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Structural and Physical Basis for Anti-IgE Therapy.

Wright JD, Chu HM, Huang CH, Ma C, Chang TW, Lim C - Sci Rep (2015)

Bottom Line: Mutagenesis studies indicate overlapping FcεRI and omalizumab-binding sites in the Cε3 domain, but crystallographic studies show FcεRI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors?These results provide a structural and physical basis as to why omalizumab cannot bind receptor-bound IgE and why omalizumab-bound IgE cannot bind to CD23/FcεRI.They reveal the key IgE residues and their roles in binding omalizumab, CD23, and FcεRI.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan [2] The Genomics Research Center, Academia Sinica 115, Taiwan.

ABSTRACT
Omalizumab, an anti-IgE antibody, used to treat severe allergic asthma and chronic idiopathic urticaria, binds to IgE in blood or membrane-bound on B lymphocytes but not to IgE bound to its high (FcεRI) or low (CD23) affinity receptor. Mutagenesis studies indicate overlapping FcεRI and omalizumab-binding sites in the Cε3 domain, but crystallographic studies show FcεRI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors? We report a 2.42-Å omalizumab-Fab structure, a docked IgE-Fc/omalizumab-Fab structure consistent with available experimental data, and the free energy contributions of IgE residues to binding omalizumab, CD23, and FcεRI. These results provide a structural and physical basis as to why omalizumab cannot bind receptor-bound IgE and why omalizumab-bound IgE cannot bind to CD23/FcεRI. They reveal the key IgE residues and their roles in binding omalizumab, CD23, and FcεRI.

No MeSH data available.


Related in: MedlinePlus

How IgE mediates an allergic reaction via interaction with its two receptors.(Left) Interactions of membrane-bound IgE (mIgE, blue) with CD23 (tangerine) on B-cells regulates soluble IgE (sIgE) production. (Right) Cross-linking of IgE bound to FcεRI (scarlet) on mast cells or basophils by allergens (brown) triggers the release of mediators, causing allergy.
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f1: How IgE mediates an allergic reaction via interaction with its two receptors.(Left) Interactions of membrane-bound IgE (mIgE, blue) with CD23 (tangerine) on B-cells regulates soluble IgE (sIgE) production. (Right) Cross-linking of IgE bound to FcεRI (scarlet) on mast cells or basophils by allergens (brown) triggers the release of mediators, causing allergy.

Mentions: Most prevalent allergic diseases, e.g., allergic asthma, allergic rhinitis, atopic dermatitis, and food allergy, are caused by immunoglobulin E (IgE) mediated type-I hypersensitivity reactions. IgE is responsible for allergic reaction caused by exposure to allergens such as dust mites, pollen, mold, animal dander, and peanuts. It mediates an allergic reaction via interaction with its two receptors, high-affinity FcεRI on mast cells and basophils1 and low-affinity CD23 on B cells. Free soluble IgE binds to FcεRI on the surface of mast cells, basophils, and antigen-presenting dendritic cells. Binding of soluble CD23 to membrane-bound IgE and the complement receptor CD21 on B cells results in an increased production of IgE (Fig. 1). In a sensitized individual, allergens bind to allergen-specific IgE and cross-link the IgE/FcεRI complexes, triggering the release of pharmacological and inflammatory mediators, causing various allergic symptoms.


Structural and Physical Basis for Anti-IgE Therapy.

Wright JD, Chu HM, Huang CH, Ma C, Chang TW, Lim C - Sci Rep (2015)

How IgE mediates an allergic reaction via interaction with its two receptors.(Left) Interactions of membrane-bound IgE (mIgE, blue) with CD23 (tangerine) on B-cells regulates soluble IgE (sIgE) production. (Right) Cross-linking of IgE bound to FcεRI (scarlet) on mast cells or basophils by allergens (brown) triggers the release of mediators, causing allergy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4481376&req=5

f1: How IgE mediates an allergic reaction via interaction with its two receptors.(Left) Interactions of membrane-bound IgE (mIgE, blue) with CD23 (tangerine) on B-cells regulates soluble IgE (sIgE) production. (Right) Cross-linking of IgE bound to FcεRI (scarlet) on mast cells or basophils by allergens (brown) triggers the release of mediators, causing allergy.
Mentions: Most prevalent allergic diseases, e.g., allergic asthma, allergic rhinitis, atopic dermatitis, and food allergy, are caused by immunoglobulin E (IgE) mediated type-I hypersensitivity reactions. IgE is responsible for allergic reaction caused by exposure to allergens such as dust mites, pollen, mold, animal dander, and peanuts. It mediates an allergic reaction via interaction with its two receptors, high-affinity FcεRI on mast cells and basophils1 and low-affinity CD23 on B cells. Free soluble IgE binds to FcεRI on the surface of mast cells, basophils, and antigen-presenting dendritic cells. Binding of soluble CD23 to membrane-bound IgE and the complement receptor CD21 on B cells results in an increased production of IgE (Fig. 1). In a sensitized individual, allergens bind to allergen-specific IgE and cross-link the IgE/FcεRI complexes, triggering the release of pharmacological and inflammatory mediators, causing various allergic symptoms.

Bottom Line: Mutagenesis studies indicate overlapping FcεRI and omalizumab-binding sites in the Cε3 domain, but crystallographic studies show FcεRI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors?These results provide a structural and physical basis as to why omalizumab cannot bind receptor-bound IgE and why omalizumab-bound IgE cannot bind to CD23/FcεRI.They reveal the key IgE residues and their roles in binding omalizumab, CD23, and FcεRI.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan [2] The Genomics Research Center, Academia Sinica 115, Taiwan.

ABSTRACT
Omalizumab, an anti-IgE antibody, used to treat severe allergic asthma and chronic idiopathic urticaria, binds to IgE in blood or membrane-bound on B lymphocytes but not to IgE bound to its high (FcεRI) or low (CD23) affinity receptor. Mutagenesis studies indicate overlapping FcεRI and omalizumab-binding sites in the Cε3 domain, but crystallographic studies show FcεRI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors? We report a 2.42-Å omalizumab-Fab structure, a docked IgE-Fc/omalizumab-Fab structure consistent with available experimental data, and the free energy contributions of IgE residues to binding omalizumab, CD23, and FcεRI. These results provide a structural and physical basis as to why omalizumab cannot bind receptor-bound IgE and why omalizumab-bound IgE cannot bind to CD23/FcεRI. They reveal the key IgE residues and their roles in binding omalizumab, CD23, and FcεRI.

No MeSH data available.


Related in: MedlinePlus