Monoclonal Antibodies to A T-Cell Death Domain Receptor

Tittle, Thomas

Abstract

TR3 is a recently described member of the Tumor Necrosis Factor Receptor (TNFR) superfamily. It is expressed on T cells following antigen-dependent activation. TR3 has a cytoplasmic death domain homologous to FAS and TNFR. These findings suggest that it would be an ideal target for immunotherapy. No immunosuppressive reagents with the specificity are available. Using a binding-motif defined human TR3 peptide we have produced antisera against this peptide in rats. We have found that these antisera apparently interact with the intact TR3 molecule on the surface of activated T cells. This interaction results in the death of activated T cells, an event that is complement independent. In this application we propose to produce monoclonal antibodies specifically reactive to the TR3 and select those antibodies that trigger TR3 dependent cell death. Monoclonal anti-TR3 antibodies that cause the death of activated (TR3+)T cells will then be evaluated in vivo. In this Phase I proposal will we use the selected monoclonal anti-TR3 antibodies to treat rats previously given encephalitogenic T cells in an Experimental Autoimmune Encephalomyelitis (EAE) adoptive transfer model. It is proposed that this antibody should prevent the development of the adoptively transferred episode of EAE. Such an observation would be an indication of the general immunosuppressive potential of these anti-TR3 antibodies and would serve as a springboard for expanded in vivo studies in a Phase II application.

Proposed Commercial Applications

Monoclonal antibodies to TR3 are likely reagents that can be developed to allow a selective depletion of activated T cells. Since T cell killing occurs following the interaction of TR3 with antibody such a selective depletion of activated T cells would be of significant utility as a means to combat certain autoimmune disease and transplant rejection. The marketplace is obviously significant for such reagents.