Wang Xi, Ding Yu, Li Shuang, Wang Fengwei, Yang Liu, Zhang Hongru, Hong Zhangyong
State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Cancer Biology Center, Frontiers Science Center for New Organic Matter, College of Life Sciences, Nankai University, Tianjin 300071, PR China.
National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin 300192, PR China.
Int J Pharm. 2025 Jan 25;669:125003. doi: 10.1016/j.ijpharm.2024.125003. Epub 2024 Nov 26.
Immunotoxin has become a highly promising therapy for treating cancer and has achieved good results in preclinical trials targeting various cancers. However, there are still some issues that limit the development and application of immunotoxins, such as short half-life and toxic side effects on healthy tissues. In this study, we designed a tumor-conditional immunotoxin called Nb-uPA-A1-PE24. Anti-HSA nanobody (Nb) was fused to the N-terminus of A1-PE24 (immunotoxin targeting mesothelin) via a linker cleavable by tumor-associated proteases, urokinase-type plasminogen activator (uPA). Nb binds to HSA (human serum albumin) in the blood circulation, which not only prolongs the half-life of immunotoxins, but also creates a certain spatial barrier between A1 and mesothelin, thereby reducing the toxicity of Nb-uPA-A1-PE24 to healthy tissues expressing mesothelin. Moreover, uPA cleavable element rendered the immunotoxin conditional activation specifically in tumor microenvironment. In animal experiments, the half-life of the newly designed immunotoxins was increased dramatically. Noted, Nb-uPA-A1-PE24 has better enrichment at tumor, and shows robust anti-tumor effects in multiple preclinical models, such as pancreatic cancer and gastric cancer models. The results indicate that this strategy has greater potential and higher safety for application in tumor treatment, providing new ideas and strategies for the development of immunotoxins for cancer patients.
免疫毒素已成为一种极具前景的癌症治疗方法，并在针对各种癌症的临床前试验中取得了良好效果。然而，仍存在一些问题限制了免疫毒素的开发和应用，例如半衰期短以及对健康组织的毒副作用。在本研究中，我们设计了一种肿瘤条件性免疫毒素，称为Nb-uPA-A1-PE24。抗人血清白蛋白纳米抗体（Nb）通过肿瘤相关蛋白酶尿激酶型纤溶酶原激活剂（uPA）可裂解的接头与A1-PE24（靶向间皮素的免疫毒素）的N端融合。Nb在血液循环中与人血清白蛋白（HSA）结合，这不仅延长了免疫毒素的半衰期，还在A1和间皮素之间形成了一定的空间屏障，从而降低了Nb-uPA-A1-PE24对表达间皮素的健康组织的毒性。此外，uPA可裂解元件使免疫毒素在肿瘤微环境中特异性地条件激活。在动物实验中，新设计的免疫毒素的半衰期显著延长。值得注意的是，Nb-uPA-A1-PE24在肿瘤部位有更好的富集，并在多种临床前模型，如胰腺癌和胃癌模型中显示出强大的抗肿瘤作用。结果表明，该策略在肿瘤治疗应用中具有更大的潜力和更高的安全性，为癌症患者免疫毒素的开发提供了新的思路和策略。
