Peptide vaccine formulations and use thereof for inducing an immune response
Inventors
SEDER, Robert • Lynn, Geoffrey
Assignees
US Department of Health and Human Services
Publication Number
US-11938177-B2
Publication Date
2024-03-26
Expiration Date
2037-02-27
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Abstract
Embodiments of a novel platform for delivering a peptide antigen to a subject to induce an immune response to the peptide antigen are provided. For example, nanoparticle polyplexes are provided that comprise a polymer linked to a peptide conjugate by an electrostatic interaction. The conjugate comprises a peptide antigen linked to a peptide tag through an optional linker. An adjuvant may be included in the nanoparticle polyplex, linked to either the polymer or the conjugate, or admixed with the nanoparticles. The nanoparticle polyplex can be administered to a subject to induce an immune response to the peptide antigen.
Core Innovation
The invention provides novel immunogenic compositions comprising nanoparticle polyplexes that include a peptide antigen conjugate linked to a polymer by electrostatic interaction. The conjugate comprises a peptide antigen linked to a peptide tag through an optional linker. An adjuvant may be included in the nanoparticle polyplex, linked to either the polymer or the conjugate, or admixed with the nanoparticles. These nanoparticle polyplexes can be administered to a subject to induce an immune response to the peptide antigen.
The problem addressed arises from the difficulty of generating effective immune responses to peptide antigens, particularly soluble peptides, using peptide-based vaccines. Peptide vaccines have broad physical and chemical diversity, making formulation unpredictable and immune responses variable depending on peptide pharmacokinetics. Traditional strategies focus on tumor-associated self-antigens, which can cause immune toxicity, or neoantigens, which are unique to tumor cells but require individualized vaccine approaches that are rapid, safe, and scalable. There is a need for a generalized, controlled, and chemically defined vaccine platform that enables formation of particulate peptide vaccines that promote high magnitude T cell responses to any peptide antigen.
The disclosed immunogenic compositions overcome these prior difficulties by using peptide antigen conjugates with peptide tags that provide electrostatic charge, facilitating nanoparticle formation with polymers of opposite charge through charge neutralization and stabilization by hydrophobic and pi orbital stacking interactions. By forming stable nanoparticle polyplexes co-delivering peptide antigen and adjuvant, enhanced uptake into immune cells and potent induction of immune responses, including T cell responses, are achieved. The approach is generalizable to different peptide antigens, including tumor-associated antigens and neoantigens, and different polymer and adjuvant combinations. It supports manufacturing accessibility, peptide solubility during synthesis, and reliable nanoparticle formation for an effective vaccine delivery platform.
Claims Coverage
The patent includes one independent claim focused on an immunogenic composition of polymer nanoparticles comprising a peptide antigen conjugate electrostatically linked to a polymer, optionally including an adjuvant.
Electrostatic linkage of peptide antigen conjugates to polymers forming nanoparticle polyplexes
The immunogenic composition comprises polymer nanoparticles where a first polymer is linked by electrostatic interaction to a conjugate comprising the peptide antigen linked to a peptide tag, forming stable nanoparticle polyplexes capable of entering immune cells to induce an immune response.
Controlled peptide tag charge ratio to facilitate nanoparticle formation
The conjugate has a net positive or negative charge at pH 7.4, with the peptide tag comprising a ratio of positively charged to negatively charged amino acids of from about 4:1 to 6:1 depending on net charge, optimizing charge neutralization and nanoparticle formation.
Use of specific polymers and charge ratios for stable nanoparticle formation
The first polymer can be sodium alginate, nucleic acid sequences, poly(methacrylic acid), or poly(L-glutamic acid), with specified charge ratios to the peptide conjugate to ensure formation of nanoparticles 20-200 nm in diameter capable of inducing potent immune responses.
Co-complexation with a polycationic second polymer
The immunogenic composition can further comprise a second polycationic polymer with net electrostatic charge opposite that of the first polymer, forming stable polyplex nanoparticles that enhance immune activation.
Inclusion and linkage of adjuvants to polymers
An adjuvant, particularly a toll-like receptor 7/8 agonist, may be linked to the first polymer through an amide bond at defined ratios to ensure co-delivery of antigen and immune stimulant within nanoparticles.
General applicability to peptide antigens from infectious agents and tumors
The antigen in the conjugate can be a tumor associated peptide antigen, viral peptide antigen, bacterial peptide antigen, or protozoan peptide antigen, allowing broad immunotherapeutic applications.
The claim covers immunogenic nanoparticle compositions comprising peptide antigen conjugates electrostatically complexed with polymers, optionally including adjuvants, with controlled charge ratios and polymer choices to form stable polyplex nanoparticles that potently induce immune responses in subjects.
Stated Advantages
The platform overcomes prior difficulties of inducing effective immune responses to peptide antigens, especially soluble peptides.
It provides a generalizable and chemically defined approach for manufacturing peptide-based nanoparticles with consistent immunogenicity.
Co-delivery of peptides with adjuvants within the same nanoparticle enhances potency of T cell responses and tumor clearance.
Use of electrostatic interactions combined with aromatic amino acids stabilizes nanoparticles and improves formulation stability.
The compositions enable rapid, scalable, and safe individualized vaccines suitable for tumor neoantigens and infectious agents.
Documented Applications
Personalized cancer vaccines using tumor-associated self-antigens or neoantigens to elicit tumor-specific T cell responses and tumor clearance.
Vaccination against infectious agents including viruses, bacteria, fungi, and protozoa by inducing immune responses to peptide antigens derived from these pathogens.
Use as immunotherapeutics to treat established tumors, prevent tumor progression and metastasis, or prophylactic vaccination in subjects at risk of cancer.
Combining with immune checkpoint inhibitors to enhance anti-cancer T cell immunity and improve survival in cancer models.
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