Structure-Based Peptide Mimicry of Tumor-Associated Antigens

Abstract

Two major obstacles in developing cancer vaccines are identifying unique tumor-associated antigens (TAA) and overcoming the lack of structural information about TAAs. Unlike progress with T cell-based vaccines, B cell vaccines are less well developed due to discontinuous or spatially disposed B cell epitopes. Synthetic peptides that emulate B cell epitopes are nevertheless proposed to induce immune responses to TAA. Currently, such antigen-mimicking peptides are identified using informatics approaches, by screening of random peptide libraries against an isolating antibody without any regard to structural principles and by rationale design methodologies. In our own studies we have developed various peptide mimics of TAAs based on combining the structural analysis of antibody-antigen complexes with the peptide library screening process. Understanding the structural context of antigen mimicry is key, as our studies show that mimicry depends on the structural and conformational features of the combining region of antibody-antigen surface amino acids. The ability of a mimic to contact the same set of amino acids found on a template antibody dictates whether or not it is a functional antigenic mimic capable of inducing TAA cross-reactive antibodies. Presented here is an overview of our current rationale and status of structure-based tumor antigenic mimics relevant for breast cancer TAAs.