2021-07-20
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 invention relates to long-acting engineered coagulation factors in which chorionic gonadotrophin carboxy terminal peptides (CTPs) are attached to the carboxy terminus of coagulation factor VII (FVII). The invention provides a method of producing a CTP-modified coagulation FVII polypeptide by attaching three to five CTPs to the carboxy terminus of a coagulation FVII polypeptide, including activated FVIIa forms.
The description presents CTP-modified FVIIa constructs, including rFVIIa-CTP3 and rFVIIa-CTP5, and further characterizes CTP-modified coagulation factors by pharmacology and efficacy measures. The CTPs are described as protectants that extend circulatory half-life while maintaining or enhancing potency, and the constructs include forms selected from SEQ ID NO: 25 and SEQ ID NO: 46, with dependent features including linker-mediated attachment and defined CTP sequence options.
The resulting CTP-modified proteins are expressed in mammalian cells, show secretion and antigen levels comparable to native rFVII, and retain serine protease activity, with noted potency reductions for additional CTP copies. The description also includes pharmacokinetics and in vivo clotting performance, with CTP-modified constructs showing longer measurable clotting activity than NovoSeven® in FVIII-deficient mice and prolonged restoration of PT and reduced bleeding in warfarin-treated rat models.
Claims Coverage
The relevant material identifies one independent claim directed to producing a CTP-modified FVII polypeptide. The dependent claims further refine the independent claim with specific CTP options, linker-mediated attachment, selection of produced CTP-modified FVII sequences, and restriction to activated FVIIa with a specified two-chain light/heavy composition. Across the identified claim set, the core inventive concept is the carboxy-terminal attachment of three to five CTPs to FVII.
Carboxy-terminal CTP modification of FVII
Attaching three to five chorionic gonadotrophin carboxy terminal peptides (CTPs) to the carboxy terminus of a coagulation Factor VII (FVII) polypeptide to produce a CTP-modified FVII polypeptide.
CTP sequence options defined by SEQ ID NO: 1 and SEQ ID NO: 2
At least one CTP consists of an amino acid sequence selected from the group consisting of SEQ ID NO: 1 and SEQ ID NO: 2.
Linker-mediated CTP attachment
At least one CTP is attached to said coagulation Factor VII polypeptide via a linker.
Produced CTP-modified FVII sequence selected from SEQ ID NO: 25 and SEQ ID NO: 46
The method is carried out using a CTP-modified Factor VII (FVII) sequence selected from the group consisting of SEQ ID NO: 25 and SEQ ID NO: 46.
Activated Factor VII substrate form
Said coagulation FVII polypeptide is an activated coagulation Factor VII (FVIIa) polypeptide.
Two-chain light/heavy composition for SEQ ID NO: 46
The two chains comprise a light chain consisting of amino acids 1-152 and a heavy chain consisting of amino acids 153-490 of SEQ ID NO: 46.
The claim coverage centers on producing an FVII polypeptide with three to five CTPs attached at the carboxy terminus, with dependent limitations defining allowable CTP sequence options, permitting linker-mediated attachment, restricting the produced CTP-modified FVII to named sequences, and refining the starting polypeptide and two-chain composition for a specified SEQ ID.
Stated Advantages
Extends circulatory half-life.
Improves Cmax/Tmax and AUC.
Maintains or enhances potency.
Reduced dosing frequency/compliance improvement is argued for in connection with longer-acting profiles.
Comparable secretion and antigen levels to native rFVII.
Retention of serine protease activity, with noted potency reductions for additional CTP copies.
Longer measurable clotting activity than NovoSeven® in FVIII-deficient mouse models.
Improved survival after a bleeding challenge in FVIII-deficient mouse models.
Improved pharmacokinetics, including increased half-life and AUC in rats.
Prolonged restoration of PT and reduced bleeding in warfarin-treated rat models compared to NovoSeven®.
Documented Applications
Therapeutic use in hemophilia and related bleeding disorders.
Hemophilia mouse models using FVIII-deficient mice for assessing clotting activity and survival after a bleeding challenge.
Pharmacokinetic and pharmacodynamic comparisons in rat models using PT restoration and bleeding outcomes, including warfarin-treated rats and comparisons of CTP-modified constructs versus NovoSeven®.
Administration route evaluation using subcutaneous and intravenous dosing, with PK/PD and survival after bleeding challenges described for the CTP-modified constructs.
Feasibility studies for FVII/FVIIa-CTP constructs in animal studies and hemophilia mouse models, with pharmacokinetics and clotting-related outcomes.
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