THE DISCOVERY AND USE OF HLA-ASSOCIATED EPITOPES AS DRUGS

: MHC receptors "display" peptide fragments to T cells. These peptides are predominantly derived from proteins expressed within or ingested by the presenting cell. Since empty MHC molecules are highly unstable, peptide ligands are bound prior to MHC surface expression and the ensuing t1/2 off rates are often on the order of days. It is the remarkable stability of MHC/peptide complexes, which provide us an opportunity to purify MHC molecules from infected, transfected, or antigen pulsed cells and subsequently identify the naturally processed peptides being presented. On the other hand, the stability of MHC/peptide complexes substantially reduces the potency of parenterally administered peptides in vivo. Using serial immuno-affinity chromatography and mass spectrometry, naturally processed peptides can be identified. When these peptides are then encoded into nucleic acid and delivered parenterally, they are highly immunogenic. Application of these techniques to induce vigorous CTL responses will be discussed.