SBIR-STTR Award

Respiratory syncytial virus (RSV) is a leading cause of infant hospitalizations in the U.S., and the disease burden among the elderly is similar to non-pandemic influenza A. Traditional strategies have failed to generate an effective RSV vaccine, and in some instances vaccination resulted in enhanced disease, underscoring the complexity of the human immune response to RSV. Although a prophylactic antibody is available (palivizumab, a humanized mouse mAb marketed by MedImmune as Synagis™), its high cost and modest efficacy have restricted its use to high-risk infants. Moreover, due to this high cost, palivizumab is inaccessible to children in developing nations and is unavailable in 4 of the 5 most populous countries – more than half the world's population does not have access to this type of treatment. The public health benefit and the worldwide accessibility would undoubtedly be improved by lowering the cost of RSV immunoprophylaxis. In this Phase 1 proposal, Dartmouth College (Hanover, NH), Adimab (Lebanon, NH), and Mapp Biopharmaceutical, Inc. (San Diego, CA), are teaming to develop a fully human mAb with the following properties: 1) > 50-fold neutralization potency versus palivizumab and at least 2-fold more potent in vitro and in vivo than Medimmune and Regeneron's current clinical candidates (MEDI8897/REGN2222); 2) binds a different epitope than palivizumab and neutralizes palivizumab-resistant strains; and 3) Increased serum half-life so injections can be administered once per RSV season rather than monthly as required for palivizumab. With a more potent mAb (i.e. lower dose) that can be dosed less frequently, the team's objective is to dramatically lower the price for RSV immunoprophylaxis. In addition, competition in the marketplace would also help to reduce costs since palivizumab currently has a monopoly on the RSV market. We propose the following Specific Aims to accomplish our objective: 1) Engineer and produce the best in vitro neutralizing mAbs with and without fucosylation of N-glycans; 2) Select lead candidates for advancement to in vivo testing using neutralization potency and manufacturability criteria; 3) Determine the in vivo potency of the neutralizing mAbs produced with or without fucosylation.

Public Health Relevance Statement:
PROJECT NARRATIVE Respiratory Syncytial Virus (RSV) infects nearly all children by 2 years of age. In the U.S., RSV is the leading cause of lower respiratory tract disease in young children and a major cause of asthma and wheezing throughout childhood. RSV has a disease burden similar to that of non-pandemic influenza A for elderly (>65 years of age) and high-risk adults (congestive heart failure or chronic pulmonary disease). Our long-term goal is to develop a safe and effective immunoprophylaxis product for RSV. In addition to infant populations, use of the product in elderly populations may provide protection in nursing homes and rehabilitation hospitals during the RSV season.

Project Terms:
2 year old; Adult; Affinity; Age; Age-Years; Antibodies; antibody engineering; Antiviral Agents; Asthma; base; Binding; Biological Products; biophysical properties; burden of illness; Cell Line; Child; Childhood; Chimeric Proteins; Chinese Hamster Ovary Cell; Chronic; clinical candidate; clinical development; college; Congestive Heart Failure; cost; Cost Effectiveness Analysis; Cotton Rats; Country; Developing Countries; Development; Disease; Dose; Elderly; Engineering; Epitope Mapping; Epitopes; Genes; Goals; Half-Life; Health Benefit; high risk; high risk infant; Hospitalization; Hospitals; Human; human monoclonal antibodies; humanized mouse; Hydrophobicity; IgG1; Immune response; Immunoglobulin A; Immunoglobulin Constant Region; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; immunoprophylaxis; improved; In Vitro; in vivo; Infant; Influenza A virus; Injection of therapeutic agent; Investigational New Drug Application; Lead; Lebanon; Length; Life; Light; Lower respiratory tract structure; Lung diseases; Memory B-Lymphocyte; Modeling; Monoclonal Antibodies; murine antibody; Mus; Mutation; neonate; neutralizing monoclonal antibodies; next generation; Nursing Homes; Palivizumab; Palivizumab resistance; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Point Mutation; Polysaccharides; Population; pre-clinical; preclinical development; prevent; Price; Process; Property; prophylactic; Public Health; Rehabilitation therapy; resistant strain; Respiratory syncytial virus; Respiratory Syncytial Virus Vaccines; Respiratory Tract Diseases; Savings; Seasons; Serum; stability testing; Testing; Thermodynamics; Vaccination; Wheezing; Work

