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

Abstract

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 (Siglec-3) antibody Gemtuzumab (Mylotarg™) is approved for treatment of acute myeloid leukemia (AML), 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 (ADCC) or complement-mediated cytotoxicity (CDC), antibody binding of Siglec-8, Siglec-9, and CD22 have 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.

Simultaneous engagement of the activatory receptors NKG2D and CD3 for retargeting of effector cells to CD33-positive malignant cells

“…None of these mutations is currently considered a disease-initiating event and previous studies have suggested the absence of mutual exclusivity amongst mutations; clonal hierarchy could not be predicted when two or more of these mutations co-exist in the same patient. 1 The recent discovery of LNK mutations in JAK2V617F-negative MPN suggested an alternative mechanism of JAK-STAT (Janus kinase/signal transducers and activators of transcription) activation and clonal erythrocytosis. 2,3 However, subsequent studies showed that JAK2 and LNK mutations are not necessarily mutually exclusive and the pathogenetic contribution of LNK mutations, in the presence of JAK2V617F, remains unclear.…”

“…Therefore, CD33 appears as promising target for immunotherapy. 1 As surface-bound immune complexes from previously described anti-CD33 antibodies are rapidly uptaken by AML blasts within the first hours, previous anti-CD33 immunotargeting strategies were mainly based on toxic drugs, which were covalently bound to the anti-CD33 antibodies (for example, gemtuzumab ozogamicin, Mylotarg) and, thereby, co-delivered to the AML cells. 2 Unfortunately, the European approval of gemtuzumab failed and recently the drug was also withdrawn from the American market for reasons of side effects.…”

Expression and preliminary functional analysis of Siglec-F on mouse macrophages

“…Through a nomenclature agreement, Siglecs unique to mice are lettered rather than numbered (Crocker et al, 1998). Despite the discovery of numerous Siglecs, the biological functions of these proteins are largely unknown, although it has been reported that Siglec-8 specifically induces eosinophil apoptosis (O′Reilly and Paulson, 2009), while Siglec-9, which is expressed on the leukocyte surface, specifically induces neutrophil death (von Gunten et al, 2005). Investigations of Siglec biology have focused on the mouse as a model organism due to the difficulties and limitations associated with this type of research in humans.…”

Mechanism and Function of Monoclonal Antibodies Targeting Siglec-15 for Therapeutic Inhibition of Osteoclastic Bone Resorption

“…Using the STAR subtractive cloning technology (2), we identified sialic acid binding immunoglobulin-like lectin-15 (Siglec-15) as an mRNA transcript highly up-regulated in mature osteoclasts compared with their non-differentiated precursor cells (3). The Siglecs are a family of type I transmembrane proteins that are distinguished by N-terminal immunoglobulin-like domains that bind to sialylated glycoconjugates and are typically expressed in subsets of hematopoietic cell types (4). We examined the importance of Siglec-15 in tissue culture models of osteoclastogenesis and found that RNAi-mediated knockdown of Siglec-15 expression impaired RANKL-induced differentiation of primary human osteoclast precursors (HOPs) and the mouse RAW264.7 cell line (3).…”