Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation

Abstract

a b s t r a c tThe immune response of hemophilia A patients to administered FVIII is a major complication that obviates this very therapy. We have recently described the use of synthetic, biodegradable nanoparticles carrying rapamycin and FVIII peptide antigens, to induce antigen-specific tolerance. Herein we test the tolerogenicity of nanoparticles that contains full length FVIII protein in hemophilia A mice, focusing on anti-FVIII humoral immune response. As expected, recipients of tolerogenic nanoparticles remained unresponsive to FVIII despite multiple challenges for up to 6 months. Furthermore, therapeutic treatments in FVIII-immunized mice with pre-existing anti-FVIII antibodies resulted in diminished antibody titers, albeit efficacy required longer therapy with the tolerogenic nanoparticles. Interestingly, durable FVIII-specific tolerance was also achieved in animals co-administered with FVIII admixed with nanoparticles encapsulating rapamycin alone. These results suggest that nanoparticles carrying rapamycin and FVIII can be employed to induce specific tolerance to prevent and even reverse inhibitor formation.Published by Elsevier Inc.

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

“…They demonstrated that NP containing both the immunosuppressant rapamycin and an antigen (coagulation factor VIII) inhibited antigen-specific CD4 + and CD8 + T-cell activation, increased regulatory cells, induced durable B-cell tolerance, and inhibited antibody responses against coagulation factor VIII. Subsequently, two studies reported that co-administration of free antigen and SVP containing rapamycin (SVP-Rapa) induced antigen-specific and SVP-Rapa-dependent immune tolerance in mice and non-human primates [18], [19]. In this study, we demonstrate that SVP-Rapa can induce immune tolerance to rhGAA and improve efficacy of ERT in GAA-knockout (KO) mice that is superior to immunosuppression with MTX.…”

Complexity of immune responses to AAV transgene products – Example of factor IX

“…In order to limit global immune suppressive effects of rapamycin, nanoparticle technologies have been developed to package rapamycin. When co-packaged or co-administered with antigen, tolerance may be induced [59, 60]. Approaches to antigen-specific tolerance induction without the use of immune suppressive drugs include oral tolerance induction, as shown by a recent proof-of-concept study [61].…”

Synthetic nanovaccines for immunotherapy

“…From the above examples, it can be concluded that the first generation of nanovaccines can enhance efficient antigen (Ag) delivery to lymphoid organs (e.g., peripheral lymph nodes), promote cytosolic delivery and cross presentation in the dendritic cells (DCs), and activate T cells, However, without any co-stimulatory molecule expression or cytokine secretion, the vaccine effect is still limited and there is a high likelihood of inducing immune tolerance [51]; additional immune stimulators may be incorporated in nanovaccines to reduce this risk.…”