An Fc-Optimized Monoclonal Antibody Against CD32B, the Human Inhibitory Fc-_γ Receptor IIB, in the Immunotherapy of B-Cell Malignanacy.

Monoclonal antibodies (mAbs) are widely used in the treatment of lymphoma and autoimmune diseases. The activity of several mAbs depends on the binding of the Fc_γ regions to low-affinity Fc_γ receptors (Fc_γR) expressed on effector cells, chiefly mononuclear phagocytes, cells that express both activating and inhibitory Fc_γRs. Fc_γRIIB (CD32B), the inhibitory Fc_γR, is expressed by normal and malignant B lymphocytes and is itself an immunotherapeutic target. A recently characterized anti-human CD32B-specific mAb (2B6) was Fc engineered to customize the Fc_γR binding profile for increased binding to the activating receptor Fc_γRIIIA (CD16A), resulting in an improved activating-to-inhibitory binding ratio. Fc-optimized versions of 2B6 showed enhanced cytotoxicity in vitro and increased potency in animal tumor models, including transgenic mice harboring the human low-affinity allele of the activating receptor, CD16A-158^phe. The enhancement in tumor depletion correlated with an increased binding to Fc_γRIV, a mouse functional homolog to human CD16A. The expression of Fc_γRIV is limited to monocyte and macrophages, consistent with the role of these cells in tumor cell killing in vivo. These data support CD32B as a target for immunotherapy of B cell lymphoproliferative disorders and Fc optimization to increase the activating-to-inhibitory Fc_γR-binding ratio as a means to designing improved antibodies.