丰富多样的海洋生物资源，不仅是人类健康重要的药食来源，而且为生物医药研究提供了难得的启示。据报道与恐龙同在侏罗纪出现的海洋古老物种鲨鱼，几乎不得癌症，最新发现其仅有重链结构的IgNAR抗体在尿素高达25%（为人血的10倍以上）和高浓度重金属等蛋白强变性剂的血液中，依然保持极高活性和超级稳定性，这无疑为研发抗癌新药提供了崭新思路和资源。本研究拟经克隆表达和活性区构效解析，研究海洋鲨鱼天然抗体IgNAR在高浓度强变性剂（尿素与汞）下仍保持稳定的原因，揭示其超级稳定的分子机制；并以其起抗体活性的可变区为基础结构，利用饱和突变法构建噬菌体纳米抗体库，筛选针对程序性死亡因子1配体1(PD-L1)的纳米抗体Nb/PD-L1，进行表达纯化与亲和性和稳定性测定后，用肺癌细胞和动物模型对其活性进行评判，以期获得比目前报道的PD-L1单抗活性和稳定性更优的候选新药，为我国蛋白类新药研发提供理论借鉴和原创品种。

Rich and diverse marine biological resources, not only are important sources of medicine and food for human health, but also provide rare inspiration for biomedical researches. According to the reports the sharks, are marine ancient as well as the dinosaurs at the Jurassic, and they are almost no cancer, and scientists newly discovered the IgNAR antibody with only heavy chain structure still maintained high activity and super stability in blood with urea up to 25% (more than 10 times in human blood) and high concentrations of heavy metals and other protein strong denaturant, which no doubt provides new ideas and resources for develop new anticancer drugs. We will study the causes of IgNAR ultrastability in the high concentration and strong denaturing agent (urea and mercury) and reveal the molecular mechanism of the ultrastability of the marine shark natural antibody; according to the basic framework of their active key variable region, we will construct phage nanobody library by saturation mutagenesis, screen the nanobody (Nb/PD-L1) targeting the programmed death 1 ligant 1(PD-L1), and then express, purify, test of affinity and stability and evaluate the activity by lung cancer cell and animal models in order to obtain better anti-PD-L1 antibody than currently reported in activity and stability as new drug candidates, which will provide theoretical references and innovative varieties for research and development of protein new drugs for China.