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Publication Number
US-9968665-B2
Publication Date
2018-05-15
Expiration Date
Abstract
Described herein are multilayer films that include modified polypeptide epitopes from Plasmodium falciparum, specifically a modified T* epitope. 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 the modified T* polypeptide epitope from a Plasmodium protozoan.
Core Innovation
The invention relates to an anti-malarial multilayer film composition comprising a plurality of oppositely charged polyelectrolyte layers. One polyelectrolyte layer includes a first antigenic polyelectrolyte comprising a modified Plasmodium falciparum circumsporozoite T* epitope of SEQ ID NO:5. The polyelectrolytes comprise a polycationic material or a polyanionic material having a molecular weight greater than 1,000 and at least 5 charges per molecule.
The disclosure further describes designed polypeptide epitopes incorporating modified Plasmodium falciparum circumsporozoite T* and related T1BT* epitopes. These antigenic polyelectrolytes include terminal charged surface adsorption regions suitable for adsorption in the multilayer film, and the modified Plasmodium falciparum circumsporozoite T* epitope may be covalently linked to the polyelectrolyte material. The antigenic polyelectrolytes may be covalently cross-linked, including amide bonds, to increase film stability.
The patent describes immune-stimulatory components in the multilayer film compositions, including toll-like receptor ligands/adjuvants such as Pam3Cys and Poly(I:C), and deposition on core particles. The disclosure reports that a serine substitution in the T* cysteine-containing epitope preserves robust humoral and T-cell responses and improves protection in a PfPb liver challenge, while an alanine substitution unexpectedly reduces IFNγ/IL-5 T-cell responses and protection. Additional data address cysteine oxidation/disulfide dimer formation during storage and show improved stability for serine-containing constructs versus cysteine-containing ones.
Claims Coverage
The partial content provides one independent claim defining a multilayer film composition, with dependent claims refining the antigenic polyelectrolyte attachment, multilayer architecture, cross-link chemistry, and an expected T-cell response outcome. Overall, the inventive features are centered on combining oppositely charged polyelectrolyte multilayers with a modified Plasmodium falciparum circumsporozoite T* epitope (SEQ ID NO:5) presented as an antigenic polyelectrolyte using high-charge polyelectrolytes (MW >1,000; ≥5 charges per molecule).
Oppositely charged polyelectrolyte multilayer film with high-charge polyelectrolytes
A multilayer film comprising a plurality of oppositely charged polyelectrolyte layers, where the polyelectrolytes comprise a polycationic material or a polyanionic material having a molecular weight of greater than 1,000 and at least 5 charges per molecule.
Modified Plasmodium falciparum circumsporozoite T* epitope in an antigenic polyelectrolyte layer
One polyelectrolyte layer comprises a first antigenic polyelectrolyte, wherein the first antigenic polyelectrolyte comprises a modified Plasmodium falciparum circumsporozoite T* epitope of SEQ ID NO:5.
Covalent linkage of the modified T* antigenic polyelectrolyte to charged polyelectrolyte material
The modified Plasmodium falciparum circumsporozoite T* epitope (SEQ ID NO:5) is covalently linked to either a polycationic material or a polyanionic material meeting a molecular weight greater than 1,000 and having at least 5 charges per molecule.
Terminal surface adsorption regions with charged-residue threshold for T* attachment
A covalently linked modified Plasmodium falciparum circumsporozoite T* epitope (SEQ ID NO:5) is attached to one or two polypeptide surface adsorption regions located at the C-terminus and/or the N-terminus, with at least one adsorption region containing five or more charged amino acid residues.
Covalently cross-linked additional polyelectrolyte layers
Aside from the layer containing the first antigenic polyelectrolyte, at least two other polyelectrolyte layers are covalently cross-linked.
Amide-bond covalent cross-links from amino acid side chain functional groups
The covalent cross-links are amide bonds formed using amino acid side chain functional groups.
Epitope-specific T-cell response characterized by IFNγ and/or IL-5
The composition, when administered to a host organism, generates an epitope-specific T-cell response characterized by IFNγ T-cell and/or IL-5 T-cell responses.
Across the independent claim and provided refinements, the claim coverage focuses on a multilayer film of oppositely charged polyelectrolyte layers using high-charge polyelectrolytes (MW >1,000; ≥5 charges per molecule), with a modified Plasmodium falciparum circumsporozoite T* epitope of SEQ ID NO:5 presented as an antigenic polyelectrolyte. Dependent features further define covalent linkage to the charged polyelectrolyte, attachment via terminal surface adsorption regions with charged residue thresholds, covalent cross-linking of additional layers, the use of amide-bond cross-links from amino acid side chain functional groups, and an expected epitope-specific T-cell response characterized by IFNγ and/or IL-5.
Stated Advantages
Serine substitution in the T* cysteine-containing epitope preserves robust humoral and T-cell responses and improves protection in a PfPb liver challenge.
Serine-containing constructs show improved stability during storage versus cysteine-containing constructs.
Documented Applications
Improved protection in a PfPb liver challenge is reported for constructs with a Cys→Ser substitution in the T* epitope.
Reduction of IFNγ/IL-5 T-cell responses and protection is reported for constructs with a Cys→Ala substitution in the T* epitope.
Improved stability during storage is reported for serine-containing constructs versus cysteine-containing ones, addressing cysteine oxidation/disulfide dimer formation.
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