Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange.
Antibodies play a central role in immunity by forming an interface with the innate immune system and, typically, mediate proinflammatory activity. We describe a novel posttranslational modification that leads to anti-inflammatory activity of antibodies of immunoglobulin G, isotype 4 (IgG4). IgG4 antibodies are dynamic molecules that exchange Fab arms by swapping a heavy chain and attached light chain (half-molecule) with a heavy-light chain pair from another molecule, which results in bispecific antibodies. Mutagenesis studies revealed that the third constant domain is critical for this activity. The impact of IgG4 Fab arm exchange was confirmed in vivo in a rhesus monkey model with experimental autoimmune myasthenia gravis. IgG4 Fab arm exchange is suggested to be an important biological mechanism that provides the basis for the anti-inflammatory activity attributed to IgG4 antibodies.
van der Neut Kolfschoten
Marijn
M
Sanquin Research-AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands.
Schuurman
Janine
J
Losen
Mario
M
Bleeker
Wim K
WK
Martínez-Martínez
Pilar
P
Vermeulen
Ellen
E
den Bleker
Tamara H
TH
Wiegman
Luus
L
Vink
Tom
T
Aarden
Lucien A
LA
De Baets
Marc H
MH
van de Winkel
Jan G J
JG
Aalberse
Rob C
RC
Parren
Paul W H I
PW
D000485:Allergens / Q000276:immunology; D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology; D052179:Antigens, Plant; D001323:Autoantibodies / Q000276:immunology; D066246:ErbB Receptors / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000737:chemistry; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D007074:Immunoglobulin G / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains; D008253:Macaca mulatta; D051379:Mice; D009154:Mutation; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology / Q000517:prevention & control; D011499:Protein Processing, Post-Translational; D011950:Receptors, Cholinergic / Q000276:immunology
D000485:Allergens; D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D052179:Antigens, Plant; D001323:Autoantibodies; D006023:Glycoproteins; D007127:Immunoglobulin Constant Regions; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D011950:Receptors, Cholinergic; D066246:ErbB Receptors; C059296:Fel d 1 protein, Felis domesticus