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Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles

Abstract

The development of antidrug antibodies (ADAs) is a common cause for the failure of biotherapeutic treatments and adverse hypersensitivity reactions. Here we demonstrate that poly(lactic-co-glycolic acid) (PLGA) nanoparticles carrying rapamycin, but not free rapamycin, are capable of inducing durable immunological tolerance to co-administered proteins that is characterized by the induction of tolerogenic dendritic cells, an increase in regulatory T cells, a reduction in B cell activation and germinal centre formation, and the inhibition of antigen-specific hypersensitivity reactions. Intravenous co-administration of tolerogenic nanoparticles with pegylated uricase inhibited the formation of ADAs in mice and non-human primates and normalized serum uric acid levels in uricase-deficient mice. Similarly, the subcutaneous co-administration of nanoparticles with adalimumab resulted in the durable inhibition of ADAs, leading to normalized pharmacokinetics of the anti-TNFα antibody and protection against arthritis in TNFα transgenic mice. Adjunct therapy with tolerogenic nanoparticles represents a novel and broadly applicable approach to prevent the formation of ADAs against biologic therapies.

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Figure 1: Inhibition of antibody responses in rodents and cynomolgus monkeys.
Figure 2: Specificity of tolerance induced by SVP-Rapamycin in combination with a free antigen.
Figure 3: Cellular response to SVP-Rapamycin and the antigen.
Figure 4: Prevention of adverse reactions to antigen exposure.
Figure 5: Prevention of anti-pegsiticase responses in mice and monkeys.
Figure 6: Prevention of adalimumab ADAs and protection from arthritis in HuTNFα transgenic mice.

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Acknowledgements

The authors gratefully acknowledge the excellent support of M. Allen, M. Mwanza and B. Woldemeskel for ELISA analyses, R. Damien for the analytical characterization of nanoparticles and Y. Gao for the preparation of the KLH-PEG. We also thank M. Schwartzschild for providing the uricase-deficient mice.

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T.K.K., J.D.F., R.A.L., P.N.K and R.A.M. designed the in vivo and ex vivo studies and analysed data, A.P.G., C.O'N., D.H.A., and L.J. designed and developed the nanoparticles, E.B. and A.C. developed the ELISA methods and analysed data, V.C. developed the method for analysis of uric acid, V.C., W.K., F.F., and N.V. developed the analytical methods to characterize the nanoparticles and analysed data, and T.K.K. and R.A.M. wrote the manuscript.

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Correspondence to Takashi K. Kishimoto.

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All authors are employees and shareholders of Selecta Biosciences.

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Kishimoto, T., Ferrari, J., LaMothe, R. et al. Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles. Nature Nanotech 11, 890–899 (2016). https://doi.org/10.1038/nnano.2016.135

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