title: Blocking Allergic Reaction through Targeting Surface-Bound IgE with Low-Affinity Anti-IgE Antibodies.
abstract: Allergic disorders have now become a major worldwide public health issue, but the effective treatment options remain limited. We report a novel approach to block allergic reactivity by targeting the surface-bound IgE of the allergic effector cells via low-affinity anti-human IgE Abs with dissociation constants in the 10-6to 10-8M range. We demonstrated that these low-affinity anti-IgE mAbs bind to the cell surface-bound IgE without triggering anaphylactic degranulation even at high concentration, albeit they would weakly upregulate CD203c expression on basophils. This is in contrast to the high-affinity anti-IgE mAbs that trigger anaphylactic degranulation at low concentration. Instead, the low-affinity anti-IgE mAbs profoundly block human peanut- and cat-allergic IgE-mediated basophil CD63 induction indicative of anaphylactic degranulation; suppress peanut-, cat-, and dansyl-specific IgE-mediated passive cutaneous anaphylaxis; and attenuate dansyl IgE-mediated systemic anaphylaxis in human FcεRIα transgenic mouse model. Mechanistic studies reveal that the ability of allergic reaction blockade by the low-affinity anti-IgE mAbs was correlated with their capacity to downregulate the surface IgE and FcεRI level on human basophils and the human FcεRIα transgenic mouse bone marrow-derived mast cells via driving internalization of the IgE/FcεRI complex. Our studies demonstrate that targeting surface-bound IgE with low-affinity anti-IgE Abs is capable of suppressing allergic reactivity while displaying an excellent safety profile, indicating that use of low-affinity anti-IgE mAbs holds promise as a novel therapeutic approach for IgE-mediated allergic diseases.
authors.affiliation: Sixal Inc., Los Angeles, CA 90095; and kzhang@ucla.edu.|Section of Clinical Immunology/Allergy, Division of Pulmonary, Critical Care, and Clinical Immunology/Allergy, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Sixal Inc., Los Angeles, CA 90095; and.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Liu
authors.affiliation: Section of Clinical Immunology/Allergy, Division of Pulmonary, Critical Care, and Clinical Immunology/Allergy, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Thao
authors.initials: T
authors.lastname: Truong
authors.affiliation: Section of Clinical Immunology/Allergy, Division of Pulmonary, Critical Care, and Clinical Immunology/Allergy, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Elyssa
authors.identifier: 0000-0002-2621-4221
authors.initials: E
authors.lastname: Zukin
authors.affiliation: Section of Clinical Immunology/Allergy, Division of Pulmonary, Critical Care, and Clinical Immunology/Allergy, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Wendy
authors.identifier: 0000-0002-4133-4918
authors.initials: W
authors.lastname: Chen
authors.affiliation: Sixal Inc., Los Angeles, CA 90095; and.|Section of Clinical Immunology/Allergy, Division of Pulmonary, Critical Care, and Clinical Immunology/Allergy, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Andrew
authors.initials: A
authors.lastname: Saxon
mesh_terms: D000707:Anaphylaxis / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D000915:Antibody Affinity; D001491:Basophils / Q000276:immunology; D015550:Cell Degranulation / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology / Q000517:prevention & control*; D007073:Immunoglobulin E / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010323:Passive Cutaneous Anaphylaxis / Q000276:immunology; D010727:Phosphoric Diester Hydrolases / Q000276:immunology; D011485:Protein Binding; D011755:Pyrophosphatases / Q000276:immunology; D060149:Tetraspanin 30 / Q000276:immunology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; C554586:CD63 protein, human; D016207:Cytokines; C427944:ENPP3 protein, human; D060149:Tetraspanin 30; C026408:anti-IgE antibodies; D007073:Immunoglobulin E; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases