The overall goal of this project is to utilize immunologic, molecular, and synthetic approaches to develop means for controlling and treating human cytomegalovirus (CMV) infections. The specific approaches to be employed include: 1) Generation of human monoclonal antibodies (HMabs) to CMV, particularly to CMV antigens that are expressed on infected cell surface. 2) Detailed studies will be performed on the interactions between susceptible cells and viral envelope glycoproteins as identified and isolated by these HMabs using immunoaffinity chromatography. 3) Production and functional characterization of immunoconjugates with different classes of reagents (selective complement activators, toxins, and anti-viral drugs) for selective targeting and destruction of infected cells expressing CMV antigens. The project involves scientists at three institutions and takes advantage of the special areas of expertise and technical resources already well established in the respective laboratories. These approaches are dependent on production of HMabs to CMV. While impaired cellular immunity is thought to be the major contributing factor in immunocompromised patients, administration of human plasma with high anti-CMV titers modifies the severity or eliminates CMV infections. The known mechanisms where by antibodies to CMV can modulate infection include neutralization of extracellular virus, complement- mediated lysis of CMV-infected neutralization of extracellular virus, complement-mediated lysis of CMV-infected cells and cell- mediated immunity by antibody-dependent cellular cytotoxicity. To begin these studies three IgG neutralizing HMabs to CMV have already been produced using human somatic cell hybridization techniques. The successful production of HMabs to CMV should eventually replace human plasma as a potentially unlimited and safe source of antibodies in the prevention of CMV infections. Their use as targeting moieties to facilitate the selective delivery of toxins of antiviral drugs to infected cells will provide a new approach to the treatment of CMV infections.

Project Start
1988-04-01
Project End
1991-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Bradshaw, P A; Duran-Guarino, M R; Perkins, S et al. (1994) Localization of antigenic sites on human cytomegalovirus virion structural proteins encoded by UL48 and UL56. Virology 205:321-8
Perkins, S; Zimmermann, U; Foung, S K (1991) Parameters to enhance human hybridoma formation with hypoosmolar electrofusion. Hum Antibodies Hybridomas 2:155-9
Foung, S; Perkins, S; Kafadar, K et al. (1990) Development of microfusion techniques to generate human hybridomas. J Immunol Methods 134:35-42
Zimmermann, U; Gessner, P; Schnettler, R et al. (1990) Efficient hybridization of mouse-human cell lines by means of hypo-osmolar electrofusion. J Immunol Methods 134:43-50
Foung, S K; Perkins, S; Bradshaw, P et al. (1989) Human monoclonal antibodies to human cytomegalovirus. J Infect Dis 159:436-43
Foung, S K; Perkins, S (1989) Electric field-induced cell fusion and human monoclonal antibodies. J Immunol Methods 116:117-22