title: 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.
authors.affiliation: Selecta Biosciences Inc., 480 Arsenal Street, Watertown, Massachusetts 02472, USA.
authors.forename: Takashi K
authors.initials: TK
authors.lastname: Kishimoto
authors.affiliation: Selecta Biosciences Inc., 480 Arsenal Street, Watertown, Massachusetts 02472, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Ferrari
authors.affiliation: Selecta Biosciences Inc., 480 Arsenal Street, Watertown, Massachusetts 02472, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: LaMothe
authors.affiliation: Selecta Biosciences Inc., 480 Arsenal Street, Watertown, Massachusetts 02472, USA.
authors.forename: Pallavi N
authors.initials: PN
authors.lastname: Kolte
authors.affiliation: Selecta Biosciences Inc., 480 Arsenal Street, Watertown, Massachusetts 02472, USA.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Griset
authors.affiliation: Selecta Biosciences Inc., 480 Arsenal Street, Watertown, Massachusetts 02472, USA.
authors.forename: Conlin
authors.initials: C
authors.lastname: O'Neil
authors.affiliation: Selecta Biosciences Inc., 480 Arsenal Street, Watertown, Massachusetts 02472, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Chan
authors.affiliation: Selecta Biosciences Inc., 480 Arsenal Street, Watertown, Massachusetts 02472, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Browning
authors.affiliation: Selecta Biosciences Inc., 480 Arsenal Street, Watertown, Massachusetts 02472, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Chalishazar
authors.affiliation: Selecta Biosciences Inc., 480 Arsenal Street, Watertown, Massachusetts 02472, USA.
authors.forename: William
authors.initials: W
authors.lastname: Kuhlman
authors.affiliation: Selecta Biosciences Inc., 480 Arsenal Street, Watertown, Massachusetts 02472, USA.
authors.forename: Fen-Ni
authors.initials: FN
authors.lastname: Fu
authors.affiliation: Selecta Biosciences Inc., 480 Arsenal Street, Watertown, Massachusetts 02472, USA.
authors.forename: Nelly
authors.initials: N
authors.lastname: Viseux
authors.affiliation: Selecta Biosciences Inc., 480 Arsenal Street, Watertown, Massachusetts 02472, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Altreuter
authors.affiliation: Selecta Biosciences Inc., 480 Arsenal Street, Watertown, Massachusetts 02472, USA.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Johnston
authors.affiliation: Selecta Biosciences Inc., 480 Arsenal Street, Watertown, Massachusetts 02472, USA.
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Maldonado
mesh_terms: D000068879:Adalimumab / Q000008:administration & dosage / Q000276:immunology; D000707:Anaphylaxis; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D001862:Bone Resorption / Q000188:drug therapy; D016503:Drug Delivery Systems; D005260:Female; D033461:Hyperuricemia / Q000188:drug therapy; D007108:Immune Tolerance / Q000187:drug effects*; D019344:Lactic Acid; D008252:Macaca fascicularis; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000008:administration & dosage* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D014614:Vaccines, Synthetic; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000068879:Adalimumab; D020123:Sirolimus