The overall goal of this phase 2 SBIR proposal is to position our novel biologic GE2 for human clinical trials in allergic disease though the completion of critical preclinical development research activities. GE2, a genetically engineered human fusion protein consisting of portions of the human gamma1 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 5-10% of the US population or an estimated 14-15 million persons, including 5 million children. There were an estimated 1.8 million US emergency department visits, 500,000 hospitalizations and 5000 deaths annually and an increase of over 100% in the United States between 1985 and 1997 with these trends stabilizing more recently. GE2 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 1 of this SBIR, we addressed the key issue of potential immunogenicity by creating the rhesus homolog of GE2 and administering it chronically to rhesus macaques. In contrast to the immunogenicity observed when human GE2 was injected repeatedly to cynomologus macaques, administration of the homologous protein was well-tolerated, producing no adverse events and no anti-GE2 antibodies. Most notably, rhesus GE2 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, GE2 appears to have a remarkable """"""""dual"""""""" therapeutic effect: inhibition of acute Fc?RI-dependent basophil/mast cell activation plus down-regulation of afferent phase IgE antibody production. This phase 2 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 1 : under GLP protocols, generate the assays, processes and reagents - including rhesus human and murine GE2 - necessary for the IND application.
Aim 2 : define the therapeutic benefit of GE2'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 3 : develop a """"""""next generation"""""""" GE2 as a potential improved candidate.
Aim 4 : evaluate the efficacy of the current candidate and """"""""next-generation"""""""" GE2 in an allergic non-human primate asthma model.
Aim 5 : prepare and file the IND. Successful completion of this phase 2 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 GE2 in US-based trias.
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 5-10% of the US population or an estimated 14-15 million persons, including 5 million children. There were an estimated 1.8 million US emergency department visits, 500,000 hospitalizations and 5000 deaths annually and an increase of over 100% in the United States between 1985 and 1997 with these trends stabilizing more recently. The overall goal of this phase 2 SBIR proposal is to position our novel biologic GE2 for human clinical trials in allergic disease though the completion of critical preclinical development research activities.
