Inducing Immunological Tolerance with Synthetic Nanoparticles

Abstract Here we describe the use of synthetic, biodegradable tolerogenic nanoparticles carrying rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor (TLR) agonists. Treatment with these synthetic vaccine particles (SVP) and antigen (inside the particles or admixed) results in the inhibition of CD4+ and CD8+ T cell activation, differentiation of T and B regulatory cells, durable B cell tolerance resistant to multiple immunogenic challenges, the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis (R-EAE) and tolerance to biologic drugs such as the coagulation factor VIII (in hemophilia A animals), adalimumab (Humira in TNFa-transgenic animals), pegylated uricase (in uricase deficient animals), even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. SVP therapy represents a potential novel approach for the treatment of treatment of allergies, autoimmune diseases, and prevention of anti-drug antibodies (ADA) against biologic therapies. Tolerogenic nanoparticle therapy for the prevention of ADAs against pegylated uricase in the treatment of hyperuricemia is currently being evaluated in Phase 2 clinical trials. Data from our Phase 1 clinical trial will be presented.