Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies.U ndesired immunogenicity can have a profound impact on human health. Allergies, including allergic asthma and severe food allergies, affect ∼20% of the population, and the prevalence has been steadily increasing over the past several decades (1). The prevalence of autoimmune diseases, including multiple sclerosis and type 1 diabetes, is ∼4.5% (2). Unwanted immunogenicity can also affect both efficacy and safety of biologic drugs (3), particularly in the case of protein replacement therapies for the treatment of genetic deficiencies, such as hemophilia A (4) and Pompe Disease (5). Immunomodulatory agents commonly used to control immunogenicity are often broadly immunosuppressive and typically require chronic administration that can lead to reactivation of latent pathogens, development of tumors, and opportunistic infections (6, 7). Therefore, antigen-specific, durable tolerogenic therapy would be highly desirable from an efficacy and safety perspective.Multiple techniques for antigen-specific immunotherapy have been described, although only allergen immunotherapy, wherein low doses of antigen are delivered in the absence of immunomodulating agents, is currently used in the clinic (1). Experimental approaches have included oral administration of antigen, high dose tolerance, and the use of altered peptide ligands (8). Although these methods have been successful in preclinical models, translation to human clinical trials has been largely disappointing (8). Alternative strategies to leverage tolerogenic programming associated with apoptotic cells include conjugating antigen to splenocytes (9-12) or synthetic microparticles (13, 14) or targeting antigen to the surface of red blood cells (15). Other approaches include loading particles with MHC complexes that present relevant peptides i...
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.
T cells reacting to self-components can promote tissue damage when escaping tolerogenic control mechanisms which may result in autoimmune disease. The current treatments for these disorders are not antigen (Ag) specific and can compromise host immunity through chronic suppression. We have previously demonstrated that co-administration of encapsulated or free Ag with tolerogenic nanoparticles (tNPs) comprised of biodegradable polymers that encapsulate rapamycin are capable of inhibiting Ag-specific transgenic T cell proliferation and inducing Ag-specific regulatory T cells (Tregs). Here, we further show that tNPs can trigger the expansion of endogenous Tregs specific to a target Ag. The proportion of Ag-specific Treg to total Ag-specific T cells remains constant even after subsequent Ag challenge in combination with a potent TLR7/8 agonist or complete Freund’s adjuvant. tNP-treated mice do not develop experimental autoimmune encephalomyelitis (EAE) after adoptive transfer of encephalitogenic T cells; furthermore, tNP treatment provided therapeutic protection in relapsing EAE that was transferred to naïve animals. These findings describe a potent therapy to expand Ag-specific Tregs in vivo and suppress T cell-mediated autoimmunity.
We have shown that treatment with biodegradable tolerogenic nanoparticles carrying rapamycin (synthetic vaccine particles, SVP) and antigen (inside the particles or admixed) induces durable, antigen-specific immune tolerance even in the presence of potent Toll-like receptor agonists. Treatment with SVP and antigen results in durable B cell tolerance, the differentiation of T and B regulatory cells, the inhibition of T and B cell activation, inhibition of hypersensitivity reactions, and the treatment of relapsing experimental autoimmune encephalomyelitis and celiac disease. Here we describe the use of SVP to promote graft tolerance and prevent acute Graft-versus-host disease (GvHD). GvHD occurs when donor T cells contained in bone marrow transplants become activated against host cells and subsequently destroy them. Current mitigation strategies involve chronic immune suppression regimens. However, prolonged immunosuppression has many side effects, including susceptibility to opportunistic infections. A favorable strategy would be to tolerize the graft to the host. To evaluate SVP we utilized two mouse models of acute GvHD: (1) B6-to-F1 and (2) B6-to-Balb/c. A single SVP administration provided at the time of the graft improved disease score, blunted inflammatory cytokines and controlled the activation of donor cells. Importantly, this resulted in a significant increase in survival compared to mock treated animals. SVP therapy represents a novel approach for the induction of immunological tolerance and the prevention of acute GvHD.
The development of anti-drug antibodies (ADAs) is a common cause for treatment failure and adverse events, such as hypersensitivity reactions, associated with biologic therapies. Therefore, prevention of ADAs in an antigen-specific manner would be highly desirable in order to improve the safety and efficacy of marketed products. Here we describe the use of SVP: polymeric, synthetic, biodegradable nanoparticles carrying a tolerogenic immunomodulator, rapamycin, to induce durable, antigen-specific immune tolerance. In mice, intravenous or subcutaneous co-injections of SVP with free antigen results in robust CD4+ T cell and B cell tolerance (i.e. the inhibition of their activation over multiple challenges), an increase in regulatory cells and the inhibition of antigen-specific hypersensitivity reactions. Only encapsulated rapamycin, not the free form, could induce immunological tolerance to a variety of antigens. Co-injections of SVP and antigen in both rats and cynomologous monkeys also results in B cell tolerance. In mice that spontaneously develop rheumatoid arthritis (RA), we show that treatment with SVP and adalimumab prevents the formation of anti-adalimumab ADAs therefore normalizing adalimumab pharmacokinetics and improving the clinical and histological manifestations of RA. SVP therapy represents a novel antigen-specific approach for the prevention of ADAs against biologic therapies, as well as the treatment of allergies and autoimmune diseases.
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