Long-acting coagulation factors and methods of producing same
Inventors
HERSHKOVITZ, Oren • Moschcovich, Laura
Assignees
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Publication Number
US-11976106-B2
Publication Date
2024-05-07
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 and pharmaceutical formulations comprising the polypeptides and polynucleotides of the disclosure and methods of using and producing same are also disclosed.
Core Innovation
The invention provides a human chorionic gonadotropin carboxy terminal peptide (CTP)-modified human active Factor VII (FVIIa) polypeptide in a substantially pure and active form. The CTP-modified FVIIa comprises three CTP molecules attached in tandem to the C-terminal end of FVIIa, comprises the amino acid sequence set forth in SEQ ID NO: 7, and has a purity of at least 90%.
The disclosed CTP-modified FVIIa is defined by a target profile of biochemical and molecular characteristics. The polypeptide has a high sialic acid content of at least 15 mol/mol, a high glycosylation form comprising an O-glycan content of at least 10 mol/mol, a low oxidized form consisting of less than 5% oxidized form, at least 60% charged N-glycans, and a high percentage of carboxylated glutamic acid (Gla) residues consisting of at least 90% Gla residues.
The document further specifies a substantially pure and active CTP-modified FVIIa with a two-chain disulfide-linked heterodimer structure, an S-S bridge between cysteine 135 and cysteine 262, and light and heavy chain amino acid ranges within SEQ ID NO: 7.
Claims Coverage
The independent claim coverage centers on a substantially pure and active CTP-modified FVIIa with three tandem CTP molecules at the C-terminal end, defined biochemical quality attributes, sequence and purity requirements, and a potency threshold.
Tandem triple CTP-modified FVIIa at the C-terminal end with required purity
A human chorionic gonadotropin carboxy terminal peptide (CTP)-modified human active Factor VII (FVIIa) polypeptide comprising three CTP molecules attached in tandem to the C-terminal end of FVIIa, wherein the polypeptide is in a substantially pure and active form, wherein the amino acid sequence is set forth in SEQ ID NO: 7, and wherein the purity is at least 90%.
Defined glycosylation, sialylation, oxidation, and charged glycan profile
A CTP-modified FVIIa polypeptide comprising high sialic acid content of at least 15 mol/mol, high glycosylation form comprising O-glycan content of at least 10 mol/mol, low oxidized form consisting of less than 5% oxidized form, and at least 60% charged N-glycans.
High carboxylated Gla content and minimum potency
A CTP-modified FVIIa polypeptide comprising a high percentage of carboxylated glutamic acid (Gla) residues consisting of at least 90% Gla residues and a potency of at least 10,500 U/mg.
The claims define triple-tandem CTP-modified active Factor VIIa at the C-terminal end, together with strict biochemical quality attributes, an SEQ ID NO: 7 sequence, at least 90% purity, and potency of at least 10,500 U/mg.
Stated Advantages
Provides a CTP-modified FVIIa polypeptide that is in a substantially pure and active form.
Achieves defined biochemical quality attributes including high sialic acid content, high O-glycan content, low oxidation, high carboxylated Gla residues, and at least 60% charged N-glycans.
Achieves high potency of at least 10,500 U/mg.
Documented Applications
Not explicitly described in patent.
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