Sialic acid‐binding immunoglobulin‐like lectin (Sigelac)‐15 is a rapidly internalised cell‐surface antigen expressed by acute myeloid leukaemia cells (original) (raw)
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British Journal of Haematology, 2021
Sialic acid-binding immunoglobulin-like lectin (Siglec)-15 has recently been identified as a critical tumour checkpoint, augmenting the expression and function of programmed death-ligand 1. We raised a monoclonal antibody, A9E8, specific for Siglec-15 using phage display. A9E8 stained myeloid leukaemia cell lines and peripheral cluster of differentiation (CD)33 + blasts and CD34 + leukaemia stem cells from patients with acute myeloid leukaemia (AML). By contrast, there was minimal expression on healthy donor leucocytes or CD34 + stem cells from non-AML donors, suggesting targeting Siglec-15 may have significant therapeutic advantages over its fellow Siglec CD33. After binding, A9E8 was rapidly internalised (half-life of 180 s) into K562 cells. Antibodies to Siglec-15 therefore hold therapeutic potential for AML treatment.
British Journal of Haematology, 2003
Sialic acid-binding immunoglobulin-like lectin (Siglec)-5 or CD170 is a CD33-related receptor, containing cytoplasmic immune receptor-based tyrosine signalling motifs, that has previously been reported to be myeloidspecific like CD33 and thus may be useful in the characterization of both normal and malignant haemopoiesis. This study showed that Siglec-5 had a distinct expression pattern to CD33 both on normal myeloid cells and in acute myeloid leukaemia (AML). In normal bone marrow and cord blood, myeloid cells predominantly expressed Siglec-5 at the later stages of granulocytic differentiation. Siglec-5 was not expressed at significant levels by CD34 + progenitors either from bone marrow or mobilized peripheral blood. During in vitro myeloid differentiation of cord blood purified CD34 + cells, Siglec-5 was upregulated later than CD33. Siglec-5 expression remained absent or very low on cultured CD34 + cells, unlike CD33, which was present on almost all CD34 + cells by day 4. However, analysis of blasts from 23 patients with AML revealed aberrant expression of Siglec-5 with CD34 in 50% (seven of 14) of patients with CD34 + AML; 61% (14 of 23) of AML cases were positive for Siglec-5 with an increased frequency in the French-American-British subtypes M3-5 (80%) compared with M0-2 (25%). All 13 acute lymphoblastic leukaemic (ALL) samples tested, including a CD33 + ALL, were Siglec-5 negative. These results support the further evaluation of Siglec-5 antibodies in the diagnosis and monitoring of AML.
Chemical Science, 2014
The siglec family of sialic acid-binding proteins are endocytic immune cell receptors that are recognized as potential targets for cell directed therapies. CD33 and CD22 are prototypical members and are validated candidates for targeting acute myeloid leukaemia and non-Hodgkin's lymphomas due to their restricted expression on myeloid cells and B-cells, respectively. While nanoparticles decorated with high affinity siglec ligands represent an attractive platform for delivery of therapeutic agents to these cells, a lack of ligands with suitable affinity and/or selectivity has hampered progress. Herein we describe selective ligands for both of these siglecs, which when displayed on liposomal nanoparticles, can efficiently target the cells expressing them in peripheral human blood. Key to their identification was the development of a facile method for chemo-enzymatic synthesis of disubstituted sialic acid analogues, combined with iterative rounds of synthesis and rapid functional analysis using glycan microarrays.
