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Fab-arm exchange

Nature Biotechnology volume 28, pages 123–125 (2010)Cite this article

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To the Editor:

In a recent Letter, Labrijn et al.1 reported that therapeutic wild-type IgG4s engage in Fab-arm exchange with endogenous human IgG4 in vivo. The work presented embellishes a theme that was revived by van der Neut Kolfschoten et al.2, who confirmed in an excellent paper previous hypotheses and findings3,4, that is, that IgG4s are dynamic molecules that exchange Fab arms by swapping a heavy chain and attached light chain (half molecule) with a heavy-light chain pair from another molecule, resulting in bispecific antibodies. Whereas van der Neut Kolfschoten et al.2 suggest that future studies should address the contribution of IgG4 Fab-arm exchange to in vivo activity of therapeutic monoclonal IgG4 antibodies, Labrijn et al.1 demonstrate that Fab-arm exchange between natalizumab (Tysabri) and endogenous human IgG4 can indeed be observed in blood samples from natalizumab-treated individuals. It is unfortunate that Labrijn et al.1 do not address the intriguing suggestion raised by van der Neut Kolfschoten et al.2, and no data are presented on how the phenomenon of Fab-arm exchange may affect the therapeutic activity of therapeutic wild-type IgG4. Instead, Labrijn et al.1 repeat what was already postulated by van der Neut Kolfschoten et al.2; that is, that Fab-arm exchange could have biological consequences in that the binding to the cognate antigen could change in time from an avidity to an affinity interaction, thereby possibly decreasing binding strength and changing homologous cross-linking to non-cross-linking behavior. Indeed, this is a significant take-home message and it contributes to the overall knowledge of an important subclass of therapeutic antibodies. The awareness of Fab-arm exchange and the subsequent undesired introduction of unpredictability for human immunotherapy, as created by van der Neut Kolfschoten et al.2 and confirmed by Labrijn et al.1, is of substantial value for antibody development companies who choose IgG4 as the preferred subclass for their products. We therefore agree with the conclusion that mutations that prevent Fab-arm exchange in vivo should be considered when designing therapeutic IgG4.

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Authors and Affiliations

  1. PanGenetics BV, Utrecht, The Netherlands

    Ellen Broug

  2. PanGenetics BV, Royston, United Kingdom

    Philip A Bland-Ward, John Powell & Kevin S Johnson

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Correspondence to Ellen Broug.

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PanGenetics is a privately held clinical development company that specializes in taking antibodies from the late research stage through to clinical proof of concept. PanGenetics relies on professional biotechnology investors for financial resources.

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Broug, E., Bland-Ward, P., Powell, J. et al. Fab-arm exchange. Nat Biotechnol 28, 123–125 (2010). https://doi.org/10.1038/nbt0210-123

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