西妥昔单抗是临床上用于头颈部鳞状细胞癌（HNSCC）治疗的唯一获批一线抗体药物，属于人鼠嵌合单抗且仅仅靶向EGFR而不能阻断EGFRvIII介导的癌细胞增殖信号，所以时常因其免疫原性及患者肿瘤耐药而导致临床治疗失败。我们前期利用人外周血B细胞建立起全人源酵母单链抗体（scFv）库，通过交替筛选新策略成功获得同时结合EGFR和EGFRvIII的候选scFv，并在此基础上融合长半衰期单体sFc及靶向NK细胞表面抗原CD16a的全人源单域抗体，成功构建了新型单链长效NK细胞衔接器（ScaLE-NK）。该ScaLE-NK兼具全人源、半衰期长、ADCC活性高等优点，本项目将对其抑制HNSCC肿瘤细胞增殖及肿瘤微环境重塑的功能及分子机制进行深入研究，拟解决目前西妥昔单抗出现的免疫原性和耐药性问题以及NK细胞衔接器体内半衰期过短的问题，为新型抗体药物突破HNSCC临床治疗瓶颈提供新依据和新方案。

Cetuximab is currently the only first-line antibody drug available for the treatment of head and neck squamous cell carcinoma (HNSCC) as approved by FDA. Due to the limited targeting range of EGFR and being a human-mouse chimeric monoclonal antibody, severe drug resistance and immunogenicity was observed in clinic. We have successfully constructed a fully human single-chain antibody fragment yeast library based on human peripheral blood B cell libraries, in which we found the scFv which specifically binds with both EGFR and EGFRvIII. In current proposal, we have constructed a single chain and long half-life NK cell engager (ScaLE-NK) with further fusing with long half-life sFc and nanobody which targeting CD16a. This new antibody is fully human, long lasting, and high ADCC activity. Studying the mechanism of its ability of inhibiting the growth of HNSCC cell and the reshaping of tumor microenvironment, to solve the drug resistance, immunogenicity and NK cell engager short half-life in vivo problems, and also, providing theoretical foundations and solutions for the breakthrough in the applications of antibody based therapeutics against HNSCC.