Cancers
Immunotherapy with targeted therapeutic antibodies is often ineffective in long-term responses in cancer patients due to resistance mechanisms such as overexpression of checkpoint molecules. Similar to T lymphocytes, myeloid immune cells express inhibitory checkpoint receptors that interact with ligands overexpressed on cancer cells, contributing to treatment resistance. While CD47/SIRPα-axis inhibitors in combination with IgA therapy have shown promise, complete tumor eradication remains a challenge, indicating the presence of other checkpoints. We investigated hypersialylation on the tumor cell surface as a potential myeloid checkpoint and found that hypersialylated cancer cells inhibit neutrophil-mediated tumor killing through interactions with sialic acid-binding immunoglobulin-like lectins (Siglecs). To enhance antibody-dependent cellular cytotoxicity (ADCC) using IgA as therapeutic, we explored strategies to disrupt the interaction between tumor cell sialoglycans and Siglecs e...
Characterization of Siglec-5, a Novel Glycoprotein Expressed on Myeloid Cells Related to CD33
Blood, 1998
We describe the characterization of siglec-5 (sialic acid-binding Ig-like lectin-5), a novel transmembrane member of the immunoglobulin superfamily, highly related to the myeloid antigen, CD33. A full-length cDNA encoding siglec-5 was isolated from a human activated monocyte cDNA library. Sequencing predicted that siglec-5 contains four extracellular immunoglobulin-like domains, the N-terminal two of which are 57% identical to the corresponding region of CD33. The cytoplasmic tail is also related to that of CD33, containing two tyrosine residues embodied in immunoreceptor tyrosine-based inhibitory motif-like motifs. The siglec-5 gene was shown to map to chromosome 19q13.41-43, closely linked to the CD33 gene. When siglec-5 was expressed on COS cells or as a recombinant protein fused to the Fc region of human IgG1, it was able to mediate sialic acid–dependent binding to human erythrocytes and soluble glycoconjugates, suggesting that it may be involved in cell-cell interactions. By us...
Current Status on Therapeutic Molecules Targeting Siglec Receptors
Cells, 2020
The sialic acid-binding immunoglobulin-type of lectins (Siglecs) are receptors that recognize sialic acid-containing glycans. In the majority of the cases, Siglecs are expressed on immune cells and play a critical role in regulating immune cell signaling. Over the years, it has been shown that the sialic acid-Siglec axis participates in immunological homeostasis, and that any imbalance can trigger different pathologies, such as autoimmune diseases or cancer. For all this, different therapeutics have been developed that bind to Siglecs, either based on antibodies or being smaller molecules. In this review, we briefly introduce the Siglec family and we compile a description of glycan-based molecules and antibody-based therapies (including CAR-T and bispecific antibodies) that have been designed to therapeutically targeting Siglecs.
Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy
Nature Medicine, 2019
hile antigen is required for T cells to initiate the activation process, the specific ligand-receptor interactions on the cell surface, such as the molecules in the B7-CD28 family and the tumor necrosis factor superfamily, transmit either positive or negative signals to T cells and determine the direction and fate of the immune response 1-3. Manipulation by antagonizing or agonizing these signals selectively amplifies immune responses and eliminates tumors 4-7. In addition to the magnitude of the immune response, the geographic location where the response is generated and executed is critical in the context of cancer immunotherapy. Selective amplification of anti-tumor immunity in the TME has led to highly efficacious cancer immunotherapies without excessive side-effects 8,9. A conceptually important advance in cancer immunology in recent years is the presence of adaptive resistance mechanisms in the TME to prevent the execution of tumor immunity. For example, B7-H1 (CD274, PD-L1) 10,11 is selectively induced in the TME, predominantly by interferon-gamma (IFN-γ) from tumor-infiltrating T-lymphocytes, which in turn initiates a series of events including the engagement of PD-1 on T cells, transmission of apoptosis and exhaustion signals that eventually leads to the dysfunction of T cells, a process collectively called adaptive resistance 7,12,13. Blockade of the B7-H1/PD-1 pathway by specific mAbs to B7-H1 or PD-1 (anti-PD therapy) prevents the dysfunction of T cells and selectively restores immune responses in the TME 7-9. This