Simultaneous engagement of FcgammaIIb and CD22 inhibitory receptors silences targeted B cells and suppresses autoimmune disease activity.
All B cell targeting therapeutic approaches used at present are unspecific and there is an urgent need for agents that silence selectively pathological autoreactive B lymphocytes only. We hypothesized that this aim could be achieved by chimeric antibodies that cross-link B cell immunoglobulin receptors with inhibitory receptors on the surface of the same targeted disease-associated cell. A hybrid molecule was constructed by coupling copies of the DNA-mimicking DWEYSVWLSN peptide and of the CD22-binding STN epitope with a free terminal sialic acid to a mouse monoclonal IgG antibody backbone. The DNA mimotope peptide binds to the immunoglobulin B cell receptor of pathological DNA-specific B cells of lupus mice, the STN epitope - to CD22 and the IgG by its Fc fragment - to FcgammaIIb on the surface of the same cell. Mass-spectra analysis showed that 4 STN epitopes plus 5 DNA mimotope peptides were coupled to a single light immunoglobulin chain and 4 STN - and 2 DNA mimotopes - to a heavy chain. Both FcgammaIIb and CD22 receptors on spleen cells from lupus MRL/lpr mice were phosphorylated after exposure to the chimeric antibody, indicating the involvement of both inhibitory pathways. The constructed chimera suppressed specifically in vitro as well as in vivo anti-DNA IgM and IgG antibody production and delayed the development of glomerulonephritis in the lupus-prone animals. The use of chimeric antibodies targeting two independent inhibitory B lymphocyte receptors represents a novel approach for the selective suppression of pathological autoreactive B cells in autoimmune diseases.
Mihaylova
Nikolina
N
Department of Immunology, Stefan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, 26, Acad. G. Bonchev St., 1113, Sofia, Bulgaria.
Voynova
Elisaveta
E
Tchorbanov
Andrey
A
Dolashka-Angelova
Pavlina
P
Bayry
Jagadeesh
J
Devreese
Bart
B
Kaveri
Srini
S
Vassilev
Tchavdar
T
D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology* / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D004247:DNA / Q000276:immunology; D000939:Epitopes; D056724:Immunity, Humoral / Q000187:drug effects*; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D015202:Protein Engineering / Q000379:methods; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology* / Q000378:metabolism
D018033:Antibodies, Bispecific; D000939:Epitopes; C499172:Fcgr2b protein, mouse; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D051918:Sialic Acid Binding Ig-like Lectin 2; D004247:DNA