Siglecs as targets for therapy in immune-cell-mediated disease

The sialic-acid-binding immunoglobulin-like lectins (siglecs) comprise a family of receptors that are differentially expressed on leukocytes and other immune cells. The restricted expression of several siglecs to one or a few cell types makes them attractive targets for cell-directed therapies. The anti-CD33 (also known as Siglec-3) antibody gemtuzumab (Mylotarg) is approved for the treatment of acute myeloid leukemia, and antibodies targeting CD22 (Siglec-2) are currently in clinical trials for treatment of B cell non-Hodgkins lymphomas and autoimmune diseases. Because siglecs are endocytic receptors, they are well suited for a 'Trojan horse' strategy, whereby therapeutic agents conjugated to an antibody, or multimeric glycan ligand, bind to the siglec and are efficiently carried into the cell. Although the rapid internalization of unmodified siglec antibodies reduces their utility for induction of antibody-dependent cellular cytotoxicity or complement-mediated cytotoxicity, antibody binding of Siglec-8, Siglec-9 and CD22 has been demonstrated to induce apoptosis of eosinophils, neutrophils and depletion of B cells, respectively. Here, we review the properties of siglecs that make them attractive for cell-targeted therapies.