strategy, collectively called normalization cancer immunotherapy 14 , is remarkably effective for the treatment of cancer, as demonstrated clinically by the regression of a broad spectrum of advanced cancers and by significant survival benefits in patients 8,15,16. Immune evasion mechanisms in the TME of advanced human cancers are highly heterogeneous. On the basis of our recent definitions used to classify tumor immunity in the microenvironment (TIME), the B7-H1/PD-1 pathway is responsible for dysfunctional immunity in fewer than 40% of human solid tumors 12,15,17. Ample evidence supports that, in addition to the upregulation of B7-H1, many other molecular or cellular mechanisms can also contribute to dysfunctional immunity in the TME. These mechanisms include, but are not limited to, a lack of sufficient immune cell infiltration, accumulation of regulatory T cells, the presence of tumor-associated macrophages (TAMs) and myeloid-derived suppressive cells, as well as upregulation of suppressive molecules, cytokines, metabolites and downregulation of immune stimulatory molecules 18,19. Many of these mechanisms, however, may not be selective for the TME and, therefore, manipulation of these pathways could lead to a broad activation of the immune system with the risk of autoimmune toxicities 8,20. The current success of anti-PD therapy highlights the importance of restoring defective immune responses in the TME as a principle for normalization cancer immunotherapy 14. Siglec-15 was originally identified as one of the Siglec gene family members with a characteristic sialic acid-binding immunoglobulin-type lectin structure 21. While the role of Siglec-15 in osteoclast differentiation and bone remodeling has been reported 22-25 , its immunological function remains largely unknown. We demonstrate that the expression of Siglec-15 is normally limited to cells in myeloid lineage but can be upregulated in many human cancers. Employing a newly developed genome-scale T cell activity array (TCAA), mice with whole-body or lineage-specific gene ablation and specific mAbs, we discovered Siglec-15 as an immune suppressive molecule largely operating in the TME and is non-redundant to the B7-H1/PD-1 pathway. Results High-throughput screening of the human transmembrane proteome for the discovery of T cell activity modulators. We constructed a high-throughput functional screening system (TCAA) to identify cell surface modulators of T cell activities in vitro (Fig. 1a). The TCAA includes over 6,500 human genes encoding >90% of
Siglec-15 as an Emerging Target for Next-generation Cancer Immunotherapy
Clinical Cancer Research, 2020
Immunomodulatory agents blocking the PD-1/PD-L1 pathway have shown a new way to treat cancer. The explanation underlying the success of these agents may be the selective expression of PD-L1 with dominant immune-suppressive activities in the tumor microenvironment (TME), supporting a more favorable tumor response-to-toxicity ratio. However, despite the big success of these drugs, most patients with cancer show primary or acquired resistance, calling for the identification of new immune modulators in the TME. Using a genome-scale T-cell activity array in combination with bioinformatic analysis of human cancer databases, we identified Siglec-15 as a critical immune suppressor with broad upregulation on various cancer types and a potential target for cancer immunotherapy. Siglec-15 has unique molecular features compared with many other known checkpoint inhibitory ligands. It shows prominent expression on macrophages and cancer cells and a mutually exclusive expression with PD-L1, sugges...
International journal of oncology, 2014
Malignant mesothelioma is a highly aggressive tumor with poor prognosis. An effective drug for treatment of malignant mesothelioma is greatly needed. Sialic acid-binding lectin (SBL) isolated from oocytes of Rana catesbeiana is a multifunctional protein which has lectin activity, ribonuclease activity and antitumor activity, so it could be developed as a new type of anticancer drug. The validity of SBL for treatment of malignant mesothelioma was assessed using three malignant mesotheliomas and a non-malignant mesothlial cell line. Effectiveness of combinatorial treatment of SBL and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) was also elucidated and characterized. SBL induced tumor-selective cytotoxicity that was attributed to induction of apoptosis. Combinatorial treatment of SBL and TRAIL showed synergistic apoptosis-inducing effect. Additional experiments revealed that Bid was the mediating molecule for the synergistic effect in SBL and TRAIL. These results sug...