Safety of engineered allergen-specific immunotherapy vaccines

Focke‐Tejkl, Margarete; Valenta, Rudolf

doi:10.1097/aci.0b013e328357ca53

Cited by 34 publications

(34 citation statements)

References 62 publications

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“…Overall, one can hypothesize that immunotherapy with mCyp c 1 will dampen Th2/IgE-skewed allergic immune responses by induction of blocking IgG/IgG 4 antibodies and of T reg /Th1-type responses [44,45]. Two alternative strategies for increasing safety and efficacy of immunotherapy under development are aiming at reducing the risk of anaphylactic side effects by either just targeting the T-cell arm (T-cell epitope peptide immunotherapy) [46] or the induction of blocking IgG antibodies (B-cell epitope peptides conjugated to immunogenic carrier proteins) [[44], and references therein].…”

Section: Discussionmentioning

confidence: 99%

Development of a Hypoallergenic Recombinant Parvalbumin for First-in-Man Subcutaneous Immunotherapy of Fish Allergy

Zuidmeer-Jongejan

Huber

Swoboda

et al. 2015

Int Arch Allergy Immunol

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Background: The FAST (food allergy-specific immunotherapy) project aims at developing safe and effective subcutaneous immunotherapy for fish allergy, using recombinant hypoallergenic carp parvalbumin, Cyp c 1. Objectives: Preclinical characterization and good manufacturing practice (GMP) production of mutant Cyp (mCyp) c 1. Methods:Escherichia coli-produced mCyp c 1 was purified using standard chromatographic techniques. Physicochemical properties were investigated by gel electrophoresis, size exclusion chromatography, circular dichroism spectroscopy, reverse-phase high-performance liquid chromatography and mass spectrometry. Allergenicity was assessed by ImmunoCAP inhibition and basophil histamine release assay, immunogenicity by immunization of laboratory animals and stimulation of patients' peripheral blood mononuclear cells (PBMCs). Reference molecules were purified wild-type Cyp c 1 (natural and/or recombinant). GMP-compliant alum-adsorbed mCyp c 1 was tested for acute toxicity in mice and rabbits and for repeated-dose toxicity in mice. Accelerated and real-time protocols were used to evaluate stability of mCyp c 1 as drug substance and drug product. Results: Purified mCyp c 1 behaves as a folded and stable molecule. Using sera of 26 double-blind placebo-controlled food-challenge-proven fish-allergic patients, reduction in allergenic activity ranged from 10- to 5,000-fold (1,000-fold on average), but with retained immunogenicity (immunization in mice/rabbits) and potency to stimulate human PBMCs. Toxicity studies revealed no toxic effects and real-time stability studies on the Al(OH)₃-adsorbed drug product demonstrated at least 20 months of stability. Conclusion: The GMP drug product developed for treatment of fish allergy has the characteristics targeted for in FAST: i.e. hypoallergenicity with retained immunogenicity. These results have warranted first-in-man immunotherapy studies to evaluate the safety of this innovative vaccine.

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Section: Discussionmentioning

confidence: 99%

Development of a Hypoallergenic Recombinant Parvalbumin for First-in-Man Subcutaneous Immunotherapy of Fish Allergy

Zuidmeer-Jongejan

Huber

Swoboda

et al. 2015

Int Arch Allergy Immunol

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“…Only since the availability of molecular biological and cloning techniques could epitopes involved in allergic inflammation be identified that can now be used in specific immunotherapies. Several novel therapeutic and prophylactic therapies against allergy are currently under investigation (for literature survey, see [248][249][250][251]). …”

Section: Vaccination In Allergy and Cancermentioning

confidence: 99%

Applications of immunochemistry in human health: advances in vaccinology and antibody design (IUPAC Technical Report)

