SIGLEC15 Specific Neutra™ Antibody Products

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Sialic Acid Binding Ig Like Lectin 15 (SIGLEC15) is a member of the immunoglobulin superfamily receptors that recognize sialic acids and are commonly expressed on immune cells. It is anticipated to play a role in organizing the actin cytoskeleton, regulating bone resorption, and modulating osteoclast development. Additionally, SIGLEC15 is predicted to be an integral component of the cell membrane and participate in protein-containing complexes, exerting its activity primarily at the plasma membrane. Diseases associated with SIGLEC15 include chromophobe renal cell carcinoma and endocervical carcinoma.

Its Gene ID: 284266, UniProtKB ID: Q6ZMC9, and OMIM ID: 618105.

SIGLEC15 Pathway

SIGLEC15 possesses an extracellular region comprised of two immunoglobulin-like domains, succeeded by a transmembrane domain featuring a crucial lysine residue essential for binding to the adapter protein DAP12, along with a cytoplasmic tail. The interaction between SIGLEC15 and DAP12 hinges on ionic bonds within their transmembrane domains. During osteoclast differentiation, SIGLEC15 on precursor cells recognizes CD44 on adjacent osteoclasts, initiating signaling via the DAP12–SYK pathway, which synergizes with the RANK–TRAF6 pathway, bolstering downstream signaling (e.g., ERK and PI3K–AKT). Sialic acids are requisite for this interaction. Additionally, within the tumor microenvironment and during microbial infections, SIGLEC15 on tumor-associated macrophages or cancer cells interacts with an unidentified receptor on T cells, inhibiting T cell responses crucial for restraining cancer proliferation. Similarly, SIGLEC15 on myeloid or epithelial cells, induced by microbial pathogens, engages an unidentified receptor on T cells, suppressing T cell responses necessary for infection control.

Fig. 1 Interactions and signaling pathways of SIGLEC-15 and its ligands.^{1, 4}

Applications of Anti-SIGLEC15 Antibodies

Therapeutic Potential of Anti-SIGLEC15 mAb in AML Treatment

SIGLEC15 has emerged as a pivotal tumor checkpoint, amplifying the expression and activity of programmed death-ligand 1. Utilizing an anti-SIGLEC15 monoclonal antibody (anti-SIGLEC15 mAb), myeloid leukemia cell lines and peripheral CD33⁺ blasts, alongside CD34⁺ leukemia stem cells from acute myeloid leukemia (AML) patients, exhibited staining. Conversely, minimal expression was observed on leukocytes from healthy donors or CD34⁺ stem cells from non-AML donors, indicating the therapeutic promise of targeting SIGLEC15 over its counterpart CD33 in AML treatment. Antibodies directed against SIGLEC15 thus hold considerable therapeutic potential for managing AML.

Fig. 2 Visualization of anti-SIGLEC15 mAb fluorescence staining depicts internalization of SIGLEC15 from the cell surface.^{2, 4}

Therapeutic Potential of Anti-SIGLEC15 mAb in Bone Loss

Harnessing mAbs to target pivotal cell-surface proteins on bone-resorbing osteoclasts offers a promising avenue for addressing cancer-associated bone loss and skeletal disorders. SIGLEC15 emerges as a promising target, markedly upregulated during osteoclast differentiation triggered by RANKL cytokine. Positioned on the plasma membrane, SIGLEC15 becomes susceptible to mAb intervention, effectively impeding osteoclast differentiation in vitro. Administering these antibodies to mice substantially elevates bone mineral density, indicative of suppressed osteoclast activity. Functionally, SIGLEC15 interacts with adapter protein DAP12, potentially activating Akt upon clustering on osteoclast surfaces, reflecting its inherent signaling role. Crucially, mAbs facilitate rapid internalization and lysosomal degradation of SIGLEC15 through receptor dimerization induction. This underscores a pivotal regulatory hub governing osteoclast differentiation and activity downstream of RANKL, underscoring the potential of SIGLEC15 antibodies as a novel therapeutic strategy for bone loss.

Fig. 3 Mechanistic model illustrating SIGLEC15 antibody action on osteoclasts.^{3, 4}

Creative Biolabs presents a wide array of antibodies targeting SIGLEC15, specifically designed for research purposes and investigating therapeutic approaches against AML, bone loss, and more. Additionally, our team of experts is on hand to deliver personalized blocking or neutralizing antibodies focused on SIGLEC15 upon request.

REFERENCES

Angata, Takashi. "Siglec-15: a potential regulator of osteoporosis, cancer, and infectious diseases." Journal of biomedical science 27.1 (2020): 10.
Cao, Huan, et al. "Siglec-15 is a rapidly internalised cell-surface antigen expressed by acute myeloid leukaemia cells." British journal of haematology (2021).
Stuible, Matthew, et al. "Mechanism and function of monoclonal antibodies targeting siglec-15 for therapeutic inhibition of osteoclastic bone resorption." Journal of Biological Chemistry 289.10 (2014): 6498-6512.
Distributed under Open Access license CC BY 4.0, without modification.

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