Anti-FcγRIIB mAb suppresses IgG-dependent anaphylaxis by Fc domain targeting of FcγRIII

The inhibitory Fcγ receptor (FcγRIIB) is expressed on human and murine bone marrow-derived cells. FcγRIIB-mediated inhibition of stimulatory Fcγ receptor signaling limits inflammation in autoimmune, infectious and atopic diseases. We evaluated the ability of the anti-mouse FcγRIIB mAb, k9.361, to influence IgG-mediated anaphylaxis. Methods Wildtype and Fcγ receptor (FcγR)-deficient mice were used to study IgG-mediated anaphylaxis, which was induced by i.v. injection of 2.4G2 (a mAb that binds both FcγRIIB and the stimulatory receptor, FcγRIII), or by actively immunizing IgE-deficient mice, then challenging them with the immunizing antigen. Pretreatment with k9.361 was assessed for ability to influence anaphylaxis in these models. Results Unexpectedly, a single k9.361 injection induced mild anaphylaxis (assessed as hypothermia), which was both FcγRIIB- and FcγRIII-dependent. Injection with k9.361 also prevented the ability of a subsequent 2.4G2 injection to induce anaphylaxis and suppressed myeloid cell expression of stimulatory FcγRs, particularly FcγRIII. Treatment with k9.361 F(ab′) 2 did not cause anaphylaxis, deplete FcγRIII, or suppress 2.4G2-induced anaphylaxis, but prevented the ability of intact k9.361 to induce anaphylaxis, without preventing the ability of intact k9.361 to suppress IgG-mediated anaphylaxis. Conclusion Anti-FcγRIIB mAb induces and then suppresses IgG-mediated anaphylaxis by targeting myeloid cell FcγRIII through its Fc domain. Sequential treatment with anti-FcγRIIB F(ab′) 2 , intact anti-FcγRIIB, and intact anti-FcγRIIB/III mAbs may provide a safe way to prevent IgG-mediated anaphylaxis.