Targeting of CD22‐positive B‐cell lymphoma cells by synthetic divalent sialic acid analogues

CD22 is an inhibitory co‐receptor of the B‐cell receptor (BCR) on B cells. Since CD22 is ubiquitously expressed in the B‐cell lineage and CD22 endocytosis can be triggered efficiently, antibodies and antibody‐based immunotoxins against CD22 are used to target B cells both in B‐cell lymphomas and leukemias, as well as in autoimmune diseases. CD22 recognizes α2,6‐linked sialic acids as endogenous ligands. We have developed new synthetic sialosides as ligands for human CD22. These sialosides bind CD22 on human B cells with high affinity and can efficiently enhance IgM‐triggered Ca²⁺ signaling. We coupled these sialosides to Pseudomonas exotoxin A to generate a novel CD22 ligand‐based immunotoxin. This sialoside‐exotoxin‐A construct can specifically kill CD22‐positive B‐cell lymphoma cells. It binds specifically to CD22‐positive B‐cell lymphoma cells and is dominant over endogenous cis‐ligands on the B‐cell surface. The sialoside‐exotoxin‐A construct is efficiently internalized by endocytosis into B‐cell lymphoma cell lines. Thus we show the development of a new therapeutic compound for targeting CD22 on human B cells, both for B‐cell lymphoma, as well as for B‐cell‐mediated autoimmune diseases.