Adeno-associated virus Factor VIII vectors, associated viral particles and therapeutic formulations comprising the same
Inventors
Bunting, Stuart • Colosi, Peter Cameron • Pungor, Erno
Assignees
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Publication Number
US-11690898-B2
Publication Date
2023-07-04
Expiration Date
Abstract
The invention provides adeno-associated virus (AAV) Factor VIII (FVIII)-encoding/expressing vectors and virus, including AAV FVIII vectors with high expression activity and AAV FVIII vectors that express full-length or truncated functional FVIII protein. The invention also relates to methods of making the herein described AAV FVIII vectors, recombinant AAV FVIII virus particles comprising or expressing such vectors, associated pharmaceutical formulations comprising the same and therapeutic uses thereof.
Core Innovation
The invention relates to recombinant AAV Factor VIII (FVIII) gene therapy using an AAV FVIII virus that expresses functional FVIII, including full-length and truncated functional FVIII. In particular, the FVIII B-domain is replaced by a 14-aa SQ, generating FVIII-SQ. The document further describes AAV viral particles comprising these recombinant AAV FVIII virus constructs.
AAV FVIII vector designs are provided as size-reduced nucleic acids, including constructs identified as Proto/Construct series with size reduction to ≤45.0 kb. The document states that these vectors include modified promoter/enhancer and intron elements, including synthetic intron insertion and liver-specific regulatory elements. The vectors use AAV2 5′ and 3′ ITRs and are associated with the Proto 1/1S/2S/3S and Proto 4/5/6/7 construct series.
The invention also provides intravenous (IV) pharmaceutical formulations containing a recombinant AAV FVIII virus and defined excipients. The document describes stable liquid formulations for AAV5-FVIII-SQ, including sodium phosphate, sodium chloride, mannitol, and poloxamer 188. The document states that the formulations are stable at ≤65°C or ≤−25°C and reports AAV viral genome concentration and associated preclinical and early human clinical performance.
Claims Coverage
The independent claim coverage is concentrated on one independent claim directed to a specific IV pharmaceutical formulation and excipient set, with additional dependent claims refining the recombinant AAV FVIII virus identity, viral vector concentration/dose ranges, liquid form, and IV administration. The inventive features across the claim set include the defined excipient concentrations and the defined recombinant AAV FVIII virus formulation context.
Recombinant AAV FVIII virus excipient formulation with defined concentration ranges
A pharmaceutical formulation comprising a recombinant AAV FVIII virus, sodium phosphate at a concentration of from about 0.1 mg/ml to about 3 mg/ml, sodium chloride at a concentration of from about 1 mg/ml to about 20 mg/ml, mannitol at a concentration of from about 5 mg/ml to about 40 mg/ml, and poloxamer 188 at a concentration of from about 0.1 mg/ml to about 4 mg/ml.
AAV5-FVIII-SQ recombinant AAV FVIII virus
The pharmaceutical formulation where the recombinant AAV FVIII virus is specified as AAV5-FVIII-SQ.
Defined AAV FVIII viral vector concentration and dose ranges
A pharmaceutical formulation containing recombinant AAV FVIII virus at defined concentration/dose ranges using vg/ml and vg/kg units, including ranges such as 1E12 to 2E14 vg/ml and dose ranges such as 6E12 to 6E13 vg/kg.
Specific viral vector concentration point
A pharmaceutical formulation provided that includes an AAV FVIII virus at a concentration of about 2E13 vg/ml.
Liquid pharmaceutical formulation
A pharmaceutical formulation in which the composition is a liquid as defined in the formulation of the independent claim.
Intravenous (IV) administration formulation
A pharmaceutical formulation formulated for intravenous (IV) administration.
Overall, the claim set is directed to an IV liquid pharmaceutical formulation comprising a recombinant AAV FVIII virus together with a defined excipient set (sodium phosphate, sodium chloride, mannitol, poloxamer 188) with concentration ranges, with dependent refinements specifying AAV5-FVIII-SQ and defined AAV FVIII viral genome concentration/dose ranges (including about 2E13 vg/ml).
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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