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Omalizumab is an anti-IgE monoclonal antibody (mAb) approved for the treatment of severe asthma and chronic spontaneous urticaria. Use of omalizumab is associated with reported side effects ranging from local skin inflammation at the injection site to systemic anaphylaxis. To date, the mechanisms through which omalizumab induces adverse reactions are still unknown. Here, we demonstrated that immune complexes formed between omalizumab and IgE can induce both skin inflammation and anaphylaxis through engagement of IgG receptors (Fc[gamma]Rs) in Fc[gamma]R- humanized mice. We further developed an Fc-engineered mutant version of omalizumab, and demonstrated that this mAb is equally potent as omalizumab at blocking IgE-mediated allergic reactions, but does not induce Fc[gamma]R-dependent adverse reactions. Overall, our data indicate that omalizumab can induce skin inflammation and anaphylaxis by engaging Fc[gamma]Rs, and demonstrate that Fc-engineered versions of the mAb could be used to reduce such adverse reactions., Introduction IgE antibodies (Abs) are key mediators of allergic diseases (1-3). Upon exposure to an allergen in allergic patients, such allergen is recognized by IgE bound to the high-affinity receptor [...]

mAb therapy for experimental metastatic melanoma relies on activating receptors for the Fc portion of IgG (FcγR). Opposing results on the respective contri-bution of mouse FcγRI, FcγRIII, and FcγRIV have been reported using the gp75-expressing B16 melanoma and the protective anti-gp75 mAb TA99. We analyzed the contribution of FcγRs to this therapy model using bioluminescent measurement of lung metastases loads, novel mouse strains, and anti-FcγR blocking mAbs. We found that the TA99 mAb-mediated effects in a combination therapy using cyclophosphamide relied on activating FcγRs. The combination therapy, how-ever, was not more efficient than mAb therapy alone. We demonstrate that FcyRI and, unexpectedly, FcyRIII contributed to TA99 mAb therapeutic efifects, whereas FcγRIV did not. Therefore, FcγRIII and FcγRI are, together, responsible for anti-gp75 mAb therapy of B16 lung metastases. Our finding that mouse FcγRIII contributes to Ab-induced tumor reduction corre-lates with clinical data on its human functional equiv-alent human FcγRIIIA (CD16A). [ABSTRACT FROM AUTHOR]