The central goal of this application is to develop a combination product comprising 2 fully human monoclonal antibodies (mAbs) produced in plants for the prevention of serious disease caused by respiratory syncytial virus (RSV). RSV causes high morbidity and mortality in certain neonate populations as well as in the elderly and in bone marrow transplant patients. Palivizumab (Synagis, Medlmmune), a mAb product, has been a powerful tool against neonatal RSV. However, palivizumab is expensive, is not being used cost-effectively, and concerns exist about selection of resistant RSV strains with widespread use of the antibody in the human population. To address these issues, a cocktail of 2 anti-RSV human mAbs (R-19 and F2-5) will be produced in transgenic plants for clinical evaluation. A cocktail of mAbs would reduce the likelihood of selecting antibody resistant strains and provide a second-defense if palivizumab-resistant RSV strains become widespread. Production in plants offers a low-cost manufacturing option capable of reducing costs 5-10 fold, and thereby enabling broader cost-effective use of an anti-RSV mAb product in both at-risk infant and adult populations.
In Specific Aim 1, existing bacterially produced R-19 and F2-5 Fabs will be tested in combination for synergistic neutralization. Additionally, the cocktail will be compared with the Fabs individually for the frequency of selecting escape mutants. Based upon this data, 1 or both of the anti-RSV human Fabs will be selected for expression in Specific Aim 2 as full-length IgG in plant and mammalian systems.
In Specific Aim 3, the full-length RSV-specific IgG molecules will be tested for improved avidity, neutralizing activity, and in vivo efficacy compared to the Fabs. Respiratory syncytial virus (RSV) causes severe illness in certain newborns as well as the elderly and patients undergoing stem cell transplants. Success in this project could result in new and cheaper drugs for prevention and therapy of disease caused by respiratory syncytial virus (RSV). Availability of these drugs would also reduce the chance of resistant strains developing. ? ? ?
| Hiatt, Andrew; Bohorova, Natasha; Bohorov, Ognian et al. (2014) Glycan variants of a respiratory syncytial virus antibody with enhanced effector function and in vivo efficacy. Proc Natl Acad Sci U S A 111:5992-7 |
| Whaley, Kevin J; Morton, Josh; Hume, Steve et al. (2014) Emerging antibody-based products. Curr Top Microbiol Immunol 375:107-26 |
| Zeitlin, Larry; Bohorov, Ognian; Bohorova, Natasha et al. (2013) Prophylactic and therapeutic testing of Nicotiana-derived RSV-neutralizing human monoclonal antibodies in the cotton rat model. MAbs 5:263-9 |
| Whaley, Kevin J; Hiatt, Andrew; Zeitlin, Larry (2011) Emerging antibody products and Nicotiana manufacturing. Hum Vaccin 7:349-56 |
