Antigens expressed on carbohydrates are difficult to include in the design of an effective vaccination approach for tumors. Prevention of some pathogen infection is hampered by the lack of effective immunization due to toxicity and/or poor immunogenicity of polysaccharide derived vaccines in the target population of immunocompromised individuals and young children. Peptide mimotopes of carbohydrate antigens provide an alternative approach to vaccination. The concept of mimicry holds enormous promise; a molecule that mimics a given antigen by eliciting a similar immune response is potentially useful as a vaccine, and is defined as a mimotope. Specific topics that are impacted by this proposal as related to cancer immunotherapy include: 1) The ability and mechanism(s) by which peptides can mimic carbohydrate antigen; (2) The ability and mechanism(s) by which mimetic peptides can induce anti-carbohydrate immune-responses; (3) The use of peptide based mimetics as tumor vaccines employing a variety of delivery modalities; and (4) The mechanism(s) of tumor immunity induced by peptide mimetics in murine models. In the first aim, the molecular interactions underlying mimicry are assessed using molecular modeling and analysis of kinetic and thermodynamic parameters associated with complex formation. In the second aim, we evaluate basic mechanisms associated with immunological mimicry. We examine aspects of the humoral and cellular responses induced by peptide mimotopes as compared with nominal antigen formulations. Contrasting the immunological presentation of peptide mimotopes with that of carbohydrate antigens and their conjugates provides a basis for understanding immunological mimicry necessary to enhance carbohydrate cross-reactive immune responses. In the third aim we define immune mechanisms that provide anti-tumor protection by using several in vivo models, focusing on methodologies to target peptide immunogens to specific antigen-presenting cells and antigen-processing pathways.
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