Respiratory syncytial virus (RSV) is a leading cause of infant hospitalizations in the U.S., and the disease burden among the elderly is similar to non-pandemic influenza A. Traditional strategies have failed to generate an effective RSV vaccine, and in some instances vaccination resulted in enhanced disease, underscoring the complexity of the human immune response to RSV. Although a prophylactic antibody is available (palivizumab, a humanized mouse mAb marketed by MedImmune as Synagis™), its high cost and modest efficacy have restricted its use to high-risk infants. Moreover, due to this high cost, palivizumab is inaccessible to children in developing nations and is unavailable in 4 of the 5 most populous countries – more than half the world's population does not have access to this type of treatment. The public health benefit and the worldwide accessibility would undoubtedly be improved by lowering the cost of RSV immunoprophylaxis. In this Phase 1 proposal, Dartmouth College (Hanover, NH), Adimab (Lebanon, NH), and Mapp Biopharmaceutical, Inc. (San Diego, CA), are teaming to develop a fully human mAb with the following properties: 1) > 50-fold neutralization potency versus palivizumab and at least 2-fold more potent in vitro and in vivo than Medimmune and Regeneron's current clinical candidates (MEDI8897/REGN2222); 2) binds a different epitope than palivizumab and neutralizes palivizumab-resistant strains; and 3) Increased serum half-life so injections can be administered once per RSV season rather than monthly as required for palivizumab. With a more potent mAb (i.e. lower dose) that can be dosed less frequently, the team's objective is to dramatically lower the price for RSV immunoprophylaxis. In addition, competition in the marketplace would also help to reduce costs since palivizumab currently has a monopoly on the RSV market. We propose the following Specific Aims to accomplish our objective: 1) Engineer and produce the best in vitro neutralizing mAbs with and without fucosylation of N-glycans; 2) Select lead candidates for advancement to in vivo testing using neutralization potency and manufacturability criteria; 3) Determine the in vivo potency of the neutralizing mAbs produced with or without fucosylation.

Public Health Relevance Statement:
PROJECT NARRATIVE Respiratory Syncytial Virus (RSV) infects nearly all children by 2 years of age. In the U.S., RSV is the leading cause of lower respiratory tract disease in young children and a major cause of asthma and wheezing throughout childhood. RSV has a disease burden similar to that of non-pandemic influenza A for elderly (>65 years of age) and high-risk adults (congestive heart failure or chronic pulmonary disease). Our long-term goal is to develop a safe and effective immunoprophylaxis product for RSV. In addition to infant populations, use of the product in elderly populations may provide protection in nursing homes and rehabilitation hospitals during the RSV season.

NIH Spending Category:
Biodefense; Biotechnology; Cost Effectiveness Research; Emerging Infectious Diseases; Immunization; Infectious Diseases; Lung; Pediatric; Pneumonia; Pneumonia & Influenza; Prevention; Vaccine Related

Project Terms:
2 year old; Adult; Affinity; Age; Age-Years; anti-viral efficacy; Antibodies; antibody engineering; Asthma; base; Binding; Biological Products; biophysical properties; burden of illness; Cell Line; Child; Childhood; Chimeric Proteins; Chinese Hamster Ovary Cell; Chronic; clinical candidate; clinical development; college; Congestive Heart Failure; cost; Cost Effectiveness Analysis; Cotton Rats; Country; Developing Countries; Development; Disease; Dose; Elderly; Engineering; Epitope Mapping; Epitopes; Genes; Goals; Half-Life; Health Benefit; high risk; high risk infant; Hospitalization; Hospitals; Human; human monoclonal antibodies; humanized mouse; Hydrophobicity; IgG1; Immune response; Immunoglobulin A; Immunoglobulin Constant Region; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; immunoprophylaxis; improved; In Vitro; in vivo; in vivo evaluation; Infant; Influenza A virus; Injections; Investigational New Drug Application; Lead; lead candidate; Lebanon; Length; Life; Light; Lower respiratory tract structure; Lung diseases; manufacturability; Memory B-Lymphocyte; Modeling; Monoclonal Antibodies; murine antibody; Mus; Mutation; neonate; neutralizing monoclonal antibodies; next generation; Nursing Homes; Palivizumab; Palivizumab resistance; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Point Mutation; Polysaccharides; Population; pre-clinical; preclinical development; prevent; Price; Process; Property; prophylactic; Public Health; Rehabilitation therapy; resistant strain; Respiratory syncytial virus; Respiratory Syncytial Virus Vaccines; Respiratory Tract Diseases; Savings; Seasons; Serum; stability testing; Structure; Thermodynamics; Vaccination; Wheezing; Work