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Structural and Physical Basis for Anti-IgE Therapy.

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 (Fc?RI) or low (CD23) affinity receptor. Mutagenesis studies indicate overlapping Fc?RI and omalizumab-binding sites in the C?3 domain, but crystallographic studies show Fc?RI 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 Fc?RI. 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/Fc?RI. They reveal the key IgE residues and their roles in binding omalizumab, CD23, and Fc?RI.

SUBMITTER: Wright JD

PROVIDER: S-EPMC4481376 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Structural and Physical Basis for Anti-IgE Therapy.

Wright Jon D JD Chu Hsing-Mao HM Huang Chun-Hsiang CH Ma Che C Chang Tse Wen TW Lim Carmay C

Scientific reports 20150626

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 omaliz ...[more]

PMID: 26113483

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