Conjugates of a factor VIII moiety having an oxime-containing linkage
Inventors
Bossard, Mary J. • Sheng, Dawei
Assignees
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Publication Number
US-11628205-B2
Publication Date
2023-04-18
Expiration Date
Abstract
The present disclosure provides conjugates comprising a Factor VIII moiety covalently attached via an oxime-containing linkage to a water-soluble polymer, such as for example, a polyethylene glycol polymer. Methods for preparing and for administering such conjugates, are also provided, as are water-soluble polymer oxyamine reagents useful for preparing the subject conjugates, among other things.
Core Innovation
The invention relates to Factor VIII–PEG conjugates in which a branched poly(ethylene glycol) polymer is covalently attached via an oxime-containing linkage to a carbohydrate of a glycosylated Factor VIII moiety. The linkage includes a residue of a carbonyl group of an oxidized carbohydrate on the Factor VIII moiety, and the conjugates target carbohydrate groups rather than lysine residues.
The branched poly(ethylene glycol) polymer is defined with structural parameters that include (m′) or (n) ranging from about 1 to about 4,000, and a spacer having an atom chain length of from 5 to 25 atoms with at least one heteroatom selected from O, S, and NH. The disclosure describes hydrolytically stable linkage performance for the oxime linkage and contrasts oxime linkage stability with hydrazide linkages.
The disclosure further provides pharmaceutically acceptable compositions that include the described conjugates with pharmaceutically acceptable excipients. Factor VIII moieties are described as glycosylated human recombinant B-domain deleted Factor VIII and glycosylated human recombinant full length Factor VIII, and the application is specified for hemophilia A.
Claims Coverage
The claims cover a branched poly(ethylene glycol)–Factor VIII conjugate covalently attached through an oxime-containing linkage to a carbohydrate on a glycosylated Factor VIII moiety. The inventive features include defined branching parameters, a heteroatom-containing spacer, specific Factor VIII variants, PEG molecular weight and PEGylation degree constraints, and pharmaceutical compositions with pharmaceutically acceptable excipients.
Branched PEG oxime-linked conjugate to Factor VIII carbohydrate
A conjugate comprising a branched poly(ethylene glycol) polymer covalently attached via an oxime-containing linkage to a carbohydrate of a Factor VIII moiety, where FVIII is a glycosylated Factor VIII moiety comprising carbohydrate groups and where CH-FVIII is a residue of a carbonyl group of an oxidized carbohydrate on the Factor VIII moiety.
Defined branched polymer extent and oxime-linked spacer heteroatoms
The conjugate having a structure selected from branched structures where (m′) or (n) for each branched structure independently ranges from about 1 to about 4,000, and X is a spacer comprising a chain of atoms having an atom chain length of from 5 to 25 atoms with at least one atom selected from O, S, and NH.
Specific glycosylated Factor VIII variant: B-domain deleted
A conjugate as in the independent claim in which the Factor VIII moiety is a glycosylated human recombinant B-domain deleted Factor VIII.
Specific glycosylated Factor VIII variant: full-length
A conjugate as in the independent claim in which the Factor VIII moiety is a glycosylated human recombinant full-length Factor VIII.
Quantitative average PEGylation degree in pharmaceutical context
A pharmaceutical composition or composition including a conjugate with the structure of the independent claim, where the average degree of PEGylation of the conjugates is between 1 and 3.5.
Constrained weight-average molecular weight of branched PEG
A conjugate as in the independent claim in which the branched poly(ethylene glycol) polymer has a weight-average molecular weight ranging from greater than 5,000 Daltons to 100,000 Daltons.
Pharmaceutically acceptable excipient formulation
A pharmaceutical composition including a conjugate of the independent claim together with a pharmaceutically acceptable excipient.
Overall, the claims cover an oxime-linked branched PEG covalently attached to carbohydrate on a glycosylated Factor VIII moiety with defined branching and spacer parameters, further specifying the Factor VIII variant and adding quantitative constraints on PEGylation degree and PEG molecular weight, as well as pharmaceutical compositions with pharmaceutically acceptable excipients.
Stated Advantages
Provides hydrolytically stable linkage performance for the oxime linkage.
Conjugates retain substantial biological activity versus unmodified Factor VIII, stated as approximately 45–75% or higher in APTT-based clotting assays.
Biological activity is dependent on PEG attachment site number, with specified ranges for linear and branched attachment sites.
Conjugates provide circulating half-life extension in Factor VIII-deficient mice.
Documented Applications
Used in connection with administration for hemophilia A.
Conjugates are characterized for biological activity using an APTT-based clotting assay and are evaluated for pharmacokinetics by circulating half-life extension in Factor VIII-deficient mice.
Pharmaceutical compositions are described for including the conjugates together with pharmaceutically acceptable excipients.
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