Suppression of mast cell degranulation through a dual-targeting tandem IgE-IgG Fc domain biologic engineered to bind with high affinity to Fc纬RIIb
- 作者：Saso Cemerski ; saso.cemerski@xencor.com ; sasocem@gmail.com ; [Author Vitae] ; Seung Y. Chu ; [Author Vitae] ; Gregory L. Moore ; [Author Vitae] ; Umesh S. Muchhal ; [Author Vitae] ; John R. Desjarlais ; [Author Vitae] ; David E. Szymkowski ; [Author Vitae]
- 关键词：Fc蓻RI ; high-affinity receptor for IgE Fc ; Fc纬RIIb ; low-affinity receptor for IgG Fc ; FSC ; forward scatter ; ITIM ; immunoreceptor tyrosine-based inhibitory motif ; ITAM ; immunoreceptor tyrosine-based activation motif ; OVA ; ovalbumin ; SSC ; side scatter
- 刊名：Immunology Letters
- 出版年：2012
- 期刊代码：115_01652478
- 类别：med
- 出版时间：30 March, 2012
- 卷：143
- 期：1
- 页码：34-43
- 文件大小：1383 K
摘要
Mast cells and basophils play a central role in allergy, asthma, and anaphylaxis, as well as in non-allergic inflammatory, neurological and autoimmune diseases. Allergen-mediated cross-linking of IgE bound to Fc蓻RI leads to cellular activation, and the low-affinity Fc receptor Fc纬RIIb is a key inhibitor of subsequent degranulation. Fc纬RIIb, when coengaged with Fc蓻RI via allergen bound to IgE, stimulates ITIM domain-mediated inhibitory signaling that efficiently suppresses mast cell and basophil activation. To assess the therapeutic potential of directed coengagement of Fc蓻RI and Fc纬RIIb in the absence of Fc蓻RI crosslinking, we developed a fusion protein comprising the coupled Fc domains of murine IgE and human IgG1. As a key functional component of this tandem Fc蓻-Fc纬 biologic, we engineered its IgG1 Fc domain to bind to human Fc纬RIIb with 100-fold enhanced affinity relative to native IgG1 Fc. Using mast cells from mice transgenic for human Fc纬RIIb, we show that this tandem Fc binds with high affinity to murine Fc蓻RI and human Fc纬RIIb on mast cells, triggers phosphorylation of Fc纬RIIb, and inhibits Fc蓻RI-dependent calcium mobilization. Control tandem Fc biologics containing a native IgG1 Fc domain or lacking binding to Fc纬 receptors were markedly less active, demonstrating that the affinity-optimized tandem Fc can inhibit degranulation through stimulation of Fc纬RIIb signaling as well as through competition with allergen-IgE immune complex for Fc蓻RI binding. We propose that in the context of a fully human tandem Fc biologic, high-affinity coengagement of Fc蓻RI and Fc纬RIIb has potential as a novel therapy for allergy and other mast cell and basophil-mediated pathologies.