{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T23:07:59Z","timestamp":1791673679099,"version":"4.3.4"},"reference-count":24,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5844","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2007,9,14]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1126\/science.1144603","type":"journal-article","created":{"date-parts":[[2007,9,13]],"date-time":"2007-09-13T17:09:55Z","timestamp":1189703395000},"page":"1554-1557","source":"Crossref","is-referenced-by-count":908,"title":["Anti-Inflammatory Activity of Human IgG4 Antibodies by Dynamic Fab Arm Exchange"],"prefix":"10.1126","volume":"317","author":[{"given":"Marijn","family":"van der Neut Kolfschoten","sequence":"first","affiliation":[{"name":"Sanquin Research\u2014AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands."},{"name":"Genmab, Yalelaan 60, 3584 CM Utrecht, the Netherlands."},{"name":"Department of Neuroscience, Institute of Mental Health and Neuroscience, University of Maastricht, Maastricht, the Netherlands."},{"name":"Neuroimmunology Group, Biomedical Research Institute (BIOMED) Hasselt University, Diepenbeek, Belgium."},{"name":"Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Schuurman","sequence":"additional","affiliation":[{"name":"Sanquin Research\u2014AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands."},{"name":"Genmab, Yalelaan 60, 3584 CM Utrecht, the Netherlands."},{"name":"Department of Neuroscience, Institute of Mental Health and Neuroscience, University of Maastricht, Maastricht, the Netherlands."},{"name":"Neuroimmunology Group, Biomedical Research Institute (BIOMED) Hasselt University, Diepenbeek, Belgium."},{"name":"Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Losen","sequence":"additional","affiliation":[{"name":"Sanquin Research\u2014AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands."},{"name":"Genmab, Yalelaan 60, 3584 CM Utrecht, the Netherlands."},{"name":"Department of Neuroscience, Institute of Mental Health and Neuroscience, University of Maastricht, Maastricht, the Netherlands."},{"name":"Neuroimmunology Group, Biomedical Research Institute (BIOMED) Hasselt University, Diepenbeek, Belgium."},{"name":"Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim K.","family":"Bleeker","sequence":"additional","affiliation":[{"name":"Sanquin Research\u2014AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands."},{"name":"Genmab, Yalelaan 60, 3584 CM Utrecht, the Netherlands."},{"name":"Department of Neuroscience, Institute of Mental Health and Neuroscience, University of Maastricht, Maastricht, the Netherlands."},{"name":"Neuroimmunology Group, Biomedical Research Institute (BIOMED) Hasselt University, Diepenbeek, Belgium."},{"name":"Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilar","family":"Marti\u0301nez-Marti\u0301nez","sequence":"additional","affiliation":[{"name":"Sanquin Research\u2014AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands."},{"name":"Genmab, Yalelaan 60, 3584 CM Utrecht, the Netherlands."},{"name":"Department of Neuroscience, Institute of Mental Health and Neuroscience, University of Maastricht, Maastricht, the Netherlands."},{"name":"Neuroimmunology Group, Biomedical Research Institute (BIOMED) Hasselt University, Diepenbeek, Belgium."},{"name":"Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Vermeulen","sequence":"additional","affiliation":[{"name":"Sanquin Research\u2014AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands."},{"name":"Genmab, Yalelaan 60, 3584 CM Utrecht, the Netherlands."},{"name":"Department of Neuroscience, Institute of Mental Health and Neuroscience, University of Maastricht, Maastricht, the Netherlands."},{"name":"Neuroimmunology Group, Biomedical Research Institute (BIOMED) Hasselt University, Diepenbeek, Belgium."},{"name":"Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara H.","family":"den Bleker","sequence":"additional","affiliation":[{"name":"Sanquin Research\u2014AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands."},{"name":"Genmab, Yalelaan 60, 3584 CM Utrecht, the Netherlands."},{"name":"Department of Neuroscience, Institute of Mental Health and Neuroscience, University of Maastricht, Maastricht, the Netherlands."