A novel peanut allergoid is safe and effective in a murine immunotherapy model for peanut allergy
Hans van Schijndel1, Hanneke van der Kleij1, Hans Warmenhoven1, Dirk-Jan Opstelten1, Raymond Pieters2, Monique Visser1, Joost Smit2
1HAL Allergy B.V., Leiden, The Netherlands, 2Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
Background: Peanut allergy accounts for the majority of severe food-related allergic reactions. Since commonly used allergen-specific immunotherapy has not been successful due to the high risk of serious side-effects, there is a need for new treatment strategies. Chemically modified allergen extracts with improved safety characteristics are being investigated for their potential use in immunotherapy.
Methods: Peanut extract (PE) from de-fatted peanut powder was modified by reduction and subsequent alkylation of the free Cys residues resulting in an allergoid PE (mPE) followed by adsorption to aluminium hydroxide (alum) if applicable. The potency of PE and mPE to induce PE-specific IgG was evaluated after i.p. injections in mice. In addition, mice were sensitized intra-gastrically for PE and either 1) s.c. challenged with different concentrations of (m)PE +/- various alum concentrations to assess the safety profile of these product candidates, or 2) de-sensitized by s.c. injections of either PE or mPE +/- alum for 3-6 weeks (immunotherapy), followed by oral and i.p. challenges to assess the efficacy profile of the preparations. Body temperature was measured after challenge as an objective parameter of an anaphylactic shock response. In addition, during the course of immunotherapy, blood samples were taken for analysis of antibody responses and mast cell activation.
Results: Mice sensitized for PE experienced severe anaphylactic symptoms upon s.c. challenge with PE. These effects were aborted after complete binding of PE to alum. Modified PE (no alum) also did not give rise to anaphylactic reactions, even when given up to 30 fold higher dosages. PE and mPE were equally potent in inducing PE-specific IgG antibodies in mice. Immunotherapy with both PE and mPE (+/- alum) resulted in a significant dose-dependent reduction of the anaphylactic response upon systemic challenge. In addition, both PE and mPE (+/- alum) were able to induce strong increases in the levels of PE-specific IgG1 and IgG2a compared to non-desensitized mice. Surprisingly, the mucosal mast cell response after challenge was decreased after immunotherapy with PE but not with mPE, independent of the binding to alum.
Conclusions: Using in vivo mouse models, we have shown that a peanut allergoid preparation adsorbed to alum has a significantly improved safety profile compared to its native counterpart while retaining its immunogenicity and efficacy.