SBIR-STTR Award

The goal of this proposal is to develop and commercialize a novel approach for allergen specific immunotherapy as treatment for severe food allergy. Food allergy affects about 3.5% of the US population and 6% to 8% of young children. It is clearly on the rise. Peanut allergy, which affects around 1% of the population, is among the most severe food allergies, resulting in 30,000 emergency room visits and over 200 deaths per year. Standard allergen protein-based desensitization - immunotherapy as is employed for allergic airways disease - has proven unsuccessful and far too dangerous to use as treatment of severe food, e.g. peanut allergy. Thus treatment to prevent severe food reactions is a major unmet need. We propose to develop and test a peanut allergen (Ara h2)-human Fc(1 chimeric fusion protein as the prototype model for an entire platform of novel allergen-Fc(1 specific immunotherapeutic proteins designed for the treatment of severe food allergy. The Ara h2-Fc(1 protein is predicted to have a marked enhanced therapeutic index as the allergen portion will act as an immunogen to induce the benefits of standard allergen immunotherapy while the Fc(1 piece functions to block any allergic reactions. Thus the Ara h2-Fc(1 protein will act as an immunogen but not an allergen and thereby provide a safe and effective form of specific immunotherapy. Underlying this approach is an extensive body of science showing the ability of human Fc(RIIb inhibitory receptors to acutely inhibit allergic effector mechanisms. These studies on food allergy will build on our success with development of a chimeric human Fc(1-cat allergen protein for respiratory allergy. Tunitas Therapeutics, Inc. has negotiated an exclusive license with the University of California to develop chimeric allergen-Fc(1 proteins for the treatment of food allergy. The current proposal will provide the initial steps on the path to commercialization of this therapeutic approach using Ara h2, the dominant peanut allergen, as a model system. Specifically we will create the required gene, express the Ara h2-Fc(1 fusion protein in an optimized CHO cell system, and purify the resulting chimeric protein. We will then show that the expressed chimeric protein retains the key features of allergen IgE and Fc(RIIb binding. Finally, we will document that the chimeric protein fails to induce allergic reactivity in vitro or in vivo. The approval of a peanut-specific chimeric vaccine therapeutic would be an opportunity to administer a safe, effective course of immunotherapy to the vast majority of peanut-allergic individuals. The current cost of a course of immunotherapy is $1500-2500, with costs spread over a 3-5 year period. With a cost for a treatment course of Ara h-Fc(1 protein immunotherapy conservatively targeted to fall in a similar range and the expectation that only the most severe peanut-allergic individuals may initially choose to receive immunotherapy, annual US sales of $100-300 MM would be expected within several years. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page

Public Health Relevance:
Treatment to prevent severe food reactions is a major unmet medical need. Peanut allergy, which affects around 1% of the population, is among the most severe food allergies, resulting in 30,000 emergency room visits and over 200 deaths per year. The goal of this proposal is to develop and commercialize a novel approach for allergen specific immunotherapy as treatment for severe food allergy.

