肿瘤酸度响应性“集束化”纳米载体递送PD-1/PD-L1抗体用于肿瘤免疫治疗的研究

PD-L1 and PD-1 pathway blockade is a highly promising therapy and has achieved exciting results in a subset of patients with a broad spectrum of cancers. Despite remarkable progress, the current checkpoint blockade-based treatments still have many limitations, including side effect and low objective response rate. Increasing research indicates that low PD-L1 expression on tumor cells, rare T lymphocytes infiltration in tumor tissues, low tumor enrichment and poor tumor penetration, and TAMs-mediated clearance are crucial factors affecting the therapeutic efficacy of PD-1/PD-L1 blocking antibodies. Nanotechnology-based drug delivery systems have shown significant promise in improving the bioavailability and antitumor efficacy of therapeutics agents. In present project, we will construct tumor acidity-sensitive cluster nanocarriers for the delivery of PD-1/PD-L1 blocking antibodies, to overcome the aforementioned barriers. The cluster delivery systems are expected to improve the pharmacokinetic profile of PD-1/PD-L1 blocking antibodies and release antibodies modified with PAMAM in response to tumor acidic microenvironment. The blood circulation, tissues biodistribution, tumor accumulation and penetration, and interaction with multiple cells of PD-1/PD-L1 blocking antibodies will be investigated deeply. This project will provide valuable reference on the design of nanoparticle-mediated checkpoint blockade for enhanced anti-tumor effect.delivery systems are expected to improve the pharmacokinetic profile of PD-1/PD-L1 blocking antibodies and release antibodies modified with PAMAM in response to tumor acidic microenvironment. The blood circulation, tissues biodistribution, tumor accumulation and penetration, and interaction with multiple cells of PD-1/PD-L1 blocking antibodies will be investigated deeply. This project will provide valuable reference on the design of nanoparticle-mediated checkpoint blockade for enhanced anti-tumor effect.

PD-1/PD-L1抗体是免疫检查点阻断疗法的典型代表，具有显著的抗肿瘤效果，但面临患者应答率偏低等问题，影响因素主要包括肿瘤细胞PD-L1表达低、T细胞浸润少等，但不可忽视的因素有抗体肿瘤富集量低、渗透能力差及易被肿瘤相关巨噬细胞清除等。纳米递送系统可显著改善药物的生物利用度和疗效，有望显著改善PD-1/PD-L1抗体功效。本项目拟利用前期发展的肿瘤酸度响应性“集束化”纳米载体递送PD-1/PD-L1抗体，以增强抗体在肿瘤组织的富集、渗透，减少肿瘤相关巨噬细胞对抗体的清除，促进T细胞与肿瘤细胞的相互作用，从而增强疗效。项目将深入研究肿瘤酸度响应性“集束化”抗体递送系统如何影响PD-1/PD-L1抗体的循环代谢、肿瘤富集与渗透，以及如何影响肿瘤细胞与肿瘤浸润免疫细胞间的相互作用等，揭示其逆转肿瘤免疫抑制、增强T细胞的抗肿瘤效应的优势，为肿瘤免疫的抗体治疗和纳米药物递送的技术发展提供新思路。

以免疫检查点抑制剂（如PD-1/PD-L1抗体）为代表的单克隆抗体药物是目前临床应用最广泛的肿瘤免疫治疗药物，但面临患者应答率总体偏低等困境。纳米递送系统可显著改善小分子、核酸等药物的生物利用度和疗效，有望显著改善免疫检查点抗体的抗肿瘤功效。本项目首先利用肿瘤酸度响应化学键“桥联”的聚己内酯-树枝状大分子聚酰胺胺（PCL-CDM-PAMAM）和聚乙二醇-聚己内酯（PEG-b-PCL）构建了肿瘤酸度响应性“集束化”纳米载体用于PD-L1抗体的递送，研究结果表明该纳米载体能够改变抗体药物的代谢行为，提高抗体药物在肿瘤组织的富集并在微酸环境刺激下释放出抗体药物，从而增强肿瘤治疗效果；同时我们发现，利用该载体同步递送免疫原性化疗药物阿霉素和PD-L1抗体能够发挥协同抗肿瘤效应。在验证纳米载体在抗体药物递送方面的优势后，我们将能够识别单克隆抗体药物保守Fc片段的抗Fc抗体键合于纳米载体表面而构建出一种通用型抗体固定平台（我们称之为“纳米适配子”）；纳米适配子与两种单克隆抗体药物混合后即可便捷、高效、可控地制备出双特异性抗体，实现单克隆抗体药物的多价态和多特异性，从而增强免疫细胞与肿瘤细胞间相互作用，促进免疫细胞对肿瘤细胞的识别和杀伤。我们在多种肿瘤模型中证实基于纳米适配子的双特异性抗体能够显著增强T细胞、NK细胞、巨噬细胞等多种免疫细胞的抗肿瘤能力。基于上述研究，项目负责人在Nat. Commun.、Nano Today、Adv. Healthcare. Mater.等高水平杂志发表论文5篇，其中IF>10论文4篇；申请中国发明专利3项，论文发表、专利申请数量以及论文质量均远超过项目既定目标。本项目的成功实施有望为肿瘤免疫的抗体治疗和纳米药物递送的技术发展提供新思路。