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Publication Number
US-11173206-B2
Publication Date
2021-11-16
Expiration Date
Abstract
The present invention relates to a poxvirus vector comprising a nucleic acid sequence encoding a fusion protein comprising: (i) a peanut allergen selected from list consisting of at least two peanut allergens from ara h 1, ara h 2, ara h 3, ara h 4, ara h 5, ara h 6. ara h 7, ara h 8, ara h 9, ara h I O and ara h I I or a derivative or part thereof having at least 70% sequence identity thereto, and (ii) a profeasome degradation tag to enhance intracellular degradation of the fusion protein. Methods of desensitizing or inducing tolerance to a peanut allergen and/or suppressing an allergic response to a peanut allergen are also disclosed.
Core Innovation
The invention relates to an immune-modulating poxvirus (vaccinia) vector comprising a nucleic acid sequence encoding a fusion protein. The fusion protein includes selected peanut allergens, including ara h 1, ara h 2, ara h 3, and ara h 6, and the allergen portion is configured as variants or parts with stated sequence identity criteria. The fusion protein further includes a proteasome degradation tag to drive intracellular proteasomal degradation.
When expressed from the vector and degraded, the fusion protein results in T-cell epitope-containing peptides that can complex with MHC class I proteins for presentation to T lymphocytes. This mechanism is used to produce a biased T_H1 immune response to the T-cell epitope-containing peptides rather than a non-biased or alternative T_H response. The document frames the goal as desensitization or tolerance and suppression or prevention of peanut allergy via the immunomodulatory outcome.
The document also describes sequence-related implementation concepts, including mapping to SEQ ID sequences and configuration choices intended to support the fusion protein expression and degradation outcome. In the described examples, a ubiquitinated construct is reported to show intracellular expression with an immunogenicity pattern consistent with increased T_H1 cytokine dominance and altered antibody responses relative to non-ubiquitinated controls. A non-ubiquitinated construct is reported to show difficulties in propagation and/or toxic or inhibitory effects in the document’s discussion.
Claims Coverage
The partial claim set includes three independent claims. The inventive features across these independent claims center on proteasome degradation tag-driven intracellular degradation, defined peanut allergen components, and the resulting MHC class I peptide presentation that biases a T_H1 immune response.
Proteasome degradation tag-enhanced intracellular degradation producing MHC class I peptides for biased T_H1 response
A vaccinia virus vector comprising a nucleic acid sequence encoding a fusion protein comprising a proteasome degradation tag to enhance intracellular degradation of the fusion protein, and wherein the fusion protein, when expressed from the vector and degraded, results in T-cell epitope-containing peptides that can complex with MHC class I proteins for presentation to T lymphocytes to produce a biased T_H1 immune response.
Defined ara h 1/ara h 2/ara h 3/ara h 6 allergen set for the MHC class I T-cell epitope presentation
The fusion protein includes peanut allergens consisting of ara h 1, ara h 2, ara h 3, and ara h 6, each defined by the specific amino acid sequences set forth as SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, and SEQ ID NO:10, respectively, such that degraded expression yields T-cell epitope-containing peptides for MHC class I complexing and presentation to T lymphocytes producing a biased T_H1 immune response.
Poxvirus vector encoding a specific fusion protein amino acid sequence
A poxvirus vector comprising a nucleic acid sequence encoding a fusion protein comprising the amino acid sequence set forth in SEQ ID NO:12.
Only four specified peanut allergens with proteasome degradation tag for biased T_H1 immune response
A vaccinia virus vector comprising a nucleic acid sequence encoding a fusion protein comprising a proteasome degradation tag to enhance intracellular degradation of the fusion protein and only the following four peanut allergens: ara h 1, ara h 2, ara h 3, and ara h 6, wherein the fusion protein, when expressed from the vector and degraded, results in T-cell epitope-containing peptides that can complex with MHC class I proteins for presentation to T lymphocytes to produce a biased T_H1 immune response.
Across the independent claims, the core claim coverage is directed to vaccinia and broader poxvirus vector-encoded fusion proteins that include a proteasome degradation tag and defined peanut allergen components, where degradation produces T-cell epitope-containing peptides that complex with MHC class I for presentation to T lymphocytes to generate a biased T_H1 immune response. One independent claim further narrows the allergen composition to only ara h 1, ara h 2, ara h 3, and ara h 6 with specified SEQ ID-defined sequences, and another independent claim defines a poxvirus fusion protein by a specific amino acid sequence.
Stated Advantages
Produces a biased T_H1 immune response to the T-cell epitope-containing peptides.
Reduces or suppresses peanut allergy by inducing tolerance or desensitization via the reported immunomodulatory mechanism.
Documented Applications
Desensitization or induction of tolerance and suppression or prevention of peanut allergy using an immune-modulating vaccinia or poxvirus vector encoding a fusion protein that is degraded to MHC class I-presented T-cell epitope-containing peptides.
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