{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T15:59:26Z","timestamp":1758815966638,"version":"3.38.0"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Options for effective prevention and treatment of epidemic allergic diseases remain limited, and particularly so for IgE-mediated food allergies. We previously found that mouse low-affinity anti-human IgE mAbs with KD in the 10\u22126\u201310\u22128 M range were capable of blocking allergic reactivity without triggering immediate allergic mediator release. In this study, we humanized three parent low affinity allergic response inhibitor (LARI) mouse anti-human IgE mAbs and characterized their biological and immunological features, refined the lead candidate for further clinical development, examined their safety profiles, determined their therapeutic efficiency, and explored the mechanism of action potentially responsible for their therapeutic effects. LARI profoundly blocked cat- and peanut-allergic IgE-mediated basophil activation, inhibited acute release of both prestored and newly synthesized mediator from human mast cells, suppressed peanut-specific IgE-mediated passive cutaneous anaphylaxis, and attenuated dansyl IgE-mediated systemic anaphylaxis in human Fc\u03b5RI\u03b1 transgenic mice. Safety testing demonstrated that concentrations of LARI well above therapeutic levels failed to trigger immediate release of prestored and newly synthesized allergic mediators, failed to promote robust cytokine\/chemokine production from allergic effector cells, and did not elicit allergic reactivity in an animal model of cutaneous and systemic anaphylaxis. Mechanistic studies revealed that LARI downregulated surface Fc\u03b5RI receptors and IgE via internalization of the IgE\/Fc\u03b5RI, promoted a partial mediator depletion pathway leading to slow release of small amount of mediators, and functioned as a partial antagonist to inhibit Fc\u03b5RI signaling phosphorylation of Syk, Akt, Erk, and p38 MAPK. These studies demonstrate that targeting surface-bound IgE with LARI profoundly suppresses human allergic reactivity while displaying an excellent safety profile.<\/jats:p>","DOI":"10.4049\/jimmunol.1900112","type":"journal-article","created":{"date-parts":[[2019,10,21]],"date-time":"2019-10-21T21:19:49Z","timestamp":1571692789000},"page":"2777-2790","source":"Crossref","is-referenced-by-count":5,"title":["Inhibition of Allergic Reactivity through Targeting Fc\u03b5RI-Bound IgE with Humanized Low-Affinity Antibodies"],"prefix":"10.1093","volume":"203","author":[{"given":"Ke","family":"Zhang","sequence":"first","affiliation":[{"name":"Sixal Inc. , Torrance, CA 90502"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Elias","sequence":"additional","affiliation":[{"name":"Joint School of Nanoscience and Nanoengineering, University of North Carolina at Greensboro , Greensboro, NC 27401"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Sixal Inc. , Torrance, CA 90502"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Liu","sequence":"additional","affiliation":[{"name":"Sixal Inc. , Torrance, CA 90502"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Kepley","sequence":"additional","affiliation":[{"name":"Joint School of Nanoscience and Nanoengineering, University of North Carolina at Greensboro , Greensboro, NC 27401"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun","family":"Bai","sequence":"additional","affiliation":[{"name":"Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7781-8260","authenticated-orcid":false,"given":"Dean D","family":"Metcalfe","sequence":"additional","affiliation":[{"name":"Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4185-2416","authenticated-orcid":false,"given":"Zachary","family":"Schiller","sequence":"additional","affiliation":[{"name":"MassBiologics of the University of Massachusetts Medical School , Boston, MA 02126"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[{"name":"MassBiologics of the University of Massachusetts Medical School , Boston, MA 02126"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Saxon","sequence":"additional","affiliation":[{"name":"Sixal Inc. , Torrance, CA 90502"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,12,1]]},"reference":[{"key":"2025030417544535200_r1","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1016\/j.jaci.2017.09.005","article-title":"Global issues in allergy and immunology: parasitic infections and allergy","volume":"140","author":"Cruz","year":"2017","journal-title":"J. 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