SBIR-STTR Award

The overall goal of this SBIR proposal is to develop and commercialize a new approach for allergen specific immunotherapy as treatment for cat allergy. This proposal will provide a novel therapeutic for a very important inhalant allergen and serve as a model for the application of this approach to other key allergens. Effective treatments to induce "allergic tolerance" for inhalant allergy (allergic rhinitis and allergic asthma) represent a major unmet need, driven by the increasing prevalence and incidence of IgE mediated allergic airway disease. The cat allergen Fel d1 is ubiquitous because of the small size of the airborne cat dander. 17% of US population, age 6-59, is skin test positive for cat allergen Fel d1 and 60% of those individuals have symptoms when exposed to cat dander. With nearly 78 million cats in the US and 40% of asthmatics sensitive to Fel d1, exposure to cat dander is a major contributor to the high prevalence of asthma throughout the world. While conventional immunotherapy is effective in reducing asthma symptoms in some cases, patients with severe acute bronchospasm or chronic asthma can remain seriously compromised during the 3-5 year regimen and suffer from the poor compliance and adverse reactions. We propose to develop and test a cat allergen Fel d1- 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 a number of specific allergic diseases, including ultimately severe food allergy. Our hypothesis, based on body of data we have generated as well as that of others is that an allergen-human Fc(1 chimeric protein will function as immunogen but not an allergen and thus will provide a mechanistically distinct and more effective form of allergen specific immunotherapy. This proposal will outline the key experimental pre-clinical steps on the path to commercialization for this approach. We have identified a lead compound - Fel d1-human Fc(1 - and have demonstrated its therapeutic efficacy in both in vitro and in vivo models. Building on the success with this initial chimeric human 31-cat allergen protein for respiratory allergy, we wish to continue its development. In this proposal, we will create and express an optimal cat human chimeric fusion protein, confirm that the expressed chimeric protein retains the key feature of the allergen, e.g., full IgE binding plus the key functional property of the human Fc(, e.g., Fc(RIIb binding, document that the chimeric protein fail to induce allergic reactivity, and derive a high level expressing cell line ready to produce material for GLP toxicology. Tunitas Therapeutics, Inc. has negotiated an exclusive license with the University of California to develop chimeric allergen-Fc(1 proteins for the treatment of allergy. This proposal will provide the critical initial steps on the path to commercialization of this therapeutic. 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 Fel d1-Fc(1 protein immunotherapy conservatively targeted to fall in a similar range and the expectation that only the most severe cat-allergic individuals may initially choose to receive immunotherapy, annual US sales of $150 MM would be expected within several years.

Public Health Relevance:
Principal Investigator/Program Director (Last, First, Middle): Narrative: Cat allergen-human Fc-gamma1 chimeric proteins to treat cat allergy Effective treatments to induce allergic tolerance for inhalant allergy/asthma represent a major unmet medical need. With nearly 78 million cats in the US and 40% of asthmatics allergic to cats, exposure to cat allergen is a major contributor to the high prevalence of asthma throughout the world. The goal of this proposal is to develop and commercialize a novel approach for allergen specific immunotherapy as treatment for severe cat allergy.

