Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
Molecules. 2022 Feb 22;27(5):1482. doi: 10.3390/molecules27051482.
The PD-1/PD-L1 pathway blockade can generate a good clinical response by reducing immunosuppression and provoking durable antitumor immunity. In addition to antibodies, aptamers can also block the interaction between PD-1 and PD-L1. For the in vivo application, however, free aptamers are usually too small in size and quickly removed from blood via glomerular filtration. To avoid renal clearance of aptamer, we conjugated the PD-L1 aptamer to albumin to form a larger complex (BSA-Apt) and evaluated whether BSA-Apt would enhance the in vivo antitumor efficacy. The PD-L1 aptamer was thiol-modified and conjugated to the amino group of BSA via a SMCC linker. The average size of BSA-Apt was 11.65 nm, which was above the threshold for renal clearance. Functionally, BSA-Apt retained the capability of the PD-L1 aptamer to bind with PDL1-expressing tumor cells. Moreover, both the free aptamer and BSA-Apt augmented the PBMC-induced antitumor cytotoxicity in vitro. Furthermore, BSA-Apt generated a significantly stronger antitumor efficacy than the free PD-L1 aptamer in vivo without raising systemic toxicity. The results indicate that conjugating the PD-L1 aptamer to albumin may serve as a promising strategy to improve the in vivo functionality of the aptamer and that BSA-Apt may have application potential in cancer immunotherapy.
PD-1/PD-L1 通路阻断可以通过减少免疫抑制和引发持久的抗肿瘤免疫来产生良好的临床反应。除了抗体，适体也可以阻断 PD-1 和 PD-L1 之间的相互作用。然而，对于体内应用，游离适体通常太小，会通过肾小球滤过迅速从血液中清除。为了避免适体被肾脏清除，我们将 PD-L1 适体与白蛋白缀合形成更大的复合物（BSA-Apt），并评估 BSA-Apt 是否会增强体内抗肿瘤疗效。PD-L1 适体经过巯基修饰，并通过 SMCC 接头与 BSA 的氨基缀合。BSA-Apt 的平均大小为 11.65nm，超过了肾脏清除的阈值。功能上，BSA-Apt 保留了 PD-L1 适体与表达 PD-L1 的肿瘤细胞结合的能力。此外，游离适体和 BSA-Apt 均增强了 PBMC 在体外诱导的抗肿瘤细胞毒性。此外，BSA-Apt 在体内产生的抗肿瘤疗效明显强于游离 PD-L1 适体，而不会引起全身毒性。结果表明，将 PD-L1 适体与白蛋白缀合可能是提高适体体内功能的一种有前途的策略，BSA-Apt 可能在癌症免疫治疗中有应用潜力。
