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- Title
Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo.
- Authors
Labrijn, Aran F.; Buijsse, Antonio Ortiz; Van den Bremer, Ewald T. J.; Verwilligen, Annemiek Y. W.; Bleeker, Wim K.; Thorpe, Susan J.; Killestein, Joep; Polman, Chris H.; Aalberse, Rob C.; Schuurman, Janine; Van De Winkel, Jan G. J.; Parren, Paul W. H. I.
- 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.
- Subjects
IMMUNOGLOBULINS; THERAPEUTICS; PHARMACODYNAMICS; GENETIC mutation; BIOTECHNOLOGY; ANTIGENS
- Publication
Nature Biotechnology, 2009, Vol 27, Issue 8, p767
- ISSN
1087-0156
- Publication type
Article
- DOI
10.1038/nbt.1553