CD147分子促侵袭表位的确认及基于抗原抗体复合物结构的新型抗肿瘤多肽设计

侵袭和转移是恶性肿瘤的显著特征之一。深入研究侵袭转移发生的分子机制并开发新型靶向药物，是肿瘤治疗研究的热点。CD147分子是一个新型广谱的癌特异性生物标志分子，本实验室研发的单抗HAb18及其人源化单抗HcHAb18均能抑制基质金属蛋白酶（MMPs）分泌和多种肿瘤细胞的侵袭转移，但其封闭的CD147分子促癌相关的功能表位还不明确。本项目拟解析CD147-HAb18（或HcHAb18）抗原抗体复合物的晶体结构，进一步明确CD147分子促进肿瘤侵袭转移的功能性位点，为相关药物的研发提供高分辨率的结构基础；基于抗原抗体复合物结构，利用计算生物学方法设计并筛选CD147表位模拟肽和同CD147分子功能性位点有良好结合活性的互补决定簇模拟肽（CDR模拟肽），通过体外肿瘤侵袭转移模型和肿瘤裸鼠转移模型筛选优化具有抗肿瘤活性的肽类分子，为靶向CD147新型肽类药物的开发奠定基础。

Invasion and metastasis is one of the prominent characteristics of malignant tumors. In-depth study of the molecular mechanism of invasion and metastasis and the development of new targeted drugs are the focus of cancer treatment research. CD147 is a novel cancer-specific biomarker. The monoclonal antibody HAb18 developed in our laboratory and its humanized monoclonal antibody HcHAb18 both can suppress matrix metalloproteinase secretion and inhibit invasion and metastasis of various tumor cells, but the cancer-promoting epitope on CD147 be blocked is still unclear. This project intends to determine the crystal structure of CD147-HAb18 (or HcHAb18) complex and identify the functional sites on CD147 which induce tumor invasion and metastasis. Based on the structure of CD147-antibody complexes, the CD147 epitope and paratope mimetic peptides could be screened virtually using computer aided rational design. Peptides with anti-tumor activity will be further screened and optimized by gelatinase assay, in vitro tumor invasion model and tumor nude mouse metastasis model, which will lay a foundation for the development of novel peptide drugs targeting CD147.