Engineering disruption : development of rapid acting anti-IgE therapeutic agents
Abstract/Contents
- Abstract
- Allergic diseases are a significant source of human morbidity and mortality. The human antibody isotype IgE plays a central role in the pathogenesis of allergic disease by mediating antigen dependent signals through the high affinity IgE receptor (FcεRI) expressed on the surface of mast cells and basophils. Upon allergen encounter, IgE:FcεRI complexes at the cell surface are crosslinked, driving mast cell/basophil activation and degranulation. This activation event drives a spectrum of allergic events ranging from local hypersensitivity reactions to systemic anaphylaxis and death. Omalizumab, an anti-IgE monoclonal antibody, blocks interactions between IgE and FcεRI and has validated IgE as a therapeutic target in multiple allergic diseases. Unlike many antibody isotypes, IgE binds FcεRI with high affinity (KD < 1nM). The slow dissociation of IgE from the high affinity receptor limits the potential of strictly competitive anti-IgE agents, and these agents cannot be employed in acute allergic settings. Therefore, our group and others have begun to investigate novel anti-IgE agents that can target preformed IgE:FcεRI complexes and accelerate the dissociation of IgE from these complexes on cells without activating them. These disruptive anti-IgE agents hold the promise of completely desensitizing an individual to allergens in minutes to hours. The work presented in this thesis defines key structural parameters of potent disruptive anti-IgE agents, develops a framework to enhance the disruptive activities via directed evolution, and captures the intermediate structure of IgE receptor disruption by an antibody. Finally, using directed evolution and structure guided design, we are able to push the therapeutic limits of disruptive agents and interrupt ongoing systemic allergic reaction in vivo.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2021; ©2021 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Pennington, Luke Franklin |
|---|---|
| Degree supervisor | Jardetzky, Theodore |
| Thesis advisor | Jardetzky, Theodore |
| Thesis advisor | Blish, Catherine |
| Thesis advisor | Galli, Stephen J |
| Thesis advisor | Nadeau, Kari |
| Degree committee member | Blish, Catherine |
| Degree committee member | Galli, Stephen J |
| Degree committee member | Nadeau, Kari |
| Associated with | Stanford University, Immunology Interdepartmental Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Luke Pennington. |
|---|---|
| Note | Submitted to the Immunology Interdepartmental Program. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/yn481jm4110 |
Access conditions
- Copyright
- © 2021 by Luke Franklin Pennington
- License
- This work is licensed under a Creative Commons Attribution 3.0 Unported license (CC BY).
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