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 Ca(2+)  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.
Chair of Genetics, Department of Biology, University of Erlangen, Erlangen, Germany.
Astrid
A
Schweizer
Miriam
M
Wöhner
Horst
H
Prescher
Reinhard
R
Brossmer
Lars
L
Nitschke
D036002:ADP Ribose Transferases / Q000235:genetics / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D002413:Cations, Divalent / Q000737:chemistry; D002454:Cell Differentiation; D019070:Cell Lineage; D003602:Cytotoxicity, Immunologic; D005098:Exotoxins / Q000235:genetics / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D000922:Immunotoxins / Q000235:genetics / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D058990:Molecular Targeted Therapy; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism*; D011549:Pseudomonas / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000378:metabolism*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D002413:Cations, Divalent; D005098:Exotoxins; D007075:Immunoglobulin M; D000922:Immunotoxins; D019158:N-Acetylneuraminic Acid; D011947:Receptors, Antigen, B-Cell; D051918:Sialic Acid Binding Ig-like Lectin 2; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A