Infectious pulmonary pathology remains a major health problem. In many cases passive immunization with pre-formed antibodies can abrogate challenge by a pathologic microorganism. However, temporal and quantitative aspects of the employment of anti-pathogen immunoglobulins, administered in the course of infection, may limit the overall efficacy of the defense. We propose a novel concept of passive immunization employing creation of an """"""""antimicrobial shield"""""""" at the site of the pathogen attack. Genetically engineered antibodies (recAbs) have been developed, which possess the antigen binding/neutralization capacity of the parent immunoglobulins. It has been shown that eukaryotic expression and secretion of recAb genes provides a means to achieve high local/regional antibody concentration, whereby they can accomplish anti-pathogen effects over and above their neutralizing capacity. For utility in the context of pulmonary infection, however, methods must be developed to achieve in situ expression of the antimicrobial recAbs at relevant sites of pathogen challenge. To this end we have developed vector approaches to achieve targeted transgene delivery to the cells relevant to pulmonary infection. We will select neutralizing antiviral recAbs from relevant hybridomas using phage display and express their genes intracellularly, in the pathogen-sensitive cells, in order to abrogate infection. It is our hypothesis that gene-based expression of recAb, at sites of pathogen challenge, will provide a novel means to apply antibody technology for treatment of pulmonary infections.
The Specific Aims : 1. To develop neutralizing recAbs against a model pathogen relevant to pulmonary infectious disease; 2.To develop methods to express recAbs within eukaryotic cells to allow abrogation of key steps of infectious pathogen attack; 3.To adapt tropism-modified adenoviral vectors to achieve in situ expression of recAb genes in targeted cells relevant to pulmonary pathogen challenge; 4. To test the concept of a gene-therapy approach of the recAb anti-microbial defense in animal model.
| Pereboev, Alexander; Borisevich, Viktoriya; Tsuladze, George et al. (2008) Genetically delivered antibody protects against West Nile virus. Antiviral Res 77:6-13 |
| Pereboev, Alexander V; Nagle, Jill M; Shakhmatov, Mikhail A et al. (2004) Enhanced gene transfer to mouse dendritic cells using adenoviral vectors coated with a novel adapter molecule. Mol Ther 9:712-20 |
