Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange

Pennington, Luke F.; Tarchevskaya, Svetlana S.; Brigger, Daniel; Sathiyamoorthy, Karthik; Graham, Michelle T.; Nadeau, Kari; Eggel, Alexander; Jardetzky, Theodore S.

doi:10.1038/ncomms11610

Cited by 98 publications

(117 citation statements)

References 54 publications

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“…For example, because allergic reactions are common during OIT and can be severe, the use of monoclonal anti bodies specific for IgE in conjunction with OIT has been explored to increase safety. The monoclonal antibody omalizumab binds to the Fc region of IgE antibodies, blocking IgE binding to FcεRI and thus preventing the Fc receptor-mediated activation and degranulation of mast cells and basophils 130 . Omalizumab was originally approved for the treatment of allergic asthma, but has now been tested in combination with OIT for the treatment of food allergies in a series of smaller studies 131–134 .…”

Section: Therapymentioning

confidence: 99%

Food allergy: immune mechanisms, diagnosis and immunotherapy

2016

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Food allergy is a pathological, potentially deadly, immune reaction triggered by normally innocuous food protein antigens. The prevalence of food allergies is rising and the standard of care is not optimal, consisting of food-allergen avoidance and treatment of allergen-induced systemic reactions with adrenaline. Thus, accurate diagnosis, prevention and treatment are pressing needs, research into which has been catalysed by technological advances that are enabling a mechanistic understanding of food allergy at the cellular and molecular levels. We discuss the diagnosis and treatment of IgE-mediated food allergy in the context of the immune mechanisms associated with healthy tolerance to common foods, the inflammatory response underlying most food allergies, and immunotherapy-induced desensitization. We highlight promising research advances, therapeutic innovations and the challenges that remain.

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Section: Therapymentioning

confidence: 99%

Food allergy: immune mechanisms, diagnosis and immunotherapy

2016

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“…The IgE-R419N-Fc3-4 mutant, in combination with OmAb, can effectively exchange cell-bound IgE for IgE-R419N-Fc3-4 and this dual inhibitor treatment blocks basophil activation more powerfully than either inhibitor alone. This approach, involving simultaneous depletion of antigen-specific IgE while engaging Fc ε RI and Fc ε RII receptors with an IgE variant, can be used to further test the role of IgE-dependent regulatory pathways during anti-IgE treatment and may provide a promising way forward for enhancing current anti-IgE therapies [108]. …”

Section: Anti-ige-based Treatmentsmentioning

confidence: 99%

IgE-Related Chronic Diseases and Anti-IgE-Based Treatments

Navinés-Ferrer

Serrano‐Candelas

Molina-Molina

et al. 2016

Journal of Immunology Research

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IgE is an immunoglobulin that plays a central role in acute allergic reactions and chronic inflammatory allergic diseases. The development of a drug able to neutralize this antibody represents a breakthrough in the treatment of inflammatory pathologies with a probable allergic basis. This review focuses on IgE-related chronic diseases, such as allergic asthma and chronic urticaria (CU), and on the role of the anti-IgE monoclonal antibody, omalizumab, in their treatment. We also assess the off-label use of omalizumab for other pathologies associated with IgE and report the latest findings concerning this drug and other new related drugs. To date, omalizumab has only been approved for severe allergic asthma and unresponsive chronic urticaria treatments. In allergic asthma, omalizumab has demonstrated its efficacy in reducing the dose of inhaled corticosteroids required by patients, decreasing the number of asthma exacerbations, and limiting the effect on airway remodeling. In CU, omalizumab treatment rapidly improves symptoms and in some cases achieves complete disease remission. In systemic mastocytosis, omalizumab also improves symptoms and its prophylactic use to prevent anaphylactic reactions has also been discussed. In other pathologies such as atopic dermatitis, food allergy, allergic rhinitis, nasal polyposis, and keratoconjunctivitis, omalizumab significantly improves clinical manifestations. Omalizumab acts in two ways: by sequestering free IgE and by accelerating the dissociation of the IgE-Fcε receptor I complex.

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“…The free ligands can be identical to the initially bound ligand [21,22,[27][28][29][30]. However, different ligand molecules [27,30,31] or even nucleic acid fragments [20] can lead to the facilitated dissociation (FD). According to the proposed molecular mechanism for FD, a free ligand binds to an already occupied binding site and destabilizes the complex by forming a ternary complex (i.e., two ligands on the same site) [19,23,27].…”

Section: Introductionmentioning

confidence: 99%

Effects of electrostatic interactions on ligand dissociation kinetics

2018

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We study unbinding of multivalent cationic ligands from oppositely charged polymeric binding sites sparsely grafted on a flat neutral substrate. Our molecular dynamics (MD) simulations are suggested by single-molecule studies of protein-DNA interactions. We consider univalent salt concentrations spanning roughly a thousandfold range, together with various concentrations of excess ligands in solution. To reveal the ionic effects on unbinding kinetics of spontaneous and facilitated dissociation mechanisms, we treat electrostatic interactions both at a Debye-Hückel (DH, or 'implicit' ions, i.e., use of an electrostatic potential with a prescribed decay length) level, as well as by the more precise approach of considering all ionic species explicitly in the simulations. We find that the DH approach systematically overestimates unbinding rates, relative to the calculations where all ion pairs are present explicitly in solution, although many aspects of the two types of calculation are qualitatively similar. For facilitated dissociation (FD, acceleration of unbinding by free ligands in solution) explicit ion simulations lead to unbinding at lower free ligand concentrations. Our simulations predict a variety of FD regimes as a function of free ligand and ion concentrations; a particularly interesting regime is at intermediate concentrations of ligands where non-electrostatic binding strength controls FD. We conclude that explicit-ion electrostatic modeling is an essential component to quantitatively tackle problems in molecular ligand dissociation, including nucleicacid-binding proteins.

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Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange

Cited by 98 publications

References 54 publications

Food allergy: immune mechanisms, diagnosis and immunotherapy

Food allergy: immune mechanisms, diagnosis and immunotherapy

IgE-Related Chronic Diseases and Anti-IgE-Based Treatments

Effects of electrostatic interactions on ligand dissociation kinetics

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