肿瘤微环境响应型PD-L1抗体-TLR7/8激动剂偶联物纳米药物研究

PD-1/PD-L1抗体药物取得了一定临床治疗效果。但经PD-1/PD-L1抗体药物治疗后，只有具有肿瘤细胞PD-L1阳性（PD-L1+）和肿瘤浸润淋巴细胞阳性（TIL+）的患者有较好的反应性。所以增加TIL数量是提高这类药物对PD-L1+和TIL-肿瘤治疗效果的有效方法。瑞喹莫德（R848）是TLR7/8激动剂，可以有效提高TIL数量，但因选择性差导致全身给药毒副作用大。因此本项目设计分别利用肿瘤微环境还原敏感和组织蛋白酶敏感Linker将R848键合到PD-L1抗体上，制备两类肿瘤微环境响应型PD-L1抗体-TLR7/8激动剂偶联物纳米药物。利用PD-L1抗体对PD-L1+肿瘤的靶向作用，将R848靶向递送到肿瘤，然后，利用肿瘤微环境特殊病理生理条件选择性释放R848，该策略可有效提高TIL数量，实现在提高PD-L1抗体对PD-L1+和TIL-肿瘤治疗效果的同时，降低R848毒副作用。

Although the antibody drugs of targeting PD-1/PD-L1 immuno-checkpoint have achieved certain clinical therapeutic effect. However, all clinical data of these drugs showed that only part patients showed better responsiveness. These patients who had two characteristics, one is positive expression of PD-L1 on tumor cells (PD-L1+) and the other is positive tumor infiltrating lymphocyte (TIL+) in tumor tissues. Therefore, increasing the number of tumor infiltrating lymphocyte (TIL) in tumor tissues is an effective way to improve the therapeutic effect of PD-1/PD-L1 antibody drugs on tumors of PD-L1+ and negative tumor infiltrating lymphocyte (TIL-). R848 is a TLR7/8 agonist, which can effectively increase the number of TIL in tumor tissues by stimulating TLR7/8. However, R848 is lack of tumor selectivity and has severe side effects. Therefore, in this project, R848 is designed to be bonded to PD-L1 antibody by tumor microenvironment reduction sensitive linker and cathepsin sensitive linker respectively for preparing two kinds of tumor microenvironment responsive PD-L1 antibody-TLR7/8 agonist conjugate nanodrugs. Which can target deliver R848 to tumor tissues by PD-L1 antibody targeting effect for PD-L1+ tumor cells, and then selective release R848 in tumor tissues by specific pathophysiological conditions of tumor microenvironment. This strategy can effectively improve the number of TIL in tumor tissues and improve the therapeutic effect of PD-L1 antibody on PD-L1+ and TIL- tumors. At the same time, the side effects of R848 were reduced remarkably.