Abstract
Sialic acid-binding Immunoglobulin-like lectin-9 (Siglec-9) is a glyco-immune negative checkpoint expressed on several immune cells. Siglec-9 exerts its inhibitory effects by binding to sialoglycan ligands expressed on cancer cells, enabling them to evade immunosurveillance. We developed a panel of human anti-Siglec-9 hybridoma clones by immunizing mice with Siglec-9-encoding DNA and Siglec-9 protein. The lead antibodies, with high specificity and functionality against Siglec-9, were identified through screening of clones. The in vitro cytotoxicity assays showed that our lead antibody enhances anti-tumor immune activity. Further, in vivo testing utilizing ovarian cancer humanized mouse model showed a drastic reduction in tumor volume. Together, we developed novel antibodies that augment anti-tumor immunity through interference with Siglec-9-mediated immunosuppression.
Highlights
Immune checkpoints are conventionally responsible for preventing unregulated immune responses to ensure limited collateral damage to surrounding cells [1,2,3,4,5]
One important approach of cancer immunotherapy is the usage of immune checkpoint inhibitors [including monoclonal antibodies] with the ability to block the immuno-regulatory interactions between tumor and immune cells [4, 6, 7]
One emerging class of immune checkpoints is Sialic acid-binding Immunoglobulin-like lectin (Siglec) receptors, which are single-pass transmembrane I-type lectins present on hematopoietic cells [5, 8,9,10]
Summary
Immune checkpoints are conventionally responsible for preventing unregulated immune responses to ensure limited collateral damage to surrounding cells [1,2,3,4,5]. Cancer cells can engage these immune checkpoints on immune cells to render them inactive/anergic, ensuring self-survival and growth [4]. One emerging class of immune checkpoints is Sialic acid-binding Immunoglobulin-like lectin (Siglec) receptors, which are single-pass transmembrane I-type lectins present on hematopoietic cells [5, 8,9,10]. The expression of sialoglycans on tumor cells surfaces facilitates tumor survival as well as growth by preventing recognition during immunosurveillance [12, 13]
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