News and Publications

Human Antibodies in Neurotropic Viral Infection

P.P. Sanna, A. De Logu,* R.A. Williamson,** R. Rozenshteyn, F. Ramiro-Ibañez, F. Bloom, D.R. Burton***

* Università di Cagliari, Cagliari, Italy
** Department of Immunology, TSRI
*** Departments of Immunology and Molecular Biology, TSRI

Passive administration of immunoglobulin confers protection against many viral and bacterial infections and in certain settings can also be an effective treatment after exposure to the infecting organism. Furthermore, recent reports strongly support the notion that antibodies play a crucial role in controlling neurotropic viral infections. The growing clinical problems associated with resistance to antiherpetic drugs, especially in immunosuppressed patients, underscore the importance of exploring novel potential therapeutic approaches. However, only a few human monoclonal antibodies suitable for passive immunization in humans have been produced, primarily because of the limited efficacy of conventional hybridoma technologies in establishing human antibodies.

We have used affinity-based antibody cloning technologies and combinatorial Fab libraries expressed on the surface of M13 bacteriophage ("phage display") as an alternative means to isolate human monoclonal antibodies to viral pathogens. With this strategy, we isolated specific antibodies to herpes simplex virus (HSV) that are effective in both in vitro and in vivo models and that may be useful in the prophylaxis and therapy of uncontrolled, medically important human infections and for diagnostic purposes.

We are now characterizing a human recombinant monoclonal antibody of great therapeutic potential that is specific for both type 1 and type 2 HSV. Epitope mapping revealed that this antibody recognizes the group I antigenic site of glycoprotein D, a highly conserved and protective type-common determinant. To our knowledge, this antibody is the first human group I monoclonal antibody ever described. The antibody also has first-order neutralization kinetics and a high neutralization rate constant, can completely inhibit formation of syncytia by a fusogenic strain of HSV type 1, and efficiently neutralizes low-passage clinical isolates of both HSV serotypes. Taken together with our earlier observations of the in vivo antiviral activities of this human recombinant antibody in animal models of HSV infection, the current results support the high therapeutic potential of this antibody.

Other research activities are aimed at characterizing in vivo mechanisms of actions of antibodies to neurotropic viruses, determining the role of antibody valence in cell-associated and cell-free antiviral actions, exploiting potential synergistic activities between antibodies of different specificities and between antibodies and cytokines, and establishing diagnostic applications of recombinant antibodies.

PUBLICATIONS

Cattani, P., Rossolini, G.M., Cresti, S., Santangelo, R., Burton, D.R., Williamson, R.A., Sanna, P.P., Fadda, G. Detection and typing of herpes simplex viruses by using recombinant immunoglobulin fragments produced in bacteria. J. Clin. Microbiol. 35:1504, 1997.

Cunningham, E.T., Stalder, A., Sanna, P.P., Liu, S., Bloom, F.E., Howes, E.L., Campbell, I.L., Margolis, T.P. Distribution of tumor necrosis factor receptor messenger RNA in normal and herpes simplex virus infected trigeminal ganglia in the mouse. Brain Res. 758:99, 1997.

Cunningham, E.T., Stalder, A., Sanna, P.P., Liu, S., Bloom, F.E., Howes, E.L., Campbell, I.L., Margolis, T.P. Localization of tumor necrosis factor receptor messenger RNA in normal and herpes simplex virus infected mouse eyes. Invest. Ophthalmol. Vis. Sci. 38:9, 1997.

Williamson, R.A., Lazzarotto, T., Sanna, P.P., Bastidas, R.B., Dalla Casa, B., Campisi, G., Burioni, R., Landini, M.P., Burton, D.R. Use of recombinant human antibody fragments for detection of cytomegalovirus antigenemia. J. Clin. Microbiol. 35:2047, 1997.