Expression vector delivery system and use thereof for inducing an immune response
Inventors
SEDER, Robert • Lynn, Geoffrey • Seymour, Leonard
Assignees
University of Oxford • US Department of Health and Human Services
Publication Number
US-10799580-B2
Publication Date
2020-10-13
Expiration Date
2036-09-09
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Abstract
Embodiments of a novel system for delivering an expression vector encoding an antigen to a subject that allows for spatiotemporal control over stimulation of the subject's immune response to the antigen are provided. In some embodiments, the expression vector delivery system includes a polymer linked to an adjuvant in prodrug form that can form polymer nanoparticles and enter a cell (such as an immune cell) under physiological conditions. In some embodiments, the adjuvant is linked to the polymer by an enzyme degradable labile bond, the cleavage of which activates the adjuvant to stimulate an immune response.
Core Innovation
The invention provides a novel system for delivering an expression vector encoding an antigen to a subject, enabling spatiotemporal control over the activation of the subject’s immune response to the antigen. The system includes a polymer linked to an adjuvant in a prodrug form capable of forming polymer nanoparticles that can enter cells such as immune cells under physiological conditions. The adjuvant is linked to the polymer by an enzyme-degradable labile bond; cleavage of this bond activates the adjuvant to stimulate an immune response.
The expression vector can be complexed with the polymer to form polymer nanoparticles that are taken up by cells, such as antigen presenting cells. Within these cells, the antigen encoded by the nucleic acid molecule is expressed, and the adjuvant prodrug is enzymatically processed to its active form. This processing is sufficiently slow to delay immune activation by the adjuvant until after antigen expression, preventing premature immune responses that could inhibit antigen production or target the expression vector itself.
The problem addressed is that nucleic acid-based vaccines (DNA or RNA) are weakly immunogenic and require adjuvants to enhance immune responses. However, conventional adjuvants stimulate immune responses that can target and reduce expression of the expression vector, reducing antigen expression and T-cell responses. Thus, there is a need for adjuvants that enhance immunity only after sufficient antigen expression has occurred. The disclosed system overcomes this by providing an adjuvant in prodrug form linked to a polymer, enabling controlled activation within cells to optimize immune stimulation without compromising antigen expression.
Claims Coverage
The patent includes one independent claim focused on a method of inducing an immune response using a polymer linked to an adjuvant prodrug and an expression vector forming polymer nanoparticles that enter cells to activate immune stimulation after antigen expression.
Expression vector delivery system with polymer-linked adjuvant prodrug
A method that administers locally an immunogenic composition comprising a polymer linked to an adjuvant prodrug and an expression vector encoding an antigen, where the polymer and expression vector form polymer nanoparticles capable of cellular entry.
Use of toll-like receptor 7/8 agonist as adjuvant prodrug
The adjuvant prodrug includes a toll-like receptor 7/8 agonist having a specified chemical structure masked by a labile bond that is cleavable intracellularly to activate immune responses.
Non-immunogenic DNA plasmid expression vector without CpG motifs
Use of a DNA plasmid expression vector lacking CpG motifs to reduce immunogenicity of the vector itself and optimize antigen expression.
Cationic polymer complexed electrostatically with expression vector
Use of cationic polymers such as poly(ethylenimine), poly(lysine), or poly(arginine) linked to the adjuvant prodrug and complexed electrostatically with the expression vector to form nanoparticles.
Controlled adjuvant activation timing via enzyme-degradable labile bond
The adjuvant prodrug is linked via an enzyme-degradable labile bond, which is cleaved intracellularly by proteases such as cathepsins, delaying immune activation until after antigen expression (typically 1–10 days post administration).
Defined polymer and monomer composition parameters
The polymer comprises from 5 to 500 monomer units and the ratio of adjuvant prodrug to monomer ranges from 1:100 to 1:1 mol/mol, optionally 1:20 to 1:10 mol/mol.
The claims cover a method of inducing an immune response by administering polymer nanoparticles comprising a polymer linked to a TLR-7/8 agonist prodrug and a nucleic acid expression vector, designed for delayed intracellular activation of the adjuvant to optimize antigen expression and immune stimulation, with specific details on polymer composition, adjuvant structure, and enzymatic cleavage.
Stated Advantages
Allows spatiotemporal control of immune activation to optimize innate immune stimulation without prematurely inhibiting antigen expression.
Delays immune activation by the adjuvant until after antigen is expressed, improving antigen-targeted T-cell responses.
Enhances retention of the prodrug adjuvant near the site of injection and lymph nodes, and promotes uptake by immune cells.
Enables use of non-immunogenic expression vectors (e.g., lacking CpG motifs) to reduce anti-vector immune responses.
Permits controlled release of active adjuvant through enzyme-degradable bonds, allowing improved safety and efficacy profiles for gene delivery vaccines.
Documented Applications
Induction of immune responses against infectious agents, including viral, bacterial, and fungal antigens encoded by the nucleic acid expression vector.
Treatment or prevention of tumors and cancers by inducing an immune response against tumor-associated or neoantigens encoded by the expression vector.
Therapeutic or prophylactic use of DNA or RNA-based vaccines encoding antigens for personalized immunotherapy, including neoantigen vaccines.
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