The ultimate goal of this project is the validation of a humanized endothelial monocyte- activating protein II (EMAP II) neutralizing monoclonal antibody (mAb) for progression to clinical evaluation as a novel treatment for patients with influenza-associated lung injury. Infection with influenza virus (IAV) remains a major world-wide health threat to high-risk populations including the young and elderly, pregnant women, and people with weakened immune systems. According to CDC data, influenza accounts for more than 23,000 deaths in US annually due to underlying respiratory and circulatory causes. The efficiency of influenza vaccination and antiviral drugs is compromised by the constant change in circulating viruses and the development of resistance in influenza virus strains. Allinaire Therapeutics, LLC is developing a first-in-class therapy which will not depend on the suppression of virus replication, and will be independent of the circulating influenza strain. Rather, the EMAP II mAb will target the pathogenic components of lung injury, including vascular endothelium apoptosis and leakage. We hypothesize that EMAP II is a key underlying factor in IAV-induced lung injury, and that a humanized EMAP II mAb will attenuate the development and serious consequences of lung damage produced by IAV. Here we present preliminary data demonstrating that IAV-induced pathologies are associated with dramatic increases in levels of EMAP II in the lung, and that administration of a rodent EMAP II mAb to influenza-A (IAV) infected mice ameliorates lung injury. Importantly, we have competed the creation of a fully humanized version of the EMAP II mAb - a crucial step towards targeting EMAP II clinically and creating a novel medicine. To evaluate our hypothesis and meet our drug discovery milestones, we plan to validate our humanized EMAP II mAb candidates in vitro in human lung cells exposed to IAV and recombinant EMAP II (Aim 1), and select the most potent and efficacious mAb to be tested in vivo in our established murine model of IAV-induced lung injury (Aim 2).
Public Health Relevance Statement: Narrative The goal of this project is the validation of a fully humanized EMAP II antibody for progression to clinical evaluation as a first-in-class treatment for patients with influenza-associated lung injury. An EMAP II targeted therapy will directly protect the lung from injury regardless of viral strain and represents a paradigm-shift in the treatment of viral respiratory infections.
Project Terms: Acute Disease; Address; Affinity; Angiogenesis Inhibitors; Antibodies; Antibody Therapy; Antiviral Agents; Apoptosis; Apoptotic; Attenuated; base; Binding; Blood; Body Weight decreased; Bronchoalveolar Lavage Fluid; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Clinical Research; cytokine; Data; Development; Dose; drug discovery; drug efficacy; Early Intervention; Elderly; Endothelial Cells; Epithelial Cells; experimental study; Extravasation; Functional disorder; Goals; Health; high risk population; Human; humanized antibody; humanized monoclonal antibodies; Immune system; In Vitro; in vitro Assay; in vivo; Infection; Infiltration; Inflammatory; Influenza; Influenza A virus; Influenza vaccination; influenza virus strain; influenzavirus; Injury; innovation; Intervention; Lung; Lung Inflammation; lung injury; Measures; Medical; Medicine; Modeling; Monoclonal Antibodies; monocyte; mouse model; Mus; neutralizing monoclonal antibodies; novel; novel therapeutics; Pathogenicity; Pathology; Patients; Pharmaceutical Preparations; Phase; pre-clinical; Pregnant Women; Proteins; Protocols documentation; Pulmonary Edema; Pulmonary Emphysema; Rattus; Recombinants; research clinical testing; Resistance; Resistance development; respiratory; Rodent; Route; Small Business Technology Transfer Research; Subcutaneous Injections; success; targeted treatment; Techniques; Testing; Therapeutic; therapeutic candidate; Treatment Protocols; Validation; Vascular Endothelium; Viral; Viral Respiratory Tract Infection; Virus; virus development; Virus Diseases; Virus Replication
