Phase I Amount
$1,268,751
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease, leading annually to 200,000 deaths and 3 million hospitalizations of young children worldwide. Immune prophylaxis with a monoclonal antibody (mAb), Synagis(tm) (Medimmune, Inc.), was shown to be effective 15 years ago to reduce complications of infection in premature birth infants, but it has not shown efficacy as a post-infection treatment in the much larger population of full term infants. No safe and effective antiviral drugs are available and no effective vaccine has been produced to date. Accordingly, there remains a large unmet medical need. Using a proprietary technology for screening single human B cells, Trellis has cloned a native human mAb, 3D3 that overcomes the limitations of Synagis, providing unprecedented curative responses in animals post exposure. The new mAb targets a different envelope glycoprotein, one that has been implicated in sabotage of the host immune response. This antibody has an affinity of 1 pM for a highly conserved epitope. It has direct antiviral activity in vitro in the presence of complement, with potency 100-fold better than Synagis. In mouse models, 3D3 has shown potent activity as both a direct antiviral agent and as an agent to block the lung inflammation linked to clinical pathology. This dual activity is qualitatively different from Synagis, or from any of the small molecule antiviral drugs under investigation for treating RSV. As expected for a native human antibody, 3D3 showed no binding to a panel of human tissues. It has been expressed in stably transformed CHO cells at 0.3 g/L prior to selection, indicating feasibility of generating a high expressing cell line. Thus,all of the goals normally associated with Phase I SBIR research have been achieved. The goals of this Direct Phase II proposal are to develop a Master Cell Bank of expressing cells with the capacity of producing 3D3 at commercially useful levels (>2 g/L), and to develop the analytical and toxicological data needed for initiation of human testing (IND data package).
Public Health Relevance Statement: Public Health Relevance: This Direct Phase II project will advance the development of 3D3, a native human therapeutic antibody against the Respiratory Syncytial Virus G protein with dual activity as an antiviral and anti-inflammatory agent. The antibody has protected animals from RSV infection by both mechanisms. The project will support the development of the antibody to IND approval in preparation for initiation of clinical trials.
Project Terms: Advanced Development; Advanced Manufacturing Technology; Affinity; Age; analytical method; Animals; Anti-inflammatory; Anti-Inflammatory Agents; Antibodies; Antiviral Agents; B-Lymphocytes; Binding (Molecular Function); Biological Models; Biological Sciences; Bioreactors; cell bank; Cell Line; Cells; Cessation of life; Child; Chinese Hamster Ovary Cell; Clinical; Clinical Pathology; Clinical Trials; Collaborations; commercialization; Complement; cost; Cost Savings; Cost-Benefit Analysis; Costs and Benefits; Cytomegalovirus; Data; Development; Drug Industry; Epitopes; experience; flasks; Funding; Glycoproteins; Goals; GTP-Binding Proteins; Hospitalization; Human; human monoclonal antibodies; human tissue; Immune; Immune response; Immune system; in vitro activity; Infant; Infection; Influenza; innovation; Investigation; Laboratories; Legal patent; Licensing; Link; Lower respiratory tract structure; Lung Inflammation; Medical; Monoclonal Antibodies; mouse model; National Institute of Allergy and Infectious Disease; Nature; novel; novel strategies; Palivizumab; Pathology; Pharmaceutical Preparations; Phase; Population; Premature Birth; Preparation; prevent; Probability; Process; process optimization; Production; Productivity; programs; Property; Prophylactic treatment; Proteins; public health relevance; Publishing; Research; Respiratory physiology; Respiratory syncytial virus; Respiratory Syncytial Virus Infections; Respiratory Tract Diseases; response; Rivers; screening; Services; shear stress; Small Business Innovation Research Grant; small molecule; Staging; System; Technology; Testing; Therapeutic antibodies; Therapeutic Monoclonal Antibodies; Tissues; Toxicology; Vaccines; Viral; Virus Diseases; Work
