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Enhanced antibody half-life improves in vivo activity

Nature Biotechnology volume 28, pages 157–159 (2010)Cite this article

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Abstract

Improved affinity for the neonatal Fc receptor (FcRn) is known to extend antibody half-life in vivo. However, this has never been linked with enhanced therapeutic efficacy. We tested whether antibodies with half-lives extended up to fivefold in human (h)FcRn transgenic mice and threefold in cynomolgus monkeys retain efficacy at longer dosing intervals. We observed that prolonged exposure due to FcRn-mediated enhancement of half-life improved antitumor activity of Fc-engineered antibodies in an hFcRn/Rag1−/− mouse model. This bridges the demand for dosing convenience with the clinical necessity of maintaining efficacy.

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Figure 1: Increasing antibody affinity to FcRn promotes half-life extension in cynomolgus monkeys.
Figure 2: Improved antibody half-life translates to greater in vivo efficacy.

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Acknowledgements

We thank The Jackson Laboratory JAX West and SNBL USA for carrying out pharmacokinetic experiments, B. Dahiyat for helpful discussions, and A. Eivazi, D.-H.T. Nguyen, H. Herman, J.M. Jacinto and U.S. Muchhal for technical contributions.

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  1. Jonathan Zalevsky

    Present address: Present address: Takeda San Diego, Inc., San Diego, California, USA.,

Authors and Affiliations

  1. Xencor, Inc., Monrovia, California, USA

    Jonathan Zalevsky, Aaron K Chamberlain, Holly M Horton, Sher Karki, Irene W L Leung, Greg A Lazar & John R Desjarlais

  2. The Jackson Laboratory, Bar Harbor, Maine, USA

    Thomas J Sproule & Derry C Roopenian

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  1. Jonathan Zalevsky
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Contributions

J.Z., A.K.C., H.M.H., G.A.L., D.C.R. and J.R.D. designed the research, J.Z., A.K.C., H.M.H., S.K., I.W.L.L. and T.J.S. carried out experiments, and J.Z., G.A.L. and J.R.D. wrote the manuscript.

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Correspondence to John R Desjarlais.

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Competing interests

J.Z., A.K.C., H.M.H., S.K., I.W.L.L., G.A.L., and J.R.D. are employees of, and have ownership interest in, Xencor.

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Supplementary Figs. 1–3, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 233 kb)

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Zalevsky, J., Chamberlain, A., Horton, H. et al. Enhanced antibody half-life improves in vivo activity. Nat Biotechnol 28, 157–159 (2010). https://doi.org/10.1038/nbt.1601

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