},{"name":"Neuroimmunology Group, Biomedical Research Institute (BIOMED) Hasselt University, Diepenbeek, Belgium."},{"name":"Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luus","family":"Wiegman","sequence":"additional","affiliation":[{"name":"Sanquin Research\u2014AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands."},{"name":"Genmab, Yalelaan 60, 3584 CM Utrecht, the Netherlands."},{"name":"Department of Neuroscience, Institute of Mental Health and Neuroscience, University of Maastricht, Maastricht, the Netherlands."},{"name":"Neuroimmunology Group, Biomedical Research Institute (BIOMED) Hasselt University, Diepenbeek, Belgium."},{"name":"Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Vink","sequence":"additional","affiliation":[{"name":"Sanquin Research\u2014AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands."},{"name":"Genmab, Yalelaan 60, 3584 CM Utrecht, the Netherlands."},{"name":"Department of Neuroscience, Institute of Mental Health and Neuroscience, University of Maastricht, Maastricht, the Netherlands."},{"name":"Neuroimmunology Group, Biomedical Research Institute (BIOMED) Hasselt University, Diepenbeek, Belgium."},{"name":"Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucien A.","family":"Aarden","sequence":"additional","affiliation":[{"name":"Sanquin Research\u2014AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands."},{"name":"Genmab, Yalelaan 60, 3584 CM Utrecht, the Netherlands."},{"name":"Department of Neuroscience, Institute of Mental Health and Neuroscience, University of Maastricht, Maastricht, the Netherlands."},{"name":"Neuroimmunology Group, Biomedical Research Institute (BIOMED) Hasselt University, Diepenbeek, Belgium."},{"name":"Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc H.","family":"De Baets","sequence":"additional","affiliation":[{"name":"Sanquin Research\u2014AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands."},{"name":"Genmab, Yalelaan 60, 3584 CM Utrecht, the Netherlands."},{"name":"Department of Neuroscience, Institute of Mental Health and Neuroscience, University of Maastricht, Maastricht, the Netherlands."},{"name":"Neuroimmunology Group, Biomedical Research Institute (BIOMED) Hasselt University, Diepenbeek, Belgium."},{"name":"Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan G.J.","family":"van de Winkel","sequence":"additional","affiliation":[{"name":"Sanquin Research\u2014AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands."},{"name":"Genmab, Yalelaan 60, 3584 CM Utrecht, the Netherlands."},{"name":"Department of Neuroscience, Institute of Mental Health and Neuroscience, University of Maastricht, Maastricht, the Netherlands."},{"name":"Neuroimmunology Group, Biomedical Research Institute (BIOMED) Hasselt University, Diepenbeek, Belgium."},{"name":"Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob C.","family":"Aalberse","sequence":"additional","affiliation":[{"name":"Sanquin Research\u2014AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands."},{"name":"Genmab, Yalelaan 60, 3584 CM Utrecht, the Netherlands."},{"name":"Department of Neuroscience, Institute of Mental Health and Neuroscience, University of Maastricht, Maastricht, the Netherlands."},{"name":"Neuroimmunology Group, Biomedical Research Institute (BIOMED) Hasselt University, Diepenbeek, Belgium."},{"name":"Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul W. H. I.","family":"Parren","sequence":"additional","affiliation":[{"name":"Sanquin Research\u2014AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands."},{"name":"Genmab, Yalelaan 60, 3584 CM Utrecht, the Netherlands."},{"name":"Department of Neuroscience, Institute of Mental Health and Neuroscience, University of Maastricht, Maastricht, the Netherlands."},{"name":"Neuroimmunology Group, Biomedical Research Institute (BIOMED) Hasselt University, Diepenbeek, Belgium."},{"name":"Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","first-page":"67","volume":"20","year":"1957","unstructured":"F. M. Burnet, Aust. J. Sci.20, 67 (1957).","journal-title":"Aust. J. Sci."},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.63.1.78"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(02)00244-9"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0161-5890(01)00050-5"},{"key":"e_1_3_1_6_2","first-page":"415","volume":"64","year":"1986","unstructured":"J. S. van der Zee, P. van Swieten, R. C. Aalberse, Clin. Exp. Immunol.64, 415 (1986).","journal-title":"Clin. Exp. Immunol."