Klein

Templeton

Schwenk

2014

Pure and Applied Chemistry

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This report discusses the history and mechanisms of vaccination of humans as well as the engineering of therapeutic antibodies. Deeper understanding of the molecular interactions involved in both acquired and innate immunity is allowing sophistication in design of modified and even synthetic vaccines. Recombinant DNA technologies are facilitating development of DNA-based vaccines, for example, with the recognition that unmethylated CpG sequences in plasmid DNA will target Toll-like receptors on antigen-presenting cells. Formulations of DNA vaccines with increased immunogenicity include engineering into plasmids with "genetic adjuvant" capability, incorporation into polymeric or magnetic nanoparticles, and formulation with cationic polymers and other polymeric and non-polymeric coatings. Newer methods of delivery, such as particle bombardment, DNA tattooing, electroporation, and magnetic delivery, are also improving the effectiveness of DNA vaccines. RNA-based vaccines and reverse vaccinology based on gene sequencing and bioinformatic approaches are also considered. Structural vaccinology is an approach in which the detailed molecular structure of viral epitopes is used to design synthetic antigenic peptides. Virus-like particles are being designed for vaccine deliveries that are based on structures of viral capsid proteins and other synthetic lipopeptide building blocks. A new generation of adjuvants is being developed to further enhance immunogenicity, based on squalene and other oil-water emulsions, saponins, muramyl dipeptide, immunostimulatory oligonucleotides, Toll-like receptor ligands, and lymphotoxins. Finally, current trends in engineering of therapeutic antibodies including improvements of antigen-binding properties, pharmacokinetic and pharmaceutical properties, and reduction of immunogenicity are discussed. Taken together, understanding the chemistry of vaccine design, delivery and immunostimulation, and knowledge of the techniques of antibody design are allowing targeted development for the treatment of chronic disorders characterized by continuing activation of the immune system, such as autoimmune disorders, cancer, or allergies that have long been refractory to conventional approaches.

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“…This allows the conservation of conformational structure and T cell epitopes of the allergen, thus achieving therapeutic effect by stimulating regulatory T cells but not resulting in severe side effects as in conventional immunotherapies [38]. The use of mimotope opens a new pathway for allergy treatment by specifically targeting at B cells devoid of T cells epitopes [39].…”

Section: Figure 2: Role Of Regulatory T Cells In Immunotherapymentioning

confidence: 99%

From Molecule Studies of Allergens to Development of Immunotherapy of Allergies

Wai¹,

Leung²,

Chu³

et al. 2012

J Aller Ther

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IntroductionAllergy is a type I hypersensitivity disease prominently influences the quality of life. Allergens can strike one through the administration of drugs, insect sting, and ingestion of food or simply inhalation, making patients hard to strictly avoid these molecules. Allergen specific immunotherapy for grass pollen allergy has been put into clinical trials since 1950s and demonstrated satisfactory therapeutic effects [1]. It therefore paves the way for extensive researches on designing different allergen specific immunotherapy and unveiling the underlying mechanisms of these therapies.Defining the immunological mechanisms leading to allergy is crucial in designing allergen-specific immunotherapy. Sensitization of allergic individuals to allergens is initialized upon presentation of the allergen-derived peptides by the antigen presenting cells (APCs) through the major histocompatibility class II molecule (MHC class II) to naïve T cells, which are then activated and differentiated into type 2 T helper cells (Th2) (Figure 1). Cytokines such as IL-4 and IL-13 from Th2 cause a class switch in B cells to produce IgE antibodies specific to the particular allergen. When the individual is exposed to the same allergen again, IgE are massively produced, cross-link with the allergen and high affinity receptor (FcεRI) on mast cells and induce degranulation. Mediators such as histamine and leukotriene are released, resulting in inflammation and other associated anaphylactic responses [2].Molecular characteristics of allergens, in particular the identification of T cell and B cell epitopes, constitute important information for the design of therapeutic regimens. T cell epitopes refer to the short peptide fragments activating Th2 via MHC class II molecules while B cell epitopes, or IgE-binding epitopes, refer to the regions recognized by IgE on the allergen. With the identification of B cell epitopes at the molecular level, hypo-allergens possessing reduced allergenicity can be constructed through the introduction of point mutations on these IgE-binding regions [3,4]. The lack of IgE reactivity reduces the risk of these hypo-allergens to form cross-links with IgE and thus prevents the development of allergic side effects during treatment [5]. Meanwhile, since the T cell epitopes are conserved, these hypo-allergens are immunogenic and thus offer therapeutic effects. Alternatively, the employment of T cell epitopes in immunotherapy is believed to be a potential strategy since small peptide fragments are incapable to form cross-link with IgE but yet immunogenic to modulate immune responses [6]. AbstractAllergies are hypersensitive reactions that affect over 25% of the world population. Extensive studies have been directed to define patho-immunological mechanisms of allergy and the molecular characteristics of allergens. The emerging B cell and T cell epitope database has greatly facilitated the development of epitope-based immunotherapy that aims at modulating patients' immune responses towards a specific allergen. Modifi...

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Safety of engineered allergen-specific immunotherapy vaccines

Cited by 34 publications

References 62 publications

Development of a Hypoallergenic Recombinant Parvalbumin for First-in-Man Subcutaneous Immunotherapy of Fish Allergy

Development of a Hypoallergenic Recombinant Parvalbumin for First-in-Man Subcutaneous Immunotherapy of Fish Allergy

Applications of immunochemistry in human health: advances in vaccinology and antibody design (IUPAC Technical Report)

From Molecule Studies of Allergens to Development of Immunotherapy of Allergies

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