Nat Biotechnol. 2009 Aug;27(8):767-71. Epub 2009 Jul 20.

Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo.

Labrijn AF, Buijsse AO, van den Bremer ET, Verwilligen AY, Bleeker WK, Thorpe SJ, Killestein J, Polman CH, Aalberse RC, Schuurman J, van de Winkel JG, Parren PW.

Source

Genmab, Utrecht, The Netherlands.

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.

Comment in

Nat Biotechnol. 2010 Feb;28(2):123-5; author reply 125-6.

PMID:: 19620983; [PubMed - indexed for MEDLINE]

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