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Measurement of serum levels of natalizumab, an immunoglobulin G4 therapeutic monoclonal antibody
Authors:Theo Rispens  Astrid van Leeuwen  Anke Vennegoor  Joep Killestein  Rob C Aalberse  Gerrit J Wolbink  Lucien A Aarden
Institution:aSanquin Research, 1066 CX Amsterdam, The Netherlands;bLandsteiner Laboratory, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;cSanquin Diagnostic Services, 1066 CX Amsterdam, The Netherlands;dDepartment of Neurology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
Abstract:Human immunoglobulin G4 (IgG4) is a poor trigger of effector functions and, therefore, is the preferred subclass for therapeutic monoclonal antibodies that merely aim to block their in vivo targets. An example is natalizumab, a recombinant IgG4 antibody directed against α4-integrin and used for treatment of multiple sclerosis. Efficient treatment requires that the pharmacokinetics of therapeutic monoclonal antibodies can be accurately monitored. For natalizumab, this requires special precautions due to recently reported structural peculiarities of human IgG4. Here we describe the development of an assay to determine serum levels of natalizumab. Compared with other IgG subclasses, human IgG4 possesses unique structural properties that influence its interactions in both in vivo and in vitro settings. Thus, IgG4 undergoes Fab arm exchange in vivo, resulting in effectively monovalent antibodies. Furthermore, IgG4 is able to bind to other human and nonhuman IgG via Fc interactions. We demonstrate how these features can interfere with measurement of specific IgG4 and describe how we addressed these issues, resulting in an assay that is not sensitive to Fab arm exchange by natalizumab or to IgG4 Fc interactions.
Keywords:IgG4  Half-molecule  Immunoglobulin  Fc interactions  Therapeutic antibody  Natalizumab  ELISA
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