Structure-guided design of an IL-1β immunogen for the treatment of autoinflammatory diseases
Systemic autoinflammatory diseases are a group of immunological disorders char-acterised by recurrent events of generalised sterile inflammation. Central to the patho-genesis of most SAIDs is the overproduction of interleukin-1β, a potent proinflamma-tory cytokine normally secreted by cells of the i...
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| Format: | Thesis |
| Language: | English |
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2024
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| _version_ | 1811139515313553408 |
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| author | Sousa Augusto, G |
| author2 | Bachmann, M |
| author_facet | Bachmann, M Sousa Augusto, G |
| author_sort | Sousa Augusto, G |
| collection | OXFORD |
| description | Systemic autoinflammatory diseases are a group of immunological disorders char-acterised by recurrent events of generalised sterile inflammation. Central to the patho-genesis of most SAIDs is the overproduction of interleukin-1β, a potent proinflamma-tory cytokine normally secreted by cells of the innate immune system in response to infections. Not surprisingly, the most advanced therapies for SAIDs are based on the precise inhibition of IL-1β, which is carried out either by a specific monoclonal anti-body or by a recombinant version of the endogenous IL-1 receptor antagonist. Although effective in ameliorating the symptoms of mild-to-moderate systemic inflammation, these biologicals offer only limited benefits to the patients suffering from the most se-vere forms of SAIDs, particularly those presenting neurological involvement. In addi-tion to their inherent poor blood-brain barrier penetrability, the monospecific nature of these inhibitors is the most likely reason for their partial efficacy, given that it allows for residual cytokine bioavailability when it occurs at extremely high concentrations, as in the event of a severe flare. Addressing this issue, we have developed a virus-like particle-vectored therapeutic vaccine capable of eliciting neutralising polyclonal anti-body responses against IL-1β protective even in the event of an extreme flare. To further improve its safety and (potentially) efficacy, we have also submitted the carried antigen to extensive modifications in a way that its interactions with IL-1β’s endogenous recep-tors were nearly abrogated, with no major effect on the cross-reactivity between the two proteins. This thesis discusses the design approach employed on this task, particularly focusing the translational potential of the devised techniques. |
| first_indexed | 2024-09-25T04:07:19Z |
| format | Thesis |
| id | oxford-uuid:9162654f-9831-4dca-aaaa-abcf8ea9e08a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:07:19Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | oxford-uuid:9162654f-9831-4dca-aaaa-abcf8ea9e08a2024-05-30T14:49:30ZStructure-guided design of an IL-1β immunogen for the treatment of autoinflammatory diseasesThesishttp://purl.org/coar/resource_type/c_db06uuid:9162654f-9831-4dca-aaaa-abcf8ea9e08aVaccine designProtein engineeringApplied immunologyEnglishHyrax Deposit2024Sousa Augusto, GBachmann, MEl-Turabi, AStuart, DSystemic autoinflammatory diseases are a group of immunological disorders char-acterised by recurrent events of generalised sterile inflammation. Central to the patho-genesis of most SAIDs is the overproduction of interleukin-1β, a potent proinflamma-tory cytokine normally secreted by cells of the innate immune system in response to infections. Not surprisingly, the most advanced therapies for SAIDs are based on the precise inhibition of IL-1β, which is carried out either by a specific monoclonal anti-body or by a recombinant version of the endogenous IL-1 receptor antagonist. Although effective in ameliorating the symptoms of mild-to-moderate systemic inflammation, these biologicals offer only limited benefits to the patients suffering from the most se-vere forms of SAIDs, particularly those presenting neurological involvement. In addi-tion to their inherent poor blood-brain barrier penetrability, the monospecific nature of these inhibitors is the most likely reason for their partial efficacy, given that it allows for residual cytokine bioavailability when it occurs at extremely high concentrations, as in the event of a severe flare. Addressing this issue, we have developed a virus-like particle-vectored therapeutic vaccine capable of eliciting neutralising polyclonal anti-body responses against IL-1β protective even in the event of an extreme flare. To further improve its safety and (potentially) efficacy, we have also submitted the carried antigen to extensive modifications in a way that its interactions with IL-1β’s endogenous recep-tors were nearly abrogated, with no major effect on the cross-reactivity between the two proteins. This thesis discusses the design approach employed on this task, particularly focusing the translational potential of the devised techniques. |
| spellingShingle | Vaccine design Protein engineering Applied immunology Sousa Augusto, G Structure-guided design of an IL-1β immunogen for the treatment of autoinflammatory diseases |
| title | Structure-guided design of an IL-1β immunogen for the treatment of autoinflammatory diseases |
| title_full | Structure-guided design of an IL-1β immunogen for the treatment of autoinflammatory diseases |
| title_fullStr | Structure-guided design of an IL-1β immunogen for the treatment of autoinflammatory diseases |
| title_full_unstemmed | Structure-guided design of an IL-1β immunogen for the treatment of autoinflammatory diseases |
| title_short | Structure-guided design of an IL-1β immunogen for the treatment of autoinflammatory diseases |
| title_sort | structure guided design of an il 1β immunogen for the treatment of autoinflammatory diseases |
| topic | Vaccine design Protein engineering Applied immunology |
| work_keys_str_mv | AT sousaaugustog structureguideddesignofanil1bimmunogenforthetreatmentofautoinflammatorydiseases |