Thesaurus Terms:
Atgn; Acute; Address; Adverse Reactions; Age; Allergens; Allergic; Allergic Disease; Allergic Asthma; Allergic Rhinitis; Allergic Rhinitis Due To Allergen; Allergic Rhinosinusitis; Allergy; Allergy, Food; Antigens; Assay; Asthma; Atopic Rhinitis; Basophilic Granulocyte; Basophilic Leukocyte; Basophils; Binding; Binding (Molecular Function); Bioassay; Biologic Assays; Biological Assay; Blood Basophil; Bronchial Asthma; Bronchial Spasm; Bronchospasm; California; Capital Financing; Capital Financings; Capital Fundings; Cats; Cell Line; Cell Lines, Strains; Cellline; Chimera Protein; Chimeric Proteins; Chronic; Clinical; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Unspecified; Collaborations; Data; Development; Domestic Cats; Dose; Drug Formulations; Drug Kinetics; Early-Stage Clinical Trials; Engineering; Engineerings; Exposure To; Extrinsic Asthma; Fc Fragments; Fc Immunoglobulins; Feline Species; Felis Catus; Felis Domestica; Felis Domesticus; Felis Sylvestris Catus; Food Hypersensitivity; Formulation; Formulations, Drug; Funding; Funding, Capital; Fusion Protein; Future; Goals; Grant; Head; High Prevalence; Human; Human, General; Hypersensitivity; Hypersensitivity Skin Testing; Itx; Ige; Immunoglobulin E; Immunoglobulins, Fc; Immunologically Directed Therapy; Immunotherapeutic Agent; Immunotherapy; In Vitro; Incidence; Individual; Inhalant Dose Form; Laboratories; Lead; Leg; Licensing; Macromolecular Structure; Mammals, Cats; Mammals, Mice; Man (Taxonomy); Man, Modern; Marrow Basophil; Mediating; Mediation; Mediator; Mediator Of Activation; Mediator Of Activation Protein; Medical; Mice; Modeling; Molecular Interaction; Molecular Structure; Murine; Mus; Negotiating; Negotiation; Patients; Pb Element; Pharmacokinetics; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phase I/Ii Trial; Population; Prevalence; Principal Investigator; Production; Programs (Pt); Programs [publication Type]; Property; Property, Loinc Axis 2; Proteins; Protocol; Protocols Documentation; Regimen; Rhinitis Allergic Atopic; Sbir; Sbirs (R43/44); Sales; Skin Tests; Small Business Innovation Research; Small Business Innovation Research Grant; Symptoms; Testing; Therapeutic; Toxicology; Treatment Efficacy; Universities; Work; Allergic Airway Disease; Atopic Asthma; Base; Biomarker; Cell Bank; Clinical Investigation; Commercialization; Cost; Cultured Cell Line; Effective Therapy; Expectation; Extrinsic Allergic Asthma; Falls; Gene Product; Heavy Metal Pb; Heavy Metal Lead; Hypersensitivity Test; Immune Therapy; Immunogen; Immunologic Preparation; Immunologic Skin Test; Immunotherapeutics; Improved; In Vivo; In Vivo Model; Inhalant; Intervention Design; Mouse Model; New Approaches; New Therapeutics; Next Generation Therapeutics; Novel; Novel Approaches; Novel Strategies; Novel Strategy; Novel Therapeutics; Phase 1 Study; Phase 1 Trial; Phase I Trial; Pre-Clinical; Preclinical; Programs; Protocol, Phase I; Prototype; Public Health Relevance; Respiratory Protein; Success; Therapeutic Efficacy; Therapeutically Effective; Therapy Design; Treatment Design

The overall goal of this phase 2 SBIR proposal is to develop and commercialize a novel biologic for allergen- specific immunotherapy as effective treatment for cat allergy/asthma. Cat allergy is common, with 17% of US population, age 6-59, being skin test positive for cat and 60% of those individuals have symptoms when exposed to cat dander Cat allergen, Fel d1, is particularly ubiquitous because of the small size of the airborne cat dander particles and is one of the key aeroallergens implicated in the current epidemic of allergic asthma. Presently, immunotherapy to treat cat allergy is problematic because it requires repeated visits to the allergists'office over a 3-5 year period and commonly elicits allergic reactions. The molecule that comprises our novel approach is a genetically engineered cat allergen-human Fc?1 fusion protein that is designed for a far greater safety profile so that it can be given as injectable immunotherapy (i) with greater safety, (ii) in a far more rapid time frame and (iii) without the pro-allergic effects of current allergen immunotherapy. In phase 1 of this SBIR, we created and expressed an optimal cat-human chimeric fusion protein and derived a current good manufacturing process (cGMP)-quality CHO cell line that is ready to produce material for good laboratory practice (GLP) toxicology. This phase 2 proposal comprises the studies that are expected to provide a strong Investigational New Drug (IND) application for full-scale Phase I/Phase IIa clinical trials upon completion. To achieve this, we will meet six key Aims. Aim 1: develop biochemical and cell-based assays for characterization of the material to be used for formulation development, GLP toxicology studies and in support of cGMP manufacture;these assays will be run under GLP SOPs with independent Quality Assurance monitoring. Aim 2: perform pre-formulation and stability experiments in preparation for transfer of the to a cGMP manufacturer. Aim 3: complete cell line development, master cell bank production, cGMP manufacture and purification, formulation and final sterile fill on the fusion protein drug product. Aim 4: develop an improved purification process, produce and formulate the material necessary for the proposed GLP toxicology studies. Aim 5: perform GLP toxicology in 2 species (rat and non-human primate) as required for IND filing. Aim 6: prepare and file an IND application with the FDA and work with that agency toward approval of this application. Successful completion of phase 2 would set the stage for the initiation of clinical trials to test the safety and efficacy of FDG in US-based trials. We envision the successful development of this fusion protein platform for cat allergy as not only an important new therapeutic for cat allergy/asthma but also as the sign post for development of this approach for the treatment of severe IgE mediated food allergy.

Public Health Relevance:
Effective treatments to for severe inhalant allergy represent a major unmet medical need with cat allergy being one of the key allergens involved. Symptomatic cat allergy affects 30 million people in the United States and is primary trigger for 30% (3 million) asthma cases as well. Cat allergen, because of the physical characteristics of the particles it is on is essentially ubiquitous in schools, public buildings and homes. Immunotherapy (allergy shots) works but it has a relatively low therapeutic index and poor compliance due to the need for multiple injections over a prolonged period of time with associated local and even systemic reactions. The goal of this proposal is to develop and commercialize a novel cat allergy vaccine that will be safer, faster and more effective than the current treatments.