title: Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo.
abstract: Two humanized IgG4 antibodies, natalizumab and gemtuzumab, are approved for human use, and several others, like TGN1412, are or have been in clinical development. Although IgG4 antibodies can dynamically exchange half-molecules, Fab-arm exchange with therapeutic antibodies has not been demonstrated in humans. Here, we show that natalizumab exchanges Fab arms with endogenous human IgG4 in natalizumab-treated individuals. Gemtuzumab, in contrast, contains an IgG4 core-hinge mutation that blocks Fab-arm exchange to undetectable levels both in vitro and in a mouse model. The ability of IgG4 therapeutics to recombine with endogenous IgG4 may affect their pharmacokinetics and pharmacodynamics. Although pharmacokinetic modeling lessens concerns about undesired cross-linking under normal conditions, unpredictability remains and mutations that completely prevent Fab-arm exchange in vivo should be considered when designing therapeutic IgG4 antibodies.
authors.affiliation: Genmab, Utrecht, The Netherlands.
authors.forename: Aran F
authors.initials: AF
authors.lastname: Labrijn
authors.forename: Antonio Ortiz
authors.initials: AO
authors.lastname: Buijsse
authors.forename: Ewald T J
authors.initials: ET
authors.lastname: van den Bremer
authors.forename: Annemiek Y W
authors.initials: AY
authors.lastname: Verwilligen
authors.forename: Wim K
authors.initials: WK
authors.lastname: Bleeker
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Thorpe
authors.forename: Joep
authors.initials: J
authors.lastname: Killestein
authors.forename: Chris H
authors.initials: CH
authors.lastname: Polman
authors.forename: Rob C
authors.initials: RC
authors.lastname: Aalberse
authors.forename: Janine
authors.initials: J
authors.lastname: Schuurman
authors.forename: Jan G J
authors.initials: JG
authors.lastname: van de Winkel
authors.forename: Paul W H I
authors.initials: PW
authors.lastname: Parren
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology* / Q000627:therapeutic use*; D051379:Mice; D018448:Models, Immunological
chemical_list: D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G