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T Cell Determinants Incorporating -Amino Acid Residues Are Protease Resistant and Remain Immunogenic In Vivo¹

Andrew I. Webb^*,, Michelle A. Dunstone, Nicholas A. Williamson^*,, Jason D. Price, Andrea de Kauwe, Weisan Chen^¶, Aaron Oakley^||, Patrick Perlmutter, James McCluskey, Marie-Isabel Aguilar^2,, Jamie Rossjohn^2, and Anthony W. Purcell^2,*

^* Department of Biochemistry and Molecular Biology, The Bio21 Molecular Science and Biotechnology Institute, and Department of Microbiology and Immunology and ImmunoID, University of Melbourne, Victoria, Australia; The Protein Crystallography Unit and Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and Department of Chemistry, Monash University, Victoria, Australia; ^¶ T Cell Laboratory, Ludwig Institute for Cancer Research, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia; and ^|| Research School of Chemistry, Australian National University, Australian Capital Territory, Australia

A major hurdle in designing successful epitope-based vaccines resides in the delivery, stability, and immunogenicity of the peptide immunogen. The short-lived nature of unmodified peptide-based vaccines in vivo limits their therapeutic application in the immunotherapy of cancers and chronic viral infections as well as their use in generating prophylactic immunity. The incorporation of -amino acids into peptides decreases proteolysis, yet its potential application in the rational design of T cell mimotopes is poorly understood. To address this, we have replaced each residue of the SIINFEKL epitope individually with the corresponding -amino acid and examined the resultant efficacy of these mimotopes. Some analogs displayed similar MHC binding and superior protease stability compared with the native epitope. Importantly, these analogs were able to generate cross-reactive CTLs in vivo that were capable of lysing tumor cells that expressed the unmodified epitope as a surrogate tumor Ag. Structural analysis of peptides in which anchor residues were substituted with -amino acids revealed the basis for enhanced MHC binding and retention of immunogenicity observed for these analogs and paves the way for future vaccine design using -amino acids. We conclude that the rational incorporation of -amino acids into T cell determinants is a powerful alternative to the traditional homologous substitution of randomly chosen naturally occurring -amino acids, and these mimotopes may prove particularly useful for inclusion in epitope-based vaccines.

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				N. S. Butler, A. Theodossis, A. I. Webb, M. A. Dunstone, R. Nastovska, S. H. Ramarathinam, J. Rossjohn, A. W. Purcell, and S. Perlman Structural and Biological Basis of CTL Escape in Coronavirus-Infected Mice J. Immunol., March 15, 2008; 180(6): 3926 - 3937. [Abstract] [Full Text] [PDF]