Although cell-based vaccines and peptides presented by common HLA alleles using MHC class I-restricted antigenic peptides are currently the major form of cancer vaccines tested clinically, novel and innovative approaches to antigen specific vaccination is urgently required. Novel vaccines designed to stimulate both antibody and T cell responses against human tumors are urgently required. It is critical to identify general rules for the definition of immunogenicity so that vaccine optimization is rational rather than empirical. Identification of the biologically relevant epitopes, devising strategies to engineer conformationally dependent sequences, adopting ways to increase the immunogenicity in an outbred population, delivering the immunogen in a safe and efficacious vehicle are at the basis of developing new anticancer vaccines. Foremost in that thinking, it is widely believed that a multi-epitope approach is the only immunotherapeutic strategy that will be effective against an antigenically heterogeneous target such as cancer. The HER-2 oncoprotein is a unique target, and passive specific immunotherapy with anti-HER-2 monoclonal antibody (mAb) is showing clinical promise. The long-term objective of this project is not only to develop a widely applicable vaccine targeting the HER-2 oncoprotein but also to elucidate the underlining mechanisms of anti-tumor effects elicited by peptide vaccines against a self-protein and to suggest an immunization strategy that might be effective in human cancer vaccines targeting self tumor antigens.
The aims of this application are: 1) to design, synthesize and characterize novel linear, conformational and glycosylated HER-2 B-cell epitopes targeting distinct HER-2 extracellular subdomains with putative function; 2) to evaluate the immunogenicity of selected Her-2 peptides encapsulated in PLGA microspheres with effective, non-toxic adjuvants, and to determine the cross-reactivity of the peptide antibodies with the native HER-2 receptor and assess the contribution of glycosylation to the conformation of B-cell determinants; 3) to assess anti-tumor activity of HER-2 peptide antibodies both in vitro and in vivo and to investigate the cellular and molecular mechanism(s) of antibody-induced growth inhibition and 4) to develop and characterize an HER-2 transgenic mouse model for testing efficacy of these peptides. A chimeric immunogen, MVF-HER-2(628-647) elicited HER-2-specific antibody with antiproliferative activity in vitro and in vivo in a xenograft model and inhibited development of tumors in 85 percent of transgenic mice destined to form focal mammary tumors due to HER-2/neu gene overexpression. This construct is now being tested in an NCI funded Phase 1b Clinical Trial at the Ohio State University. The result of this study may provide insight for the development of peptide vaccines against other tumor-associated antigens.
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