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Publication Number
US-9302001-B2
Publication Date
2016-04-05
Expiration Date
Abstract
Multilayer films comprised of polypeptide epitopes and a toll-like receptor ligand. The multilayer films are capable of eliciting an immune response in a host upon administration to the host. The multilayer films can include at least one designed peptide that includes one or more polypeptide epitopes from a virus, bacteria, fungus or parasite.
Core Innovation
The disclosed subject matter provides compositions and methods that elicit an immune response in a vertebrate organism by administering a composition comprising a multilayer film. The multilayer film comprises a plurality of oppositely charged polyelectrolyte layers formed by electrostatic layer-by-layer deposition, and one polyelectrolyte layer comprises an antigenic polyelectrolyte that contains a covalently linked viral, bacterial, fungal or parasite epitope as a polypeptide epitope.
The multilayer film further comprises a toll-like receptor ligand (TLR ligand), where the TLR ligand is covalently linked to the antigenic polyelectrolyte. The polyelectrolytes used in the multilayer film include a polycationic material or a polyanionic material having a molecular weight greater than 1,000 and at least 5 charges per molecule.
Core-templated multilayers are described using cores such as CaCO3, and the multilayer films can be stabilized via covalent crosslinking, including disulfide crosslinking and amide bonds. The antigenic polyelectrolytes can be designed as highly charged peptides or polypeptides, and the disclosure emphasizes viral, bacterial, fungal, and parasite polypeptide epitopes together with TLR ligand examples including Pam3Cys for TLR2, MPLA for TLR4, and imiquimod for TLR7.
In malaria-focused examples, a multilayer composition containing T1B peptide-containing multilayer microparticles is described, where adding Pam3Cys increases antibody potency, shifts antibody isotype toward a Th1-associated profile, and improves T-cell ELISPOT responses. The disclosure further describes that these compositions confer protection against PfPb challenge, and includes additional examples where MPLA-coated particles activate TLR-4 cells dose-dependently and imiquimod can be incorporated or retained in microparticles with dose-dependent binding.
Claims Coverage
The partial content provides one independent claim covering a method of eliciting an immune response by administering a multilayer polyelectrolyte film that includes covalently linked antigenic polyelectrolytes bearing viral, bacterial, fungal, or parasite epitopes together with a covalently linked TLR ligand, with polyelectrolyte charge and molecular-weight constraints. Dependent claims refine this by specifying TLR binding targets, named TLR ligand options, crosslinking of polypeptide polyelectrolytes, amide-bond crosslinks, and multi-film or multi-epitope architectures.
Multilayer polyelectrolyte immune-response film with covalently linked epitope polyelectrolyte layer
A method of eliciting an immune response in a vertebrate organism by administering a composition comprising a first multilayer film comprising a plurality of oppositely charged polyelectrolyte layers, wherein one polyelectrolyte layer comprises a first antigenic polyelectrolyte that comprises a covalently linked viral, bacterial, fungal, or parasite epitope.
Covalently linked toll-like receptor ligand in the multilayer film
The multilayer film comprises a toll-like receptor ligand (TLR ligand) and the TLR ligand is covalently linked to the first antigenic polyelectrolyte.
Polyelectrolyte charge and molecular weight constraints
The polyelectrolytes in the multilayer film comprise a polycationic material or a polyanionic material having a molecular weight of greater than 1,000 and at least 5 charges per molecule.
TLR binding target specification across TLR1-TLR9
The method is carried out such that a TLR ligand binds to one or more specified TLRs (TLR1 through TLR9).
Specific TLR ligand selection and combinations
The method is performed using a TLR ligand selected from Pam3Cys, Pam2Cys, monophospholipid A, imiquimod, or combinations thereof.
Covalently crosslinked polypeptide polyelectrolyte within the multilayer film
The method includes forming a multilayer film that contains a polypeptide polyelectrolyte whose polypeptide is covalently crosslinked within the multilayer film.
Amide-bond crosslink chemistry from amino acid side chain functional groups
The covalent crosslinks are amide bonds formed between amino acid side chain functional groups.
Second multilayer film with different antigenic epitopes
Forming a second multilayer film with oppositely charged polyelectrolyte layers, where one layer contains a second antigenic polyelectrolyte comprising a viral, bacterial, fungal, or parasite polypeptide epitope, and the first and second antigenic polyelectrolytes contain different polypeptide epitopes from the same or different organisms.
Overall, the claims cover administering a multilayer electrostatically assembled film of oppositely charged polyelectrolytes in which an antigenic polyelectrolyte bearing a covalently linked viral, bacterial, fungal, or parasite epitope is covalently linked to a TLR ligand, under defined polyelectrolyte molecular-weight and charge constraints. Dependent refinements specify TLR binding targets, provide named TLR ligand options, require covalent crosslinking of polypeptide polyelectrolytes with amide-bond crosslinks, and optionally add a second multilayer film carrying different antigenic epitopes.
Stated Advantages
In malaria-focused examples, adding Pam3Cys increases antibody potency.
In malaria-focused examples, adding Pam3Cys shifts antibody isotype toward a Th1-associated profile.
In malaria-focused examples, adding Pam3Cys improves T-cell ELISPOT responses.
In malaria-focused examples, the compositions confer protection against PfPb challenge.
MPLA-coated particles activate TLR-4 cells dose-dependently.
Imiquimod can be incorporated or retained in microparticles with dose-dependent binding.
Documented Applications
Eliciting immune responses in a vertebrate organism by administering compositions comprising multilayer polyelectrolyte films with covalently linked epitope polyelectrolytes and covalently linked TLR ligands.
Malaria-focused immunization: using multilayer microparticles containing T1B peptide and adding Pam3Cys to increase antibody potency, shift antibody isotype toward a Th1-associated profile, improve T-cell ELISPOT responses, and confer protection against PfPb challenge.
TLR-4 activation assay context: MPLA-coated particles activate TLR-4 cells dose-dependently.
Imiquimod incorporation or retention context: imiquimod can be incorporated or retained in microparticles with dose-dependent binding.
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