Stable aqueous formulations of adenovirus vectors
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Publication Number
US-9254332-B2
Publication Date
2016-02-09
Expiration Date
Abstract
The present invention is based on the surprising discovery that the inclusion of an anionic polymer in the adenovirus formulation enhances long-term stability of the vector composition. An aqueous formulation comprising an adenovirus vector and at least one anionic polymer is provided, together with methods of the preparation of a storage stable adenovirus aqueous formulation.
Core Innovation
The patent describes stable aqueous adenovirus vector formulations in which an anionic polymer, specifically dextran sulfate or a salt form thereof, is included at a concentration ranging from about 0.5 mg/mL to about 10 mg/mL. The aqueous formulation comprises an adenovirus vector and dextran sulfate, and the dextran sulfate is characterized by defined average molecular weight ranges. The disclosure emphasizes that inclusion of the dextran sulfate enhances long-term infectivity stability of the adenovirus vector in storage.
The formulation is further described using combinations of components including TRIS and benzoate ion, EDTA, sucrose, polysorbate 80, and polyvinyl alcohol, with pH values about 6, about 7, or about 6.5 depending on the formulation variant. Additional formulation constraints include limiting infectivity loss over defined storage conditions, including storage at 25°C, and specifying measurement approaches such as TCID50 or FACS. Divalent cation salts can also be included from a defined list, and dextran sulfate molecular weight ranges can be selected to form single or mixed molecular-weight components.
In the context of storage stability, the disclosure reports that dextran-sulfate-containing aqueous formulations maintain high infectivity over extended periods, with targets described for up to about 24 months at 2–8°C and about 3 months at 25°C. The patent includes comparisons indicating improved performance of dextran-sulfate-containing formulations versus cited prior art under both accelerated and longer-term conditions. Overall, the core innovation is the use of dextran sulfate and defined variants in aqueous adenovirus vector formulations to achieve enhanced infectivity stability during storage.
Claims Coverage
The independent claims cover three main inventive features: a basic aqueous formulation comprising an adenovirus vector and dextran sulfate or salt form thereof at a specified concentration range, a more specific aqueous formulation reciting defined dextran sulfate molecular-weight ranges together with a particular component set and pH values, and a method for preparing a storage stable adenovirus aqueous liquid formulation by forming a mixture to reach the same formulation concentration range.
Dextran sulfate aqueous formulation at a defined concentration range
An aqueous formulation comprising an adenovirus vector and a dextran sulfate or salt form thereof at a concentration ranging from about 0.5 mg/mL to about 10 mg/mL.
Multiple dextran sulfate molecular-weight ranges with defined component set and pH
An aqueous formulation comprising an adenovirus vector; a dextran sulfate with an average molecular weight between about 6500 Da and about 10000 Da; a dextran sulfate with an average molecular weight between about 500000 Da and about 3000000 Da; a combination of TRIS and benzoate ion; EDTA; sucrose; polysorbate 80; and polyvinyl alcohol, wherein the pH of the formulation is about 6; or alternatively wherein the component set is modified as recited and the pH is about 7; or alternatively wherein the component set is modified as recited and the pH is about 6.5.
Forming a mixture to prepare a storage stable adenovirus aqueous liquid formulation
A method for the preparation of a storage stable adenovirus aqueous liquid formulation, comprising forming a mixture of an adenovirus vector and a dextran sulfate or salt form thereof at a concentration ranging from about 0.5 mg/mL to about 10 mg/mL.
The claims primarily protect dextran sulfate-containing aqueous adenovirus vector formulations that achieve storage stability, with independent claim coverage spanning a general formulation concentration range, a specific formulation variant defined by dextran sulfate molecular-weight ranges plus a component set and pH values, and a corresponding method based on forming the dextran sulfate mixture at the same concentration range. Dependent claims further narrow to specific dextran sulfate molecular weights, specify displaced buffer relationships, define infectivity-loss thresholds after storage, and limit the adenovirus vector identity to human adenovirus, including Ad5 or Ad35.
Stated Advantages
Enhances long-term infectivity stability of the adenovirus vector in aqueous storage formulations.
Maintains high infectivity over extended storage periods, including targets described for up to about 24 months at 2–8°C and about 3 months at 25°C.
Improved performance of dextran-sulfate-containing formulations versus cited prior art under accelerated and longer-term conditions.
Documented Applications
Storage of adenovirus vector aqueous liquid formulations with demonstrated infectivity stability over defined time periods at 2–8°C and at 25°C.
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