A pilot study on using rapamycin-carrying synthetic vaccine particles (SVP) in conjunction with enzyme replacement therapy to induce immune tolerance in Pompe disease

Lim, Hyung Bin; Yi, Haiqing; Kishimoto, Takashi; Gao, Fengqin; Sun, Baodong; Kishnani, Priya S.

doi:10.1016/j.ymgmr.2017.03.005

Cited by 23 publications

(21 citation statements)

References 34 publications

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“…We have previously demonstrated the functional benefit of using SVP[Rapa] to mitigate the formation of anti-drug antibodies (ADAs) against a variety of biologic drugs, including coagulation factor VIII in a model of hemophilia A 23 , anti-TNF monoclonal antibody in a model of spontaneous arthritis 18 , acid alpha-glucosidase in Pompe disease mice 20 , immunotoxins in a model of mesothelioma 21 , and pegylated uricase in uricase-deficient mice and in nonhuman primates 18 . Additionally, the safety and ability of SVP[Rapa] to inhibit the formation of ADAs against pegisticase, a highly immunogenic enzyme therapy, in a dose-dependent manner was demonstrated in a phase 1 clinical trial (Clinicaltrials.gov NCT02648269) 22 .…”

Section: Discussionmentioning

confidence: 99%

Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration

et al. 2018

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Gene therapy mediated by recombinant adeno-associated virus (AAV) vectors is a promising treatment for systemic monogenic diseases. However, vector immunogenicity represents a major limitation to gene transfer with AAV vectors, particularly for vector re-administration. Here, we demonstrate that synthetic vaccine particles encapsulating rapamycin (SVP[Rapa]), co-administered with AAV vectors, prevents the induction of anti-capsid humoral and cell-mediated responses. This allows successful vector re-administration in mice and nonhuman primates. SVP[Rapa] dosed with AAV vectors reduces B and T cell activation in an antigen-selective manner, inhibits CD8+ T cell infiltration in the liver, and efficiently blocks memory T cell responses. SVP[Rapa] immunomodulatory effects can be transferred from treated to naive mice by adoptive transfer of splenocytes, and is inhibited by depletion of CD25+ T cells, suggesting a role for regulatory T cells. Co-administration of SVP[Rapa] with AAV vector represents a powerful strategy to modulate vector immunogenicity and enable effective vector re-administration.

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Section: Discussionmentioning

confidence: 99%

Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration

et al. 2018

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“…The advantages from a drug development stand point are the elimination of Ag risk, as the Ag is the biologic drug, the ability to first assess tolerance in a prophylactic treatment setting and clear biomarker readout (i.e., ADAs). We have demonstrated the ability of NPs encapsulating rapamycin to inhibit the formation of ADAs against a variety of biologic drugs in preclinical studies, including coagulation factor VIII in hemophilia A mice ( 19 ), myozyme (or acid alpha glucosidase) in a murine model of Pompe disease ( 17 ), humira in a spontaneous model of inflammatory arthritis, and pegylated uricase enzyme in both Urox-deficient mice and non-human primates ( 16 ). The safety and efficacy of SEL-212, a combination of NP-encapsulated rapamycin co-administered with pegylated uricase, is currently being evaluated in an ongoing multidose Phase 2 clinical study in symptomatic gout patients with hyperuricemia (NCT02959918).…”

Section: Discussionmentioning

confidence: 99%

Tolerogenic Nanoparticles Induce Antigen-Specific Regulatory T Cells and Provide Therapeutic Efficacy and Transferrable Tolerance against Experimental Autoimmune Encephalomyelitis

LaMothe

Kolte

et al. 2018

Front. Immunol.

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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.

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“…These rapamycin-containing tNPs were effective in preventing IgE-mediated anaphylaxis in models of allergy, IgG-mediated anaphylaxis associated with repeated intravenous challenges with antigen, and the formation of anti-drug antibodies (ADAs) to a wide range of biologic drugs. Coadministration of tNPs containing rapamycin with free biologic drugs was effective in preventing ADAs against coagulation FVIII (Advate ® ) in a model of hemophilia A ( 66 , 67 ); human TNFα-blocking antibody adalimumab (Humira ® ) in a model of inflammatory arthritis ( 30 ), acid-α-glucosidase (Lumizyme ® ) in a model of Pompe disease ( 70 ), recombinant immunotoxin in a model of mesothelioma ( 71 ), adeno-associated virus gene therapy vectors ( 68 ) and pegylated uricase (pegsiticase) in uricase-deficient mice and non-human primates ( 30 ). Currently the combination of tNP-rapamycin and pegsiticase (SEL-212) is in Phase 2 clinical trials (NCT02959918) in patients with symptomatic gout and hyperuricemia (see Human Translation ).…”

Section: Tolerogenic Nps That Harness Tolerogenic Pharmacological Agementioning

confidence: 99%

Nanoparticles for the Induction of Antigen-Specific Immunological Tolerance

2018

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Antigen-specific immune tolerance has been a long-standing goal for immunotherapy for the treatment of autoimmune diseases and allergies and for the prevention of allograft rejection and anti-drug antibodies directed against biologic therapies. Nanoparticles have emerged as powerful tools to initiate and modulate immune responses due to their inherent capacity to target antigen-presenting cells (APCs) and deliver coordinated signals that can elicit an antigen-specific immune response. A wide range of strategies have been described to create tolerogenic nanoparticles (tNPs) that fall into three broad categories. One strategy includes tNPs that provide antigen alone to harness natural tolerogenic processes and environments, such as presentation of antigen in the absence of costimulatory signals, oral tolerance, the tolerogenic environment of the liver, and apoptotic cell death. A second strategy includes tNPs that carry antigen and simultaneously target tolerogenic receptors, such as pro-tolerogenic cytokine receptors, aryl hydrocarbon receptor, FAS receptor, and the CD22 inhibitory receptor. A third strategy includes tNPs that carry a payload of tolerogenic pharmacological agents that can “lock” APCs into a developmental or metabolic state that favors tolerogenic presentation of antigens. These diverse strategies have led to the development of tNPs that are capable of inducing antigen-specific immunological tolerance, not just immunosuppression, in animal models. These novel tNP technologies herald a promising approach to specifically prevent and treat unwanted immune reactions in humans. The first tNP, SEL-212, a biodegradable synthetic vaccine particle encapsulating rapamycin, has reached the clinic and is currently in Phase 2 clinical trials.

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A pilot study on using rapamycin-carrying synthetic vaccine particles (SVP) in conjunction with enzyme replacement therapy to induce immune tolerance in Pompe disease

Cited by 23 publications

References 34 publications

Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration

Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration

Tolerogenic Nanoparticles Induce Antigen-Specific Regulatory T Cells and Provide Therapeutic Efficacy and Transferrable Tolerance against Experimental Autoimmune Encephalomyelitis

Nanoparticles for the Induction of Antigen-Specific Immunological Tolerance

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