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Publication Number
US-11826423-B2
Publication Date
2023-11-28
Expiration Date
Abstract
The present invention provides DNA vaccines for the treatment or prevention of an allergic response. The vaccines comprise the coding sequence for Allergen X or fragments thereof fused in-frame with the lumenal domain of the lysosomal associated membrane protein (LAMP) and the targeting sequence of LAMP. The vaccines allow for presentation of properly configured three dimensional epitopes for production of an immune response when administered to a subject. The vaccines can be multivalent molecules, and/or can be provided as part of a multivalent vaccine containing two or more DNA constructs.
Core Innovation
The invention relates to DNA and related vaccines for allergy treatment in which an allergen is encoded by an isolated nucleic acid and is presented through a LAMP-associated trafficking architecture. The nucleic acid encodes a polypeptide comprising a LAMP lumenal domain, at least one allergen, and a LAMP transmembrane domain/cytoplasmic tail arranged to direct the antigen to endosomal/lysosomal compartments.
The allergen sequences used in the constructs include allergen amino acid sequences corresponding to specific sequence identifiers, and allergen-containing designs are described as in-frame fusions with the LAMP lysosomal trafficking machinery. The disclosure further provides chimeric construct architecture options and alternative endocytic receptor trafficking domains as part of the construct architecture.
The results report improved antibody responses, including preferential IgG over IgE and changes in IgG isotypes, including an IgG2a:IgG1 ratio consistent with Th1-skewing for certain LAMP-antigen fusion designs. Representative allergen sequences are listed in a table with corresponding sequence identifiers.
Claims Coverage
The independent claim covers an isolated nucleic acid encoding a LAMP-associated membrane polypeptide with an allergen defined by specific sequence identifiers, arranged with a LAMP lumenal domain and a LAMP transmembrane domain/cytoplasmic tail. The inventive features are further bounded by dependent claim refinements such as specific LAMP-domain sequence choices, identity thresholds for variants, and the selection of domain combinations that may include trafficking domains.
LAMP lumenal domain–allergen–LAMP transmembrane/cytoplasmic tail fusion
An isolated nucleic acid encoding a polypeptide comprising a lysosomal associated membrane protein (LAMP) lumenal domain, at least one allergen comprising the amino acid sequence of SEQ ID NO: 45, 49, 53, 57, and/or 61, and a LAMP transmembrane domain/cytoplasmic tail.
Specified LAMP lumenal domain segments with variant identity thresholds
The LAMP lumenal domain contains an amino acid sequence selected from SEQ ID NO:2, SEQ ID NO:3, amino acids 29-381 of SEQ ID NO:4, or amino acids 25-370 of SEQ ID NO:5, or a variant of any of these that is at least about 90%, 95%, 96%, 97%, 98%, or 99% identical to the selected sequence.
Specified LAMP transmembrane/cytoplasmic tail sequences with variant identity thresholds
A LAMP transmembrane domain/cytoplasmic tail is specified as including defined amino-acid sequences or a highly identical variant, with identity thresholds of at least about 90%, at least about 95%, 96% identical, 97% identical, 98% identical, or 99% identical.
Nucleic-acid compositions using selected polynucleotide sequence identifiers and domain combinations
The nucleic acid includes polynucleotide sequences SEQ ID NO: 44, 48, 52, 56 or 60 and/or polynucleotides encoding polypeptides with amino acid sequences SEQ ID NO: 45, 49, 53, 57, and/or 61, including configurations with LAMP lumenal domain together with a LAMP transmembrane domain/cytoplasmic tail and, in some versions, a trafficking domain plus the LAMP transmembrane domain/cytoplasmic tail.
Vaccine comprising the LAMP-allergen nucleic acid via vector or host cell
A vaccine includes nucleic acid encoding the LAMP-associated allergen polypeptide, or a vector containing that nucleic acid, or a host cell containing either the nucleic acid or the vector.
Vaccination method with priming and boosting steps
A method is further defined as including a priming step and at least one boosting step.
Overall, the claim set centers on an isolated nucleic acid encoding an allergen fused into a LAMP lumenal domain with a LAMP transmembrane domain/cytoplasmic tail, while dependent features specify allowed LAMP-domain sequence segments and variant identity thresholds, optionally adding a trafficking domain. The scope includes vaccine formats using vectors and host cells and a vaccination regimen that includes priming and at least one boosting step.
Stated Advantages
Preferential IgG over IgE responses.
Improved antibody titers for certain LAMP-antigen fusion designs.
An IgG2a:IgG1 ratio consistent with Th1-skewing for certain LAMP-antigen fusion designs.
Documented Applications
DNA and related vaccines for allergy treatment using LAMP-associated antigen delivery to promote MHC class II processing and immune responses.
Immunogenicity evaluation in mice, including Balb/c mice, using active versus weak/non-active vaccine constructs, with antibody readouts including IgG and IgE.
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