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Long-acting coagulation factor vii and methods of producing same

A technology of active factors and molecules, applied in coagulation/fibrinolytic factors, chemical instruments and methods, prolonging plasma life fusion, etc.

Pending Publication Date: 2019-04-02
OPKO BIOLOGICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the cost of FIX and issues with relatively rapid clearance make developing long-acting FIX a challenging task

Method used

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  • Long-acting coagulation factor vii and methods of producing same
  • Long-acting coagulation factor vii and methods of producing same
  • Long-acting coagulation factor vii and methods of producing same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0440] FVII-CTP 3 Feasibility study in FVIII-deficient hemophiliac mice

[0441] Tested FVII-CTP, FVII-CTP 2 and FVII-CTP 3 Study of harvest PK profile and coagulation activity relative to commercial FVII. Relative to FVII-CTP and FVII-CTP 2 Harvest or rhFVII, FVII-CTP 3 Exhibits an improved PK profile while maintaining its coagulation activity. To further characterize FVII-CTP 3 characterized in vitro and in vivo, generated small stable libraries of expressed and secreted proteins, and developed purification and activation procedures.

[0442] In the current study, FVIIa-CTP was tested in FVIII-deficient mice 3 pharmacokinetic and pharmacodynamic properties. Evaluate the PK profile of the protein. Establish a PK profile based on FVIIa-specific activity and compare with commercial products Compare. In addition, FVIIa-CTP after tail null transection (survival study) was tested 3 Long-lasting in vivo hemostatic ability to induce coagulation in FVIII-deficient mice.

...

Embodiment 2

[0530] Biochemical Properties of MOD-5014 Relative to Commercial Recombinant hFVIIa - Effect of Carboxy-Terminal Peptide (CTP) on Factor VIIa Activity

[0531] Project Rationale and Summary

[0532] These studies were designed to evaluate the biochemical properties of MOD-5014 relative to commercial recombinant hFVIIa (referred to herein as MOD-5000).

[0533] Research checks:

[0534] Cleavage of synthetic substrate of MOD-5014

[0535] Tissue factor (TF) binding of MOD-5014 measured by synthetic substrate cleavage

[0536] TF binding of MOD-5014 measured by Factor X (FX) activation

[0537] Kinetics of FX activation by TF-bound MOD-5014

[0538] Lipid binding of MOD-5014 measured by FX activation

[0539] Kinetics of factor activation by lipid-bound MOD-5014

[0540] Inactivation of MOD-5014 by antithrombin (AT)

[0541] Inactivation of MOD-5014 by TFPI

[0542] The overall data suggest that MOD-5014 has a similar mechanism of action with slightly reduced catalytic a...

Embodiment 3

[0625] Production of CTP-modified activator VII

[0626] Purpose

[0627] The purpose of the preparative method was to develop a fed-batch upstream method using CHO cells in a chemically defined medium by recombinant DNA technology followed by a robust and scalable downstream method for the purification of hyperglycosylated and hyper-γ-carboxylated MOD-5014. In other words, produce and purify MOD-5014 with the highest γ-carboxylation content and effectively remove process and production related impurities. It is important to analyze O-glycans, N-glycans, percent sialic acid, oxidation-associated forms, potency (tested by STA-CLOT assay), percent Gla domain (or percent uncarboxylated glutamic acid residues , and the percentage of unactivated FVII).

[0628] production process

[0629] Transfection and stable clone selection

[0630] The cDNA encoding MOD-5014 was transfected into CHO cells (dhfr-negative CD DG44 cells suitable for growth in protein-free media and suspension ...

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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 polynucleotidesencoding the same are disclosed. Pharmaceutical compositions and pharmaceutical formulations comprising the polypeptides and polynucleotides of the disclosure and methods of using and producing sameare also disclosed.

Description

technical field [0001] Polypeptides comprising at least one carboxy-terminal peptide (CTP) of chorionic gonadotropin linked to the carboxy-terminus of a coagulation factor and polynucleotides encoding the polypeptides are disclosed. Also disclosed are pharmaceutical compositions and pharmaceutical formulations comprising the polypeptides and polynucleotides of the disclosure and methods of using and producing them. Background technique [0002] The development of clotting factor replacement therapy has changed the lives of many individuals with hemophilia. Hemophilia is a group of inherited genetic disorders that impair the body's ability to control blood clotting, or clotting. People with hemophilia do not produce sufficient amounts of the Factor VIII or Factor IX proteins, which are necessary for effective blood clotting. In people with severe hemophilia, even minor injuries can cause blood loss for days or weeks, and complete healing may not occur, leading to possible p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/59C07K14/61
CPCC07K14/59C07K14/745C07K2319/31C07K14/61A61P7/04A61K38/00A61K47/64A61K38/36
Inventor 奥伦·赫什科维茨劳拉·莫斯科维奇
Owner OPKO BIOLOGICS
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