Stable aqueous formulations of adenovirus vectors
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Publication Number
US-9744242-B2
Publication Date
2017-08-29
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 disclosed subject matter concerns stable aqueous adenovirus vector formulations. The formulations include an adenovirus vector containing a whole transgene and carboxymethyl cellulose or a salt form thereof at a concentration ranging from about 0.5 mg/mL to about 10 mg/mL. The document relates that inclusion of an anionic polymer such as carboxymethyl cellulose enhances long-term infectivity stability of the adenovirus vector.
The document further specifies formulation parameters that maintain infectivity over time. It describes conventional buffer systems versus displaced buffers and relates constraints involving pH and pKa relationships for displaced buffers. In addition, it describes optional excipients and additives including sucrose or other tonicity modifiers, non-ionic surfactants, EDTA, and divalent cation salts, together with other polymers such as PVA, and it includes discussion of anionic polymer forms such as dextran sulfate.
The document reports that infectivity stability is evaluated using log infectivity loss and compared across formulation variations. It describes storage conditions and resulting stability duration, including long-term stability at refrigerated temperatures and shorter-term stability at room temperature. It also reports quantitative infectivity measurements using TCID50 and FACS infectivity measurements and compares the disclosed compositions with prior art formulations.
Claims Coverage
The partial content includes three independent claims (clm-00001, clm-00012, and clm-00016). Across these independent claims, the inventive features focus on specific aqueous adenovirus vector formulations using a defined concentration of carboxymethyl cellulose (or salt forms), optional co-components (buffer systems and EDTA), defined pH, and an aqueously mixed preparation for storage stability. Additional dependents narrow adenovirus identity to specified human serotypes (Ad5 and Ad35) and add stability and measurement-related limitations.
Carboxymethyl cellulose aqueous adenovirus vector formulation
An aqueous formulation comprising an adenovirus vector containing a whole transgene and carboxymethyl cellulose or a salt form thereof at a concentration ranging from about 0.5 mg/mL to about 10 mg/mL.
Carboxymethyl cellulose formulation at about pH 7 with specific buffer/chelant combinations
An aqueous formulation comprising either (i) an adenovirus vector containing a whole transgene; carboxymethyl cellulose or a salt form thereof at a concentration ranging from about 0.5 mg/mL to about 10 mg/mL; and a combination of TRIS and benzoate ion; and EDTA; wherein the pH of the formulation is about 7; or (ii) an adenovirus vector containing a whole transgene; carboxymethyl cellulose or a salt form thereof at a concentration ranging from about 0.5 mg/mL to about 10 mg/mL; and a combination of phosphate and citrate ion; wherein the pH of the formulation is about 7.
Storage-stable aqueous formulation preparation by mixing adenovirus vector and carboxymethyl cellulose
A method for the preparation of a storage stable adenovirus vector aqueous liquid formulation, comprising forming a mixture of an adenovirus vector containing a whole transgene and carboxymethyl cellulose or a salt form thereof at a concentration ranging from about 0.5 mg/mL to about 10 mg/mL.
Overall, the claim coverage centers on aqueous adenovirus vector formulations that use carboxymethyl cellulose (or salt forms) at about 0.5 mg/mL to about 10 mg/mL, optionally paired with specific buffer ion systems (TRIS/benzoate plus EDTA or phosphate plus citrate) at about pH 7, and on a method comprising forming the mixture to obtain a storage stable adenovirus vector aqueous liquid formulation. Dependent claims in the provided partial content further narrow embodiments to human adenovirus serotypes Ad5 or Ad35 and include stability/infectivity measurement limitations.
Stated Advantages
Enhanced long-term infectivity stability of the adenovirus vector in an aqueous formulation containing carboxymethyl cellulose.
Maintains infectivity over long-term storage and shorter-term storage under described temperature conditions, with low infectivity loss thresholds as characterized by log infectivity loss.
Documented Applications
Use as storage stable adenovirus vector aqueous liquid formulations, characterized by infectivity stability measurements (TCID50 and FACS infectivity measurements) under described storage conditions.
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