Synthesis And Functional Studies Of Self-Adjuvanting Multicomponent Anti-Her2 Cancer Vaccines

Breast cancer is the leading cause of cancer-related deaths among women worldwide. Human epidermal growth factor receptor 2 (HER2) overexpression is significantly associated with higher breast tumor proliferation rates. MFCH401, a 9-mer specific peptide fragment (DTILWKDIF) in the extracellular domain of the HER2 protein, is an attractive epitope for developing anti-HER2 cancer vaccines. However, the inherent low immunogenicity of MFCH401 limits its application. Herein, to induce a stronger and more durable immune response, a self-adjuvanting MFCH401-conjugated multiple-component anti-HER2 cancer vaccine was designed and synthesized by incorporating MFCH401 with lipopeptide Pam(3)CSK(4) and a helper T cell epitope derived from tetanus toxoid P2 via an iterative condensation reaction. In vivo immunological evaluation demonstrated that the tricomponent anti-HER2 vaccine induced stronger humoral and cellular immune responses than the two-component conjugates. In addition, the induced antibodies effectively bound to HER2-overexpressing human BT474 cells. Our data clearly indicated that the MFCH401-based tricomponent anti-HER2 cancer vaccine could effectively enhance the immunogenicity of MFCH401. Structure-activity relationship analysis demonstrated that Pam(3)CSK(4) confers better immunostimulatory activity than the helper T cell epitope P2 when conjugated with MFCH401.