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Publication Number
US-9556246-B2
Publication Date
2017-01-31
Expiration Date
Abstract
Polypeptides are susceptible to denaturation or enzymatic degradation in the blood, liver or kidney. Due to the low stability of some polypeptides, it has been required to administer polypeptide drugs in a sustained frequency to a subject in order to maintain an effective plasma concentration of the active substance. Furthermore, pharmaceutical compositions of therapeutic peptides preferably have a shelf-life of several years in order to be suitable for common use. However, peptide compositions are inherently unstable due to sensitivity towards chemical and physical degradation. In part, the invention provides SAP variant proteins, compositions, pharmaceutical preparations and formulations having a prolonged in vivo half-life, prolonged shelf-life, or rather increased in vitro stability, or increased manufacturing efficiency compared to human SAP. Advantages of increased plasma half-life include, but are not limited to, reducing the amount and/or frequency of dosing.
Core Innovation
Serum Amyloid P (SAP) variant proteins are provided as a pharmaceutical composition comprising five SAP protomers, where each protomer has an amino acid sequence at least 95% identical to SEQ ID NO: 1. Across the five protomers, all include an amino acid at position 167 of SEQ ID NO: 1 that is not E, and the composition further includes a pharmaceutically acceptable ophthalmic vehicle.
The SAP variants incorporate amino acid substitutions at positions associated with glycan-site disruption and protease resistance, together with reduced glycosylation, and covalently crosslinked SAP oligomers are described, including covalent attachment of inert polymers such as PEG or dextran. Site-specific conjugation is achieved using introduced cysteine or via a transglutaminase amine acceptor (glutamine).
Documented examples relate these design changes to reduced calcium-mediated aggregation and maintained or comparable fibrocyte-potency, as well as improved plasma half-life and in vitro/in vivo stability compared with serum-derived SAP variants such as asialo hSAP. The disclosure also describes specific cross-linker classes for SAP oligomer formation and pharmaceutical preparation for ophthalmic administration.
Claims Coverage
The primary independent claim covers a pharmaceutical composition comprising a five-protomer SAP variant and an ophthalmic vehicle. The inventive features emphasized include the five-protomer composition, sequence identity to SEQ ID NO: 1, the position-167 non-E substitution, and the ophthalmic vehicle context; dependents further specify position-167 allowable amino acids and functional resistance to calcium-dependent autoaggregation, plus ophthalmic treatment and intraocular injection.
Five-protomer SAP variant composition
A pharmaceutical composition comprising a Serum Amyloid P (SAP) variant comprising five SAP protomers.
High sequence identity to SEQ ID NO: 1
Each of the SAP protomers have an amino acid sequence at least 95% identical to SEQ ID NO: 1.
Position 167 not E across all protomers
All five SAP protomers comprise an amino acid at position 167 of SEQ ID NO: 1 that is not E.
Ophthalmic vehicle in the pharmaceutical composition
The pharmaceutical composition comprises a pharmaceutically acceptable ophthalmic vehicle.
Resistance to calcium-dependent autoaggregation
The SAP variant is more resistant to calcium-dependent autoaggregation than a corresponding sample of non-variant human SAP.
Allowed amino acids at position 167
Each SAP protomer has, at position 167 of SEQ ID NO: 1, one of aspartate (D), asparagine (N), glutamine (Q), alanine (A), or histidine (H).
Ophthalmic disease treatment by administration
A method treating macular degeneration, retinal or vitreal retinopathy, fibrosis related disorder or condition following trabeculectomy or other filtration surgery of the eye, Grave's ophthalmopathy, diabetic retinopathy, or glaucoma by administering the pharmaceutical composition of claim 2 to a patient in need thereof.
Intraocular injection administration
The pharmaceutical composition is administered by intraocular injection.
Across the independent-claim focus, the disclosed inventive concept is a five-protomer SAP variant defined by sequence identity to SEQ ID NO: 1 and a position-167 substitution that is not E, formulated with a pharmaceutically acceptable ophthalmic vehicle, with further narrowing to include resistance to calcium-dependent autoaggregation, specified allowable amino acids at position 167, and ophthalmic treatment via intraocular injection.
Stated Advantages
Prolonged plasma half-life compared with human serum-derived SAP, including examples versus asialo hSAP.
Increased in vitro stability and in vivo stability compared with human serum-derived SAP variants.
Enhanced manufacturing efficiency.
Reduced calcium-mediated aggregation.
Maintained or comparable bioactivity, including maintained or similar fibrocyte-potency and comparable activity in PEGylated SAP examples.
Documented Applications
Pharmaceutical composition for treating macular degeneration, retinal or vitreal retinopathy, fibrosis related disorder or condition following trabeculectomy or other filtration surgery of the eye, Grave's ophthalmopathy, diabetic retinopathy, or glaucoma.
Ophthalmic administration context including administration by intraocular injection.
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