Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo.
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.
Labrijn
Aran F
AF
Genmab, Utrecht, The Netherlands.
Buijsse
Antonio Ortiz
AO
van den Bremer
Ewald T J
ET
Verwilligen
Annemiek Y W
AY
Bleeker
Wim K
WK
Thorpe
Susan J
SJ
Killestein
Joep
J
Polman
Chris H
CH
Aalberse
Rob C
RC
Schuurman
Janine
J
van de Winkel
Jan G J
JG
Parren
Paul W H I
PW
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
D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G