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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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.
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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