Thesaurus Terms:
0-11 Years Old; Atgn; Accident And Emergency Department; Affect; Allergen Immunotherapy; Allergens; Allergic; Allergic Reaction; Allergy; Allergy To Peanuts; Allergy, Food; Animal Model; Animal Models And Related Studies; Antigens; Basophilic Granulocyte; Basophilic Histiocyte; Basophilic Leukocyte; Basophils; Basophils, Tissue; Binding; Binding (Molecular Function); Biological Models; Blood Basophil; Cho Cells; California; Cats; Cells; Cessation Of Life; Characteristics; Child; Child Youth; Children (0-21); Chimera Protein; Chimeric Proteins; Chinese Hamster Ovary Cell; Data; Death; Development; Domestic Cats; Emergencies; Emergency Department; Emergency Situation; Emergency Room; Engineering; Engineerings; Fus-1 Protein; Fc Fragments; Fc Immunoglobulins; Feline Species; Felis Catus; Felis Domestica; Felis Domesticus; Felis Sylvestris Catus; Food; Food Hypersensitivity; Fusion 1 Protein; Fusion Protein; Future; Gene Expression; Genes; Goals; Groundnut Hypersensitivity; Groundnuts; Human; Human, Child; Human, General; Hypersensitivity; Hypersensitivity Skin Testing; Itx; Ige; Immunoglobulin E; Immunoglobulins, Fc; Immunologically Directed Therapy; Immunotherapeutic Agent; Immunotherapy; In Vitro; Individual; Lead; Leg; Licensing; Mammals, Cats; Mammals, Mice; Man (Taxonomy); Man, Modern; Marrow Basophil; Marrow Mast Cell; Measures; Mediation; Mediator; Mediator Of Activation; Mediator Of Activation Protein; Medical; Mice; Model System; Modeling; Models, Biologic; Molecular Interaction; Murine; Mus; Negotiating; Negotiation; Pdgfa Associated Protein 2; Pb Element; Peanut Hypersensitivity; Peanuts; Peanuts - Dietary; Phase; Population; Principal Investigator; Production; Programs (Pt); Programs [publication Type]; Proteins; Reaction; Receptor Protein; Sttr; Sales; Science; Skin Tests; Small Business Technology Transfer Research; Staging; System; System, Loinc Axis 4; Testing; Therapeutic; Therapeutic Index; Universities; Visit; Allergic Airway Disease; Allergic To Peanuts; Base; Biomarker; Children; Commercialization; Cost; Desensitization; Effective Therapy; Efficacy Testing; Expectation; Falls; Food Allergen; Gene Product; Heavy Metal Pb; Heavy Metal Lead; Hypersensitivity Test; Immune Therapy; Immunogen; Immunologic Preparation; Immunologic Skin Test; Immunotherapeutics; In Vivo; Intervention Design; Mast Cell; Mastocyte; Model Organism; New Approaches; Novel; Novel Approaches; Novel Strategies; Novel Strategy; Peanut Allergy; Prevent; Preventing; Programs; Prototype; Public Health Relevance; Receptor; Respiratory Protein; Success; Therapeutic Vaccine; Therapy Design; Treatment Design; Youngster

The overall goal of this Phase 2 STTR is to develop and commercialize a novel approach for allergen specific immunotherapy as a treatment for severe food allergy. Currently treatment to prevent severe food reactions is a major unmet need. There is no effective therapy, the only treatment being strict avoidance and emergency measures should an exposure occur. The molecules that comprise this platform are genetically engineered food allergen-human Fc?1 chimeric fusion proteins. Having achieved the production of the first peanut-human chimeric (AraH2)2-Fc?1, we now plan to define the optimal type of chimeric protein or mixture of proteins necessary for specific peanut immunotherapy. This Phase 2 proposal will serve to accomplish the major milestones necessary for commercialization of this therapeutic approach for severe food allergy. In Phase 1, the lead molecule (AraH2)2-Fc?1 (AraH2-G) was constructed and tested as a model for other peanut allergens. In Phase 2, we will define and generate the optimal product for IND-enabling studies and clinical development by accomplishing the following Specific Aims. In Aim 1 we will establish research-level expression systems and characterize several types of the key peanut allergen-Fc?1 proteins. These will include (a) production of "classic" dimers, beyond (AraH2)2-G; (b) monomeric AraH-G proteins in which a single AraH protein is joined to the Fc?1 dimer; (c) polymeric (AraH2+AraH1)2-G; and (d) double-dimers, in which an AraH dimer is joined to two Fc?1 dimers. These variants may improve manufacturability of the final product and will be tested for key feature of an improved safety profile in Aim 3. In Aim 2 we will test the hypothesis that cross-desensitization can be generated for AraH-G proteins. If it does, this strategy could be game changing as it would simplify overall food allergy immunotherapy, speed product commercialization and decrease the cost of the therapy. Aim 3 will define the optimal clinical candidate(s) chimeric peanut-human FcG protein(s) through a series of in vitro and in vivo experiments defining both their safety and efficacy; safety being their inability to act as allerge while efficacy being their ability to induce tolerance to peanut in previously sensitized animals. The exact experiments and the likely lead compound(s) will be greatly impacted if we observe cross-desensitization in Aim 2. Finally, in Aim 4 we will establish stable high-expressing GMP-quality cell lines producing the final clinical candidate(s) identified by accomplishing Specific Aims 1-3. Success in Phase 2 will set the stage for production of material for formal IND-enabling studies and GMP material for a first-in human trial designed to demonstrate the lack of allergenicity of the clinical candidate. If successful with peanut, extending this approach to othe key food antigens will be relatively straightforward.

