Immunoglobulin E (IgE) in the lung plays a key role in allergic asthmatic inflammation. Asthmatic patients also exhibit elevated serum IgE levels, which may re-equilibrate with the lung IgE pool or enhance IgE-mediated allergic asthma. A seminal finding of IgE downregulation by active IgE immunization was first reported in our lab. This led to the product concept of the mAb omalizumab, and a subsequent collaboration with the pharmaceutical industry led to FDA approval of the XolairÒ. In the proposed project, the native conformation of receptor-binding IgE loops (e.g., the XolairÒ binding FG loop epitope) are conformationally constrained in a selected thermostable b-strand pair (dubbed super-b strands) and then fused to an immunogenic and thermostable protein scaffold as a bifunctional vaccine. The use of ImiquimodÔ(IMQ, 3M, Inc.) through a safe transcutaneous route of administration, followed by vaccine IN challenge in saline, ensures that mucosal IgA and IgG subclass anti-IgE antibodies target asthmogenic lung IgE as well as the removal of serum IgE by systemic anti-IgE antibodies. This specific targeting improves safety, and is unlikely to cause type 2 hypersensitivity or chronic urticaria. In the absence of a vaccine reboost, emerging anti-IgE producing B-cells are naturally tolerized by the endogenous self-IgE recovered during the rest period as another safety feature. A just-in-time vaccine reboost is required to break self-IgE tolerance to protect against allergen re-exposure. The lack of persistent IgE suppression preserves IgE competence for parasitic defenses. Our three aims are: Aim 1: Study immunogenicity of human FG supersite vaccine in rodents: location, duration, and efficacies. Aim 2: Evaluate therapeutic vaccination in alleviating IgE-mediated asthmatic inflammation and AHR in rodent models. Aim 3: Evaluate therapeutic vaccination in alleviating IgE-mediated asthmatic inflammation and AHR in rhesus macaques.
Public Health Relevance Statement: Project Narrative Allergic asthma afflicts 30 million people in the US, including 16 million children (20-30% of adult asthma cases are not related to allergy). Immunoglobulin E (IgE) in the lung plays a key role in allergic asthmatic inflammation. Studies of XolairÒ have shown that IgE is a central mediator of asthmatic inflammation in human allergic asthma. Administration of XolairÒ is known to improve severe asthmatic syndromes of inner city asthmatics by ameliorating IgE-mediated responses and reducing IgE-amplified innate immunity to pathogenic house dust mites (HDM), cockroaches, and pet allergens (NEJM, 2011). A seminal finding of downregulating IgE by active immunization was first reported in our lab. This led to the product concept of the mAb anti-IgE omalizumab, and a subsequent collaboration with the pharmaceutical industry led to the FDA approval of the product, XolairÒ. IgE binding loops to FceRI on mast cells (e.g., the XolairÒ binding FG loop epitope) that are appropriately conformationally-constrained can serve as a therapeutic pan-IgE supersite active vaccine for eliciting broadly neutralizing (BN) anti-IgE antibodies to neutralize as well as to remove IgE from cells and inflammatory tissues. Therefore. this phase 2 Project aims to develop a BN pan-IgE supersite vaccine. The high cost of Xolair ($15,000 to $35,000 per patient) limits its availability to only ~50,000 severe asthmatics, while the low vaccine cost renders it affordable to ~ 30 million patients with mild, moderate, moderate to severe, and severe allergic asthma in the US. Therefore, developing this innovative pan-IgE vaccine product will meet the market need.
Project Terms: Active Immunization; Adult asthma; Affinity; airway inflammation; Allergens; Allergic; Amino Acid Sequence; Anaphylaxis; Antibodies; Antigen-Antibody Complex; Asthma; asthmatic; asthmatic patient; B-Lymphocytes; base; Basophils; Binding; Blocking Antibodies; Blood Circulation; CD4 Positive T Lymphocytes; Cell Line; Cells; Child; Chronic; Collaborations; Competence; Complex; cost; dander; Dendritic Cells; Dictyoptera; Diffusion; DNA Sequencing Facility; Down-Regulation; Drug Industry; Ensure; eosinophil; Epithelial Cells; Epitopes; Excision; Exhibits; Extrinsic asthma; Half-Life; Household; Human; Hypersensitivity; Hypersensitivity skin testing; IgE; IgE Receptors; Imiquimod; Immunization; immunogenic; immunogenicity; Immunoglobulin A; Immunoglobulin G; improved; Inflammation; Inflammatory; inner city; innovation; Location; Lung; Macaca; Macaca mulatta; Marketing; mast cell; Mediating; Mediator of activation protein; meetings; Modality; Modeling; Molecular Conformation; Mus; Natural Immunity; neutrophil; omalizumab; Patients; Phase; Play; prevent; Product Approvals; Pyroglyphidae; receptor binding; Recovery; Reporting; respiratory smooth muscle; response; Rest; Reticuloendothelial System; Risk; Rodent; Rodent Model; Route; Safety; Saline; Scaffolding Protein; Secretory Immunoglobulin A; Seminal; Serum; Smooth Muscle Myocytes; Source; subcutaneous; Syndrome; Testing; Therapeutic; Time; Tissues; Translations; Ursidae Family; Urticaria; Vaccinated; Vaccination; vaccine efficacy; Vaccines; Xolair
