title: The mechanistic impact of CD22 engagement with epratuzumab on B cell function: Implications for the treatment of systemic lupus erythematosus.
abstract: Epratuzumab is a B-cell-directed non-depleting monoclonal antibody that targets CD22. It is currently being evaluated in two phase 3 clinical trials in patients with systemic lupus erythematosus (SLE), a disease associated with abnormalities in B-cell function and activation. The mechanism of action of epratuzumab involves perturbation of the B-cell receptor (BCR) signalling complex and intensification of the normal inhibitory role of CD22 on the BCR, leading to reduced signalling and diminished activation of B cells. Such effects may result from down-modulation of CD22 upon binding by epratuzumab, as well as decreased expression of other proteins involved in amplifying BCR signalling capability, notably CD19. The net result is blunting the capacity of antigen engagement to induce B-cell activation. The functional consequences of epratuzumab binding to CD22 include diminished B-cell proliferation, effects on adhesion molecule expression, and B-cell migration, as well as reduced production of pro-inflammatory cytokines, such as IL-6 and TNF. Studies in patients treated with epratuzumab have revealed a number of pharmacodynamic effects that are linked to the mechanism of action (i.e., a loss of the target molecule CD22 from the B-cell surface followed by a modest reduction in peripheral B-cell numbers after prolonged therapy). Together, these data indicate that epratuzumab therapy affords a unique means to modulate BCR complex expression and signalling.
authors.affiliation: Department of Medicine/Rheumatology and Clinical Immunology, Charité Berlin and DRFZ Berlin, 10117 Berlin, Germany. Electronic address: thomas.doerner@charite.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dörner
authors.affiliation: UCB Pharma, 208 Bath Road, Slough, West Berkshire, SL1 3WE, UK. Electronic address: tony.shock@ucb.com.
authors.forename: Anthony
authors.initials: A
authors.lastname: Shock
authors.affiliation: Immunomedics Inc., Morris Plains, NJ, USA. Electronic address: dmg.gscancer@att.net.
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
authors.affiliation: Formerly National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: peterlipsky@comcast.net.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lipsky
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C497867:CD22 protein, human; D011947:Receptors, Antigen, B-Cell; D051918:Sialic Acid Binding Ig-like Lectin 2; C448700:epratuzumab
keywords: B cells; Biologic therapies; CD22; Epratuzumab; Systemic lupus erythematosus