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-12324828-B2
Publication Date
2025-06-10
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 disclosure describes Factor VIIIPEG oxime conjugates formed by oxidizing Factor VIII carbohydrates to generate aldehyde groups and coupling the aldehydes with polymeric oxyamine reagents that include an oxyamine group. The coupling forms a covalent oxime linkage between the polymeric reagent and the Factor VIII moiety, producing PEG-containing conjugates.
Polymeric oxyamine reagents include linear PEG-oxymine and reverse urethane (RU)-PEG-2 oxime, each configured to react through oxyamine groups to attach PEG to the Factor VIII moiety. The disclosure also describes a polymeric oxyamine reagent having a selected spacer fragment X and each (n) ranging from about 1 to about 4,000, including a specific spacer fragment -NH(CH2)2NHC(O)CH2-.
The disclosure addresses carbohydrate-directed PEGylation for FVIII by contrasting it with lysine PEGylation, noting that the carbohydrate sites are fewer than lysines. It also describes oxidation to generate a carbonyl suitable for oxime formation, including periodate oxidation to provide a carbonyl/aldehyde on FVIII carbohydrates for subsequent oxime linkage formation without additional enzymes or protein engineering, and pharmaceutical compositions and administration are described for treating hemophilia A using the FVIII conjugates with pharmaceutically acceptable excipients.
Claims Coverage
The document portion provided supports one independent claim directed to a polymeric oxyamine reagent structure, with dependent claims refining spacer identity, a repeat parameter value, and a branched poly(ethylene glycol) molecular-weight range. The independent claim defines the core structure of the oxyamine reagent via the spacer fragment X and the range of (n).
Polymeric oxyamine reagent with defined spacer X and (n) range
A polymeric oxyamine reagent having a structure selected such that X is NH(CH2)1-6NHC(O)CH2 4 and each (n) ranges from about 1 to about 4,000.
Spacer X fixed as a specific oxyamine-containing ethylene spacer
The polymeric oxyamine reagent is defined such that X equals NH(CH2)2NHC(O)CH2 4.
Polymeric oxyamine reagent with (n) about 227
The polymeric oxyamine reagent is defined such that each (n) is approximately 227.
Branched poly(ethylene glycol) molecular weight range
The branched poly(ethylene glycol) polymer in the polymeric oxyamine reagent has a weight-average molecular weight greater than 5,000 Daltons to 100,000 Daltons.
Across the independent claim and its dependents, the inventive concept is centered on a polymeric oxyamine reagent defined by a specific oxyamine-containing spacer fragment X, a defined repeat parameter (n), and a molecular-weight-limited branched poly(ethylene glycol) polymer component.
Stated Advantages
Conjugation is described as carbohydrate-directed PEGylation, contrasted with lysine PEGylation, with an emphasis that there are fewer carbohydrate sites than lysines.
Retention of biological activity in PEG-oxime-FVIII conjugates versus native FVIII is described.
Retained Factor VIII clotting activity for PEG-oxime conjugates is reported.
Higher retained clotting activity is reported for RU-PEG2-oxime examples relative to linear PEG-oxime conjugates.
Documented Applications
Treating hemophilia A using FVIII conjugates in pharmaceutical compositions with pharmaceutically acceptable excipients.
Conjugation of PEG oxyamines to Factor VIII to form PEGFactor VIII conjugates (PEG-oxime-FVIII conjugates) is described.
Pharmaceutical formulations are described in connection with the conjugates and pharmaceutically acceptable salts.
Hemophilia A treatment context is described via Factor VIII and conjugate performance considerations.
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