Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles

Nat Nanotechnol. 2016 Oct;11(10):890-899. doi: 10.1038/nnano.2016.135. Epub 2016 Aug 1.


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.

MeSH terms

  • Adalimumab / administration & dosage
  • Adalimumab / immunology
  • Anaphylaxis
  • Animals
  • Arthritis, Experimental / drug therapy
  • Bone Resorption / drug therapy
  • Drug Delivery Systems
  • Female
  • Hyperuricemia / drug therapy
  • Immune Tolerance / drug effects*
  • Lactic Acid
  • Macaca fascicularis
  • Mice, Transgenic
  • Nanoparticles / administration & dosage*
  • Nanoparticles / adverse effects
  • Nanoparticles / chemistry
  • Polyglycolic Acid
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Rats, Sprague-Dawley
  • Sirolimus / administration & dosage*
  • Sirolimus / immunology
  • T-Lymphocytes, Regulatory / drug effects
  • Tumor Necrosis Factor-alpha / genetics
  • Vaccines, Synthetic / administration & dosage
  • Vaccines, Synthetic / immunology*


  • Tumor Necrosis Factor-alpha
  • Vaccines, Synthetic
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid
  • Adalimumab
  • Sirolimus