Anti-FcγRIIB monoclonal antibody suppresses murine IgG-dependent anaphylaxis by Fc domain targeting of FcγRIII

Publication date: Available online 15 June 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Corey D. Clay, Richard T. Strait, Ashley Mahler, Marat V. Khodoun, Fred D. Finkelman
BackgroundThe inhibitory receptor, FcγRIIB, is expressed on human and murine bone marrow-derived cells and limits inflammation by suppressing signaling through stimulatory receptors.ObjectiveEvaluate the effects of K9.361, a mouse IgG2a alloantibody to mouse FcγRIIB, on murine anaphylaxis.MethodsWild-type and FcγR-deficient mice were used to study anaphylaxis, which was induced by injection of 2.4G2 (rat IgG2b mAb that binds both FcγRIIB and the stimulatory receptor, FcγRIII); by actively immunizing IgE-deficient mice, then challenging with the immunizing Ag; and by passive immunization with IgG or IgE anti-TNP mAb, followed by injection of TNP-ovalbumin. Pretreatment with K9.361 was assessed for ability to influence anaphylaxis.ResultsUnexpectedly, K9.361 injection induced mild anaphylaxis, which was both FcγRIIB- and FcγRIII-dependent and was greatly enhanced by β-adrenergic blockade. K9.361 injection also decreased expression of stimulatory Fcγreceptors, especially FcγRIII, and strongly suppressed IgG-mediated anaphylaxis, without strongly affecting IgE-mediated anaphylaxis. The F(ab')2 fragment of K9.361 did not induce anaphylaxis, even after β-adrenergic blockade, and failed to deplete FcγRIII or suppress IgG-mediated anaphylaxis; but prevented intact K9.361-induced anaphylaxis, without diminishing intact K9.36 suppression of IgG-mediated anaphylaxis.ConclusionCrosslinking FcγRIIB to stimulatory FcγRs through the Fc domains of an anti-FcγRIIB mAb induces, then suppresses IgG-mediated anaphylaxis without affecting IgE-mediated anaphylaxis. Because IgG- and IgE-mediated anaphylaxis can be mediated by the same cell types, this suggests that desensitization acts at the receptor, rather than the cellular level. Sequential treatment with the F(ab')2 fragment of anti-FcγRIIB mAb followed by intact anti-FcγRIIB, safely prevents IgG-mediated anaphylaxis.



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