A Human Fc Bifunctional Fusion Protein to Treat Severe Allergic Asthma

DESCRIPTION provided by applicant The overall goal of this phase SBIR proposal is to position our novel biologic GE for human clinical trials in allergic disease though the completion of critical preclinical development research activities GE a genetically engineered human fusion protein consisting of portions of the human gamma Fc linked to portions of the human epsilon Fc chain has unique mechanistic properties that should translate to a next generation therapeutic option for patients with severe allergic asthma and food allergy Effective treatments for severe inhalant allergy asthma and food allergy represent major unmet needs Asthma affects of the US population or an estimated million persons including million children There were an estimated million US emergency department visits hospitalizations and deaths annually and an increase of over in the United States between and with these trends stabilizing more recently GE had been shown to directly inhibit Fc RI effector function a validated mechanism for treatment of human allergic disease and efficacy has been demonstrated in several non human primate models of allergic disease In phase of this SBIR we addressed the key issue of potential immunogenicity by creating the rhesus homolog of GE and administering it chronically to rhesus macaques In contrast to the immunogenicity observed when human GE was injected repeatedly to cynomologus macaques administration of the homologous protein was well tolerated producing no adverse events and no anti GE antibodies Most notably rhesus GE blocked the rise in allergen specific IgE in the animals actively sensitized to house dust mite a finding we predicted might occur based on in vitro findings with human B cells Thus GE appears to have a remarkable andquot dualandquot therapeutic effect inhibition of acute Fc RI dependent basophil mast cell activation plus down regulation of afferent phase IgE antibody production This phase proposals comprises complimentary mechanism of action experiments efficacy studies and critical preclinical activities 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 five key Aims Aim under GLP protocols generate the assays processes and reagents including rhesus human and murine GE necessary for the IND application Aim define the therapeutic benefit of GE andapos s dual mechanism of action in rhesus macaques in single and multiple dose protocols exploring the functional consequence of IgE inhibition and transient basophil decrease Aim develop a andquot next generationandquot GE as a potential improved candidate Aim evaluate the efficacy of the current candidate and andquot next generationandquot GE in an allergic non human primate asthma model Aim prepare and file the IND Successful completion of this phase SBIR would in conjunction with GMP manufacturing and GLP toxicology set the stage for the initiation of clinical trials to test the safety and efficacy of GE in US based trias PUBLIC HEALTH RELEVANCE A Human Fc Bifunctional Fusion Protein to Treat Severe Allergic Asthma Effective treatments for severe inhalant allergy asthma and food allergy represent major unmet needs Asthma affects of the US population or an estimated million persons including million children There were an estimated million US emergency department visits hospitalizations and deaths annually and an increase of over in the United States between and with these trends stabilizing more recently The overall goal of this phase SBIR proposal is to position our novel biologic GE for human clinical trials in allergic disease though the completion of critical preclinical development research activities