Development of ImmTOR Tolerogenic Nanoparticles for the Mitigation of Anti-drug Antibodies

Abstract

The development of anti-drug antibodies (ADAs) is a common cause for treatment failure and hypersensitivity reactions for many biologics. The focus of this review is the development of ImmTOR, a platform technology designed to prevent the formation of ADAs that can be applied broadly across a wide variety of biologics by inducing immunological tolerance with ImmTOR nanoparticles encapsulating rapamycin. The induction of tolerance is antigen-specific and dependent on the incorporation of rapamycin in nanoparticles and the presence of the antigen at the time of administration of ImmTOR. Evidence for the induction of specific immune tolerance vs. general immune suppression is supported by the findings that: (1) ImmTOR induces regulatory T cells specific to the co-administered antigen; (2) tolerance can be transferred by adoptive transfer of splenocytes from treated animals to naïve recipients; (3) the tolerance is durable to subsequent challenge with antigen alone; and (4) animals tolerized to a specific antigen are capable of responding to an unrelated antigen. ImmTOR nanoparticles can be added to new or existing biologics without the need to modify or reformulate the biologic drug. The ability of ImmTOR to mitigate the formation of ADAs has been demonstrated for coagulation factor VIII in a mouse model of hemophilia A, an anti-TNFα monoclonal antibody in a mouse model of inflammatory arthritis, pegylated uricase in hyperuricemic mice and in non-human primates, acid alpha-glucosidase in a mouse model of Pompe disease, recombinant immunotoxin in a mouse model of mesothelioma, and adeno-associated vectors in a model of repeat dosing of gene therapy vectors in mice and in non-human primates. Human proof-of concept for the mitigation of ADAs has been demonstrated with SEL-212, a combination product consisting of ImmTOR + pegadricase, a highly immunogenic enzyme therapy for the treatment of gout. ImmTOR represents a promising approach to preventing the formation of ADAs to a broad range of biologic drugs.

Strategies to Use Nanoparticles to Generate CD4 and CD8 Regulatory T Cells for the Treatment of SLE and Other Autoimmune Diseases

“…Human proof-of concept for the mitigation of anti-drug antibodies has been demonstrated in a phase II study in patients with refractory gout with NPs that are that loaded with pegadricase, a pegylated formulation of uricase, an enzyme that breaks down uric acid. Since pegadricase is strongly immunogenic, the NPs also contain rapamycin which converts strong immunogenic signals mediated by the PI3K/Akt/mTOR pathway to weaker tolerogenic signals ( 69 ). In addition, clinical trials using low dose IL-2 to repair and enhance Treg function are in progress for the treatment SLE and other autoimmune diseases.…”

“…Many of the biological agents now in use for the treatment of human autoimmune diseases are antigen and can elicit antibodies that block their therapeutic effects. Tolerogenic polylactide NPs that block the production of these antibodies can have useful beneficial effects and are in clinical trials ( 69 ).…”

Overcoming Immunological Challenges Limiting Capsid-Mediated Gene Therapy With Machine Learning

“…ML-powered capsid design and engineering will transform the landscape of GT delivery modalities, however non-capsid improvements are also relevant from an immunological perspective and can also increase therapeutic effectiveness. Reducing the activation of innate immunity by engineering the vector genome (66,67), co-administration with targeted immune-modulators to induce tolerance toward the vector (68) or depletion of pre-existing anti-capsid antibodies (69) should work in synergy with engineered capsids to pave a path for repeat vector administration, while further increasing the safety and tolerability of next generation GTs.…”

Harnessing Tolerogenic Histone Peptide Epitopes From Nucleosomes for Selective Down-Regulation of Pathogenic Autoimmune Response in Lupus (Past, Present, and Future)

“…Therefore, peptide delivery should be considered in fail-safe tolerogenic vehicles, such as Nanoparticles (NP), which are described in detail by experts in this field in other articles as part of this research topic. Just as a brief synopsis, the peptide epitopes may be delivered within the nanoparticles, or administered around the same time, but separately from tolerogenic nanoparticles (185). There are many issues in choosing the right nanoparticles for such therapy, specifically for lupus; for instance, liposome derived NP can activate complement, and rapamycin containing NP may interfere with initial Treg generation (186,187), although rapamycin is effective in maintaining Treg, once they are induced (188).…”