},{"key":"e_1_3_1_7_2","first-page":"15","year":"1990","unstructured":"R. Jefferis, in The Human IgG Subclasses, F. Shakib, Ed. (Pergamon Press, Oxford, 1990), pp. 15\u201330.","journal-title":"The Human IgG Subclasses"},{"key":"e_1_3_1_8_2","doi-asserted-by":"crossref","first-page":"3566","DOI":"10.4049\/jimmunol.137.11.3566","volume":"137","year":"1986","unstructured":"J. S. van der Zee, P. van Swieten, R. C. Aalberse, J. Immunol.137, 3566 (1986).","journal-title":"J. Immunol."},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.06.040188.002535"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2567.1999.00845.x"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.0019-2805.2001.01341.x"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.cji.0000199196.97845.c3"},{"key":"e_1_3_1_13_2","unstructured":"Materials and methods are available as supporting material on Science Online."},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1159\/000024062"},{"key":"e_1_3_1_15_2","unstructured":"For calculations see supporting online material. A maximum of 50% of IgG4-Betv1 half-molecules are incorporated in bispecific antibodies if equal amounts of IgG4 are mixed and if exchange is stochastic. The term stochastic indicates that exchange occurs without preference and results in complete mixing at equilibrium."},{"key":"e_1_3_1_16_2","unstructured":"We prefer to describe the classical bivalency of IgG as monospecific cross-linking activity."},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.11.5512"},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-01-0039"},{"key":"e_1_3_1_19_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.7.4699"},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awh612"},{"key":"e_1_3_1_21_2","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.4049\/jimmunol.158.4.1919","volume":"158","year":"1997","unstructured":"Y. F. Grauset al., J. Immunol.158, 1919 (1997).","journal-title":"J. Immunol."},{"key":"e_1_3_1_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M202069200"},{"key":"e_1_3_1_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1129594"},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2004.08.049"},{"key":"e_1_3_1_25_2","unstructured":"We thank P. de Heer J. Scheik A. Ortiz Buijsse A. Verwilligen and G. Perdok for technical assistance; H. de Vrieze for providing patient sera; J. Werkman for his help with the generation of the IgG mutants; K.V. Toyka H. Brok and B. 't Hart for their help with the rhesus monkey model; J. Bakker for graphics; and S. Ruuls for critically reviewing the manuscript. This work was supported by grants from the Prinses Beatrix Fonds L'Association Fran\u00e7aise contre les Myopathies a Marie Curie Fellowship project grant QLG3-CT-2001-00225 of the European Community program \u201cquality of life and management of living resources \u201d the European Union Sixth Framework Programme (FP6) MYASTAID LSHM-CT-2006-037833 Joghem van Loghem Foundation and Genmab. Genmab is an international biotechnology company that creates and develops human antibodies for immunotherapy. Genmab has partnered antibody products with Amgen Roche and GlaxoSmithKline. Authors specified below have a financial interest in Genmab. J.S. W.K.B. L.W. T.V. J.G.J.W. and P.W.H.I.P. have stock and\/or warrants; L.A.A. and R.C.A. received consulting fees."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.1144603","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T04:00:24Z","timestamp":1704859224000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.1144603"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,9,14]]},"references-count":24,"journal-issue":{"issue":"5844","published-print":{"date-parts":[[2007,9,14]]}},"alternative-id":["10.1126\/science.1144603"],"URL":"https:\/\/doi.org\/10.1126\/science.1144603","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1091010.551961","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.1091010.544385","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.1091010.544415","asserted-by":"object"}]},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,9,14]]}}}