In glioblastoma with typical immunosuppressive characteristics, immune checkpoint inhibitors treatment showed unsatisfactory clinical effects, attributable to the exclusion of antibodies by blood-brain barrier (BBB) to a large extent. Herein, a conjugate of anti-programmed death ligand 1 antibody (αPDL1) and the targeting moiety p-hydroxybenzoic acid (pHA) was designed to realize crossing BBB of antibody based on the dopamine receptor mediated transcytosis. Conjugation with pHA did not influence the binding affinity of αPDL1 with PD-L1 protein, thus maintaining the capability of PD pathway blockade. Importantly, pHA-αPDL1 crossed BBB, demonstrated by the increased distribution in both the brain and the glioma after intravenous administration of pHA-αPDL1. Compared with the unmodified αPDL1, pHA-αPDL1 prolonged the survival time and suppressed tumor growth more effectively in an orthotopic glioblastoma model by activating glioma-infiltrating T cells. Our results suggested the potential of the antibody-pHA conjugate to improve efficacy for cerebral diseases by providing a potential platform for macromolecules to play therapeutics role in the brain.

中文翻译：

---

用对羟基苯甲酸将抗PD-L1递送到大脑中，以增强对胶质母细胞瘤的免疫治疗效果。

在具有典型免疫抑制特征的胶质母细胞瘤中，免疫检查点抑制剂治疗显示出令人满意的临床效果，这在很大程度上归因于血脑屏障（BBB）排除了抗体。在此，基于多巴胺受体介导的胞吞作用，设计了抗程序死亡配体1抗体（αPDL1）和靶向部分对羟基苯甲酸（pHA）的缀合物，以实现抗体的交叉BBB。与pHA的结合不会影响αPDL1与PD-L1蛋白的结合亲和力，从而保持了PD途径阻断的能力。重要的是，pHA-αPDL1越过血脑屏障，静脉注射pHA-αPDL1后在脑和神经胶质瘤中分布的增加证明了这一点。与未修饰的αPDL1相比，在原位胶质母细胞瘤模型中，pHA-αPDL1通过激活胶质瘤浸润性T细胞，可以延长生存时间并更有效地抑制肿瘤生长。我们的结果表明，抗体-pHA偶联物通过为大分子提供在大脑中发挥治疗作用的潜在平台，可以改善脑部疾病的疗效。