Therapies can either work against the Siglec or its ligand. The easiest method is to make an antibody to Block Siglec. One of the approaches is simply blocking antibodies that do not dimerize and distress the Siglec. Blocking the Siglec ligand is another approach. The blockade is not a possibility for Siglecs with poorly defined ligands. Instead, Desialylation can prevent Siglec interactions.
The only Siglec-targeted treatments that the Food and Drug Administration (FDA) has currently authorized are Siglec-Targeted Antibody-Drug Conjugates (ADCs) against CD22 and CD33, which recognize target cells using the Siglec as a tumour-specific antigen. In general, dimerization is agonistic because immune cell function is inhibited by crosslinking antibodies that target Siglecs with the immunoreceptor tyrosine-based inhibition motif (ITIM) domain. On a multivalent scaffold, glycomimetic Siglec ligands are also visible. It is more likely that antibodies, single-chain variable fragments (scFvs), or highly-affinity glycomimetic ligands will act as antagonists. CD BioGlyco provides a Glycosylation Site-specific ADC Development Platform for customers to study ADCs developments. If you are interested in our services, please feel free to contact us.
Fig.1 Modalities for Siglec-targeted therapies. (Smith & Bertozzi, 2021)
Sialic acid-Siglec axis contributes to immunological homeostasis and any imbalance can result in a variety of illnesses, including cancer and autoimmune disorders. Many therapies that bind to Siglecs have been created to treat all of this, either based on antibodies or smaller compounds. Several ADCs target CD22 on B cell leukemias and lymphomas. Additionally, CD22 unexpectedly entered the field of neurodegeneration. CD22 is expressed on mouse-aged and damage-associated microglia. Treatment of elderly mice with a CD22-blocking antibody increased microglia-mediated clearance of Aβ and α-synuclein and, enhanced cognitive performance.
Immunosuppression is caused by contact between a sialylated glycan on a cancer cell and an inhibitory Siglec on an immune cell, as shown in the image. In order to prevent them from suppressing an immune response, anti-Siglec binding to a Siglec prevents binding. Once bound, it desialylates the ligand to stop immunological suppression brought on by interactions between Siglec and sialic acid. An effective sialic acid trap is a Siglec-Fc fusion. The Siglec part can bind sialic acid to the tumor or immune cells, preventing inhibitory immunological signaling, whilst the Fc portion facilitates localization to immune cells.
Fig.2 Therapies targeting Siglecs as immune modulators. (Läubli, et al., 2022)
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