AK002, A NOVEL SIGLEC-8 ANTIBODY DEPLETES HUMAN EOSINOPHILS AND INHIBITS ANAPHYLAXIS IN HUMANIZED MICE

Abstract

Introduction Pathologic accumulation and over-activation of mast cells and eosinophils have been implicated in certain allergic and inflammatory diseases. Siglec-8 is an inhibitory receptor selectively expressed on human eosinophils, mast cells, and, to a significantly lesser extent, basophils. Antibodies to Siglec-8 have the potential to be broadly anti-inflammatory by inducing apoptosis of eosinophils and inhibiting mast cell activation. AK002 is a novel, humanized, non-fucosylated IgG1 monoclonal antibody to Siglec-8. This study examines the ex vivo activity of AK002 on blood and tissue eosinophils and in vivo activity against human mast cells. Methods The apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) activity of AK002 or an isotype-matched control antibody was assessed using human blood and tissue eosinophils by flow cytometry. In addition, the activity of a mouse AK002 precursor (mAK002) was tested in a model of IgE-induced systemic and cutaneous anaphylaxis in humanized mice. Results In the presence of peripheral blood NK cells, AK002 demonstrated potent ADCC activity against blood eosinophils. AK002 also directly induced apoptosis of cytokine-activated blood eosinophils. In ex vivo human lung tissue, Siglec-8 expression was found on all tissue eosinophils and AK002 significantly reduced these cells compared to an isotype control. Lastly, mAK002 inhibited passive systemic and cutaneous anaphylaxis in humanized mice, consistent with mast cell inhibition (Figure 1). Conclusions AK002 selectively depletes blood and tissue eosinophils and inhibits IgE-mediated anaphylaxis. AK002 may represent a novel therapeutic agent for patients with eosinophil and mast cell driven inflammatory diseases.