Induction of antigen-specific immune tolerance with synthetic nanoparticle vaccines

The context in which dendritic cells encounter antigen can determine the outcome of the immune response. Conventional vaccines provide antigen in the context of an adjuvant to stimulate antigen-specific immune responses. We have recently engineered nanoparticles to present antigen in the context of a tolerogenic signal provided by rapamycin to induce antigen-specific immune tolerance. These self-assembling, biodegradable poly(lactide-co-glycolide) (PLGA) nanoparticles containing rapamycin together with either co-encapsulated antigen or admixed with free antigen are capable of inducing durable antigen-specific tolerance that control adaptive immune responses and withstand multiple immunogenic challenges with antigen. We demonstrate that administration of tolerogenic nanoparticles through multiple routes (e.g. subcutaneous and intravenous) inhibits the activation of antigen-specific T cells and B cells while inducing antigen-specific regulatory cells. Tolerance induction is dependent on the encapsulation of rapamycin, as free rapamycin is ineffective. In a model of experimental autoimmune encephalomyelitis, tolerogenic nanoparticles dosed therapeutically at the peak of disease completely inhibited disease relapse. Immune tolerance could be adoptively transferred to naïve mice in this model. The use of tolerogenic nanoparticles can also be applied for the prevention of anti-drug antibodies (ADAs) to biologic therapies. The development of ADAs is a common cause for treatment failure and adverse events, such as hypersensitivity reactions, associated with biologic therapies. We have demonstrated immune tolerance induction to a variety of antigens, including coagulation factor VIII in a model of hemophilia A, anti-TNF monoclonal antibody in a model of spontaneous arthritis, pegylated uricase in uricase deficient mice and in nonhuman primates, and adeno-associated vectors used in gene therapy. Tolerogenic nanoparticle therapy for the prevention of ADAs against pegylated uricase in the treatment of gout is currently being evaluated in Phase 1 clinical trials