Characterization of SM201, an anti-hFcγRIIB antibody not interfering with ligand binding that mediates immune complex dependent inhibition of B cells.
The monoclonal antibody SM201 specifically recognizes the human inhibitory FcγRIIB without showing cross-reactivity to the related but activating FcγRIIA. The epitope recognized by SM201 is located outside the IgG-binding site of FcγRIIB. As a result, the antibody does not interfere with hIgG binding to the receptor. It was therefore hypothesized that SM201 may amplify the inhibitory signaling of FcγRIIB after coligation of B cell receptor (BCR) and FcγRIIB by immune complexes (ICs). Mechanistic and functional studies were conducted in established B cell lines as well as in primary B cells from healthy donors to substantiate the anticipated working principle. Using an experimental setup mimicking IC binding, we were able to demonstrate that SM201 enhances the extent of ITIM phosphorylation of FcγRIIB. The antibody works synergistically with ICs and the mode of action is strictly dependent on their presence. Additionally, SM201 did not induce apoptosis, cellular depletion or NK cell activation, which indicates an advantageous safety profile. This establishes an innovative approach for the treatment of antibody-mediated autoimmune diseases.
SuppreMol GmbH, Martinsried, Germany.
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N
Rieth
SuppreMol GmbH, Martinsried, Germany.
A
A
Carle
SuppreMol GmbH, Martinsried, Germany.
M A
MA
Müller
SuppreMol GmbH, Martinsried, Germany.
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D
ter Meer
SuppreMol GmbH, Martinsried, Germany.
C
C
Direnberger
SuppreMol GmbH, Martinsried, Germany.
T
T
Pohl
SuppreMol GmbH, Martinsried, Germany. Electronic address: sondermann@suppremol.com.
P
P
Sondermann
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D000915:Antibody Affinity; D000918:Antibody Specificity; D000936:Antigen-Antibody Complex / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D016466:CHO Cells; D045744:Cell Line, Tumor; D003412:Cricetulus; D005786:Gene Expression Regulation; D006801:Humans; D006825:Hybridomas / Q000737:chemistry / Q000276:immunology; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D008024:Ligands; D061251:Primary Cell Culture; D011485:Protein Binding; D051381:Rats; D011947:Receptors, Antigen, B-Cell / Q000819:agonists / Q000235:genetics / Q000276:immunology; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; C080568:Fc gamma receptor IIA; C080571:Fc gamma receptor IIB; D007074:Immunoglobulin G; D008024:Ligands; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins
Autoimmune disease; B cell signaling; FcγRIIB; Immune complex