Immunoglobulin E (IgE) antibody plays a key role in allergic disease. IgE primes the IgE-mediated allergic response by binding to Fc receptors found on the surface of mast cells and basophils. Fc receptors include FcεRI and FcεRII. IgE that can specifically recognize an allergen has a unique, long-lived interaction with its high-affinity receptor FcεRI such that basophils and mast cells become primed and ready to release and/or secrete histamine, leukotrienes, additional vasoactive mediators, proteolytic enzymes, and certain interleukins. The release of these chemicals can cause symptoms associated with allergy, including airway constriction, local inflammation, increased mucous secretion, increased vascular permeability, and anaphylaxis.
Anaphylaxis is an acute and potentially life-threatening hypersensitivity reaction involving the release of mediators from mast cells, basophils, and recruited inflammatory cells. Anaphylaxis is the term given to signs and symptoms that occur after exposure to a provoking agent. These signs and symptoms can develop within minutes or hours of exposure. Anaphylaxis can range from mild to severe in nature. Severe initial symptoms develop rapidly, reaching peak severity within 5 to 120 minutes. Death from shock, asthma, or airway swelling can occur within minutes of onset of anaphylaxis. In some instances, protracted anaphylaxis can occur, with symptoms persisting for days.
Anaphylaxis is mediated by immediate hypersensitivity reactions in which the activation of inflammatory cells by the crosslinking of immunoglobulin (Ig) Fc receptors (R) leads rapidly to the release of vasoactive mediators, such as histamine and platelet activating factor (PAF), cytokines, and proteolytic enzymes. Such immediate hypersensitivity reactions are the critical pathogenic mechanism in anaphylaxis and IgE-mediated food allergy. In both humans and mice, immediate hypersensitivity reactions can be mediated by antigen crosslinking of antigen-specific IgE bound to the high affinity IgE receptor, FcεRI, on mast cells and basophils.
Although some allergic disorders can be treated pharmacologically, immunotherapy offers another therapeutic option. Allergen immunotherapy involves administering increasing doses of allergen to accustom the body to substances that are generally harmless (grass, pollen, dust mites), thereby inducing desensitization, which is usually short term, or tolerance, which can be long-lasting. Although effective, administration of allergen can be of limited utility in individuals who are allergic to multiple antigens. In addition, the presence of serum antibodies, including IgG, which can bind to inoculated allergens, may make rapid desensitization more risky if the initial, small allergen doses are neutralized before they can access mast cell or basophil bound IgE, such that the first dose of allergen that interacts with cell-bound IgE is sufficiently large to induce a severe reaction, which may include anaphylaxis.
Desensitization with antibodies such as anti-FcεRIα monoclonal antibody (mAb) and anti-IgE mAb provides another option for inhibiting IgE-mediated hypersensitivity. See, for example, U.S. Publication No. 2014/0314783, by Finkelman, et al., incorporated herein by reference in its entirety. However, in certain instances, particular dosing regimens of such antibodies can also induce IgE-mediated anaphylaxis.
The need exists to develop compositions and methods for suppressing IgE-mediated anaphylaxis, particularly, but not exclusively, for use in methods of allergen desensitization via administration of antigen or monoclonal antibodies such as anti-IgE and anti-FcεRIα.