Feng Qi, Yu Xiaoyue, Wang Yixue, Li Shiyang, Yang Yang
Department of Nephrology, The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 P. R. China
Henan Province Research Center For Kidney Disease Zhengzhou 450052 P. R. China.
RSC Adv. 2021 Oct 15;11(53):33814-33822. doi: 10.1039/d1ra06146a. eCollection 2021 Oct 8.
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 PamCSK and a helper T cell epitope derived from tetanus toxoid P2 an iterative condensation reaction. 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 PamCSK confers better immunostimulatory activity than the helper T cell epitope P2 when conjugated with MFCH401.
乳腺癌是全球女性癌症相关死亡的主要原因。人表皮生长因子受体2（HER2）过表达与较高的乳腺肿瘤增殖率显著相关。MFCH401是HER2蛋白胞外域中的一个9聚体特异性肽片段（DTILWKDIF），是开发抗HER2癌症疫苗的一个有吸引力的表位。然而，MFCH401固有的低免疫原性限制了其应用。在此，为了诱导更强、更持久的免疫反应，通过将MFCH401与脂肽PamCSK和源自破伤风类毒素P2的辅助性T细胞表位进行迭代缩合反应，设计并合成了一种自佐剂化的MFCH401缀合多组分抗HER2癌症疫苗。免疫学评估表明，三组分抗HER2疫苗比双组分缀合物诱导更强的体液免疫和细胞免疫反应。此外，诱导产生的抗体能有效结合HER2过表达的人BT474细胞。我们的数据清楚地表明，基于MFCH401的三组分抗HER2癌症疫苗能有效增强MFCH401的免疫原性。构效关系分析表明，与MFCH401缀合时，PamCSK比辅助性T细胞表位P2具有更好的免疫刺激活性。
