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Publication Number
US-11530401-B2
Publication Date
2022-12-20
Expiration Date
Abstract
Short-acting Factor VII peptides are disclosed. A shortened half-life is desirable for treatment of acute bleeding and similar disorders. Modification of the sialylation and/or glycosylation of Factor VII and variants thereof produced peptides useful in treating conditions of acute bleeding.
Core Innovation
The invention relates to isolated variant Factor VII polypeptides having an amino acid sequence with at least 90% identity to the amino acid sequence of SEQ ID NO: 16 and containing mutation(s) in the Gla domain. The mutation(s) increase the variant Factor VII polypeptide affinity for activated platelets, and the variant comprises N-linked glycosylation sites of wild-type human Factor VII at amino acid residues 145 and 322 with reference to SEQ ID NO: 16.
The variant Factor VII polypeptide further has a ratio of moles of conjugated sialic acid to moles of N-linked glycan between 0 and 2.0. The disclosed variants are engineered to reduce conjugated sialic acid while retaining the wild-type N-linked glycosylation sites at residues 145 and 322.
This is associated with short-acting behavior intended for acute bleeding treatment. The document reports that variant preparations with reduced conjugated sialic acid exhibit retained or increased in vitro procoagulant activity and show markedly shortened in vivo pharmacokinetic half-lives relative to longer-acting forms.
Claims Coverage
The independent claims are directed to isolated variant Factor VII polypeptides with specified sequence identity, Gla-domain mutations that increase affinity for activated platelets, retention of wild-type N-linked glycosylation sites at residues 145 and 322, and a defined conjugated sialic acid:N-linked glycan mole ratio between 0 and 2.0. Across the independent claims, the inventive coverage is organized around three inventive features.
Gla-domain mutations that increase activated platelets affinity with retained 145 and 322 glycosylation sites
An isolated variant Factor VII polypeptide comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 16 and comprising mutation(s) in the Gla domain that increase the variant Factor VII polypeptide affinity for activated platelets, wherein the variant Factor VII polypeptide comprises N-linked glycosylation sites of wild-type human Factor VII at amino acid residues 145 and 322 with reference to SEQ ID NO: 16 and further wherein the variant Factor VII polypeptide has a ratio of moles of conjugated sialic acid to moles of N-linked glycan between 0 and 2.0.
Increased activated platelets affinity variant with retained 145 and 322 glycosylation sites and low conjugated sialic acid ratio
An isolated variant Factor VII polypeptide comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 16 and comprising mutation(s) that result in increased Factor VII polypeptide affinity for activated platelets, wherein the variant Factor VII polypeptide comprises N-linked glycosylation sites of wild-type human Factor VII at amino acid residues 145 and 322 with reference to SEQ ID NO: 16 and further wherein the variant Factor VII polypeptide has a ratio of moles of conjugated sialic acid to moles of N-linked glycan between 0 and 2.0.
Overall, the independent claim set covers short-acting isolated variant Factor VII polypeptides defined by sequence identity to SEQ ID NO: 16, Gla-domain mutation(s) that increase affinity for activated platelets, preservation of N-linked glycosylation sites at residues 145 and 322, and a conjugated sialic acid to N-linked glycan mole ratio between 0 and 2.0. Dependent claims further narrow embodiments by specifying particular Gla-domain mutations and tighter ratio thresholds, and they also include preparation methods and therapeutic treatment for bleeding-related disorders.
Stated Advantages
Short duration of action intended to treat acute bleeding/hemorrhage.
Retained or increased in vitro procoagulant activity.
Markedly shortened in vivo pharmacokinetic half-lives (faster clearance).
Reduced blood loss in in vivo models.
Reduced thrombin generation marker (TAT) and reduced thrombus formation in thrombosis models.
Therapeutic intent to reduce thromboembolic risk via short duration of action.
Documented Applications
Treating a disease or disorder in which blood clot formation is desirable, where the disorder is selected from hemorrhage and related bleeding conditions including gastrointestinal bleeding, uncontrolled bleeding, bleeding during transplantation or resection or surgery, variceal bleeding, thrombocytopenia-related bleeding contexts, hemophilia, intracranial hemorrhage, traumatic injuries, and reversals of anticoagulants (as listed), among others.
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