Siglec-2, also known as CD22, is a member of the immune inhibitory Siglecs family, which carries ITIM motifs to transmit immunosuppressive signals. These signals result in reduced phagocytosis, diminished inflammation, and inhibition of danger-associated molecular pattern (DAMP)/pathogen-associated molecular pattern (PAMP)-mediated inflammation.
Siglec-2 is a cell surface receptor predominantly expressed on B cells, where it regulates B-cell proliferation, survival, signaling, and antibody production. The cytoplasmic tail of Siglec-2 contains six tyrosine residues, four of which are located within ITIM motifs: Y783, Y843, Y863, and Y828. Upon cross-linking of B-cell receptors (BCRs), these tyrosine residues become phosphorylated, recruiting Src homology region 2 (SH2) domain-containing protein tyrosine phosphatase-1 (SHP-1). This recruitment leads to the dephosphorylation of BCR-proximal signaling complexes.
Given its unique presence on B lymphocytes, Siglec-2 is an attractive therapeutic target. Currently, there are numerous ongoing trials assessing the safety and efficacy of CD22-directed chimeric antigen receptor (CAR) therapies, particularly in children with relapsed or refractory B-cell leukemia. Additionally, the development of novel CARs, such as bispecific CD20/CD22 CARs and CD19/CD22 CARs, is underway.