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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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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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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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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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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DOI: https://doi.org/10.1038/nbt.1601
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