Research Project
9621366
PROJECT SUMMARY 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.
