Design, production and immunomodulatory potency of a novel allergen bioparticle

Abstract

Allergen immunotherapy (AIT) is the only disease-modifying treatment with evidence for sustained efficacy. However, it is poorly developed compared to symptomatic drugs. The main reasons come from treatment duration implying monthly injections during 3 to 5 years or daily sublingual use, and the risk of allergic side-effects. To become a more attractive alternative to lifelong symptomatic drug use, improvements to AIT are needed. Among the most promising new immunotherapy strategies is the use of bioparticles for the presentation of target antigen to the immune system as they can elicit strong T cell and B cell immune responses. Virus-like particles (VLPs) are a specific class of bioparticles in which the structural and immunogenic constituents are from viral origin. However, VLPs are ill-suited for use in AIT as their antigenicity is linked to structure. Recently, synthetic biology has been used to produce artificial modular bioparticles, in which supramolecular assemblies are made of elements from heterogeneous biological sources promoting the design and use of in vivo-assembling enveloped bioparticles for viral and non-viral antigens presentation. We have used a coiled-coil hybrid assembly for the design of an enveloped bioparticle (eBP) that present trimers of the Der p 2 allergen at its surface, This bioparticle was produced as recombinant and in vivo assembled eBPs in plant. This allergen biotherapeutic was used to demonstrate i) the capacity of plants to produce synthetic supramolecular allergen bioparticles, and ii) the immunomodulatory potential of naturally-assembled allergen bioparticles. Our results show that allergens exposed on eBPs induced a very strong IgG response consisting predominantly of IgG2a in favor of the TH1 response. Finally, our results demonstrate that rDer p 2 present on the surface of BPs show a very limited potential to stimulate the basophil degranulation of patient allergic to this allergen which is predictive of a high safety potential.

Cationic liposomes bearing Bet v 1 by coiled coil-formation are hypo-allergenic and induce strong immunogenicity in mice

“…This protocol is based on the sensitization protocol that we used in a previously published study ( 26 ). Our results ( 29 )suggest that in our case the low humoral response may have been at least partly due to the chosen administration route ( 30 ). Moreover, in all experiments, IgG induction was only detected at the last time point.…”

“…For example, despite being recognized by IgE, intact Fel d 1 displayed on the surface of virus-like particles failed to efficiently cross-link IgE on mast cells ( 27 , 28 ). Similarly, trimeric Der p 2 displayed at high density on plant-produced bioparticles also showed reduced IgE cross-linking potential ( 29 ). How high-density surface expression translates into hypo-allergenicity is not completely clear.…”

“…How high-density surface expression translates into hypo-allergenicity is not completely clear. The tight interaction between allergens and the particle surface could sterically mask IgE epitopes from IgE binding, thereby preventing efficient IgE cross-linking and downstream induced mediator release ( 29 ). Alternatively, combined with a lower diffusion coefficient, the effective free allergen concentration of allergen bearing nanoparticles is strongly reduced which provides another physical explanation for the reduced IgE cross-linking capacity ( 28 ).…”

Fel d 1 surface expression on plant‐made eBioparticles combines potent immune activation and hypoallergenicity

“…Previous in vivo experiments indicate that this eBP platform induces a robust protective IgG response more potently than the alum-adsorbed allergen. 2 In this study, we assessed but also with alum-adsorbed Fel d 1. Earlier publications based on virus-like particles displaying allergens have reported similar hypoallergenic outcomes for 3D allergen presentation.…”

Nanoparticles in allergen immunotherapy

“…This hybrid bioparticle was used to demonstrate the capacity of plants to produce synthetic supramolecular allergen bioparticles, and the immunomodulatory potential of naturally-assembled synthetic allergen bioparticles. This new expression platform was used not only for the production of soluble natural-like allergens, but also to develop an immunostimulatory allergen presentation system that triggers a strong Th1/Treg-biased response with reduced allergenicity [62 ▪▪ ].…”