Public Health Relevance:
Therapeutic peanut allergen-Fc-gamma chimeric proteins to treat food allergy Effective treatments to for severe allergic food allergy represent a major unmet medical need. As opposed to inhalant allergy, standard allergen immunotherapy has proven too dangerous to undertake for food allergy. Severe food allergy affects 2.5% of the US population, an estimated 8 million persons, including 3 million children, resulting in more than 200,000 annual US emergency department visits. Additionally, fear of unsuspected exposures places a large emotional burden on the patient and their family and has had a wide societal impact in schools and other public forums. Peanut is the most prevalent and profound food allergy and thus we have chosen to address peanut both as key food allergen and as a model for other important food allergens. The goal of this proposal is to develop and commercialize a safe and efficient peanut allergen vaccine platform employing of peanut-allergen human Fc?1 fusion proteins capable of being used to induce allergic tolerance to the food allergen.

Public Health Relevance Statement:
Therapeutic peanut allergen-Fc-gamma chimeric proteins to treat food allergy Effective treatments to for severe allergic food allergy represent a major unmet medical need. As opposed to inhalant allergy, standard allergen immunotherapy has proven too dangerous to undertake for food allergy. Severe food allergy affects 2.5% of the US population, an estimated 8 million persons, including 3 million children, resulting in more than 200,000 annual US emergency department visits. Additionally, fear of unsuspected exposures places a large emotional burden on the patient and their family and has had a wide societal impact in schools and other public forums. Peanut is the most prevalent and profound food allergy and thus we have chosen to address peanut both as key food allergen and as a model for other important food allergens. The goal of this proposal is to develop and commercialize a safe and efficient peanut allergen vaccine platform employing of peanut-allergen human Fc?1 fusion proteins capable of being used to induce allergic tolerance to the food allergen.

Project Terms:
Accident and Emergency department; Address; Affect; Allergen Immunotherapy; Allergens; Allergic; Allergy to peanuts; Animal Model; Animals; base; Basophils; Binding (Molecular Function); Biological Assay; biomarker; Breathing; Cell Line; Cells; Child; Chimeric Proteins; Clinical; Clinical Trials Design; commercialization; Complex; cost; desensitization; Development; dimer; Dose; effective therapy; Emergency Situation; Emotional; Engineering; Family; Fc Immunoglobulins; Felis catus; Food; food allergen; food antigen; food challenge; Food Hypersensitivity; Fright; FUS-1 Protein; Future; gastrointestinal; Goals; GTP-Binding Proteins; Human; Hypersensitivity; IgE; Immunotherapy; improved; In Vitro; in vivo; Ingestion; Inhalant dose form; Lead; mast cell; Measures; Mediator of activation protein; Medical; Modeling; Mus; novel strategies; Patients; Peanuts - dietary; Persons; Phase; Population; pre-clinical; prevent; Production; Proteins; Reaction; Research; research study; respiratory; Safety; Schools; Series; Serum; Small Business Technology Transfer Research; Speed (motion); Staging; success; System; Testing; Therapeutic; Transgenic Mice; Vaccines; Variant; Visit