Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange

Marijn van der Neut Kolfschoten; Janine Schuurman; Mario Losen; Wim K Bleeker; Pilar Martínez-Martínez; Ellen Vermeulen; Tamara H den Bleker; Luus Wiegman; Tom Vink; Lucien A Aarden; Marc H De Baets; Jan G J van de Winkel; Rob C Aalberse; Paul W H I Parren

doi:10.1126/science.1144603

Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange

Science. 2007 Sep 14;317(5844):1554-7. doi: 10.1126/science.1144603.

Authors

Marijn van der Neut Kolfschoten¹, Janine Schuurman, Mario Losen, Wim K Bleeker, Pilar Martínez-Martínez, Ellen Vermeulen, Tamara H den Bleker, Luus Wiegman, Tom Vink, Lucien A Aarden, Marc H De Baets, Jan G J van de Winkel, Rob C Aalberse, Paul W H I Parren

Affiliation

¹ Sanquin Research-AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands.

PMID: 17872445
DOI: 10.1126/science.1144603

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allergens / immunology
Animals
Antibodies, Bispecific / immunology
Antibodies, Monoclonal / immunology
Antigens, CD20 / immunology
Antigens, Plant
Autoantibodies / immunology
ErbB Receptors / immunology
Glycoproteins / immunology
Humans
Immunoglobulin Constant Regions / chemistry
Immunoglobulin Fab Fragments / chemistry*
Immunoglobulin Fab Fragments / immunology*
Immunoglobulin Fab Fragments / metabolism
Immunoglobulin G / chemistry*
Immunoglobulin G / immunology*
Immunoglobulin G / metabolism
Immunoglobulin Heavy Chains
Macaca mulatta
Mice
Mutation
Myasthenia Gravis, Autoimmune, Experimental / immunology
Myasthenia Gravis, Autoimmune, Experimental / prevention & control
Protein Processing, Post-Translational
Receptors, Cholinergic / immunology

Substances

Allergens
Antibodies, Bispecific
Antibodies, Monoclonal
Antigens, CD20
Antigens, Plant
Autoantibodies
Glycoproteins
Immunoglobulin Constant Regions
Immunoglobulin Fab Fragments
Immunoglobulin G
Immunoglobulin Heavy Chains
Receptors, Cholinergic
ErbB Receptors
Fel d 1 protein, Felis domesticus