复旦大学药学院余科团队宣布他们研究出新型抗HER2纳米体药物偶联物可增强实体瘤和血脑屏障的穿透力，减少全身暴露并具有优异的抗肿瘤疗效。相关论文于2025年8月18日发表在《中国药理学报》杂志上。

在这项研究中，该课题组产生了新的抗HER2纳米体（VHH2, VHH3），它们具有出色的靶标亲和力和肿瘤抑制作用。静脉注射后，VHH3-Fc在皮下肿瘤和颅内肿瘤中的分布比曲妥珠单抗高4 ~ 5倍。在体外血脑屏障通透性试验中，VHH3-Fc和VHH3-ABD也具有更高的渗透性。VHH3-Fc或VHH3-ABD与抗微管MMAE或抗拓扑异构酶-1 Dxd载荷的位点特异性偶联产生了具有高效持久抗肿瘤功效的纳米药物偶联物（NDCs）。在相同连接载荷（GGFG-Dxd）剂量下进行评估时，VHH3-Fc-Dxd（DAR3.9）在皮下和颅内肿瘤模型中的表现都优于T-Dxd （DAR8）。

此外，经治疗的肿瘤组织的免疫组化染色和RNA-seq分析显示cGAS-STING-IFNs通路参与介导药物活性。与T-Dxd相比，VHH3-Fc-Dxd对基因表达和蛋白功能的调节更为深刻。与较高的肿瘤分布不同，小鼠血清PK研究显示，相对于T-Dxd， VHH3-Fc-Dxd的清除率（T1/2）更快，暴露量（AUC）更低，体积分布（Vz）更高。他们的研究结果为下一代HER2-NDC提供了一个具有显著差异的药代动力学和药效学特征的例子，这将进一步有利于治疗结果和治疗窗口。

据了解，抗体-药物偶联物（ADC）代表了肿瘤靶向化疗的一个有前途的范例。Trastuzumab deruxtecan （T-Dxd/DS-8201）是第二代HER2 ADC，显著改善了乳腺癌患者的治疗结果。但由于分子量较大，ADC的性能仍然受到肿瘤穿透性低、血脑屏障通透性不足以及长时间全身暴露于正常组织的限制。

附：英文原文

Title: Novel anti-HER2 nanobody-drug conjugates with enhanced penetration of solid tumor and BBB, reduced systemic exposure and superior antitumor efficacy

Author: Wang, Yue, Liu, Liang, Yang, Qi-yu, Yu, Ker

Issue&Volume: 2025-08-18

Abstract: Antibody-drug conjugate (ADC) represents a promising paradigm for tumor-targeted delivery of chemotherapy. Trastuzumab deruxtecan (T-Dxd/DS-8201), a second-generation HER2-ADC, has significantly improved treatment outcomes for breast cancer patients. But due to the large molecular weight, the performance of ADC is still limited by lower tumor penetration, insufficient BBB permeability, and prolonged systemic exposure to normal tissues. In this study, we generated novel anti-HER2 nanobodies (VHH2, VHH3) that exhibited outstanding target affinity and tumor inhibition. After i.v. injection, VHH3-Fc fusion distributed 4 to 5-fold higher in subcutaneous tumor and intracranial tumor compared with trastuzumab. VHH3-Fc and VHH3-ABD were also more penetrant in an in vitro BBB permeability assay. Site-specific conjugation of VHH3-Fc or VHH3-ABD fusions with anti-microtubule MMAE or anti-topoisomerase-1 Dxd payload produced nanobody-drug conjugates (NDCs) with highly potent and durable antitumor efficacy. When evaluated on the same linker-payload (GGFG-Dxd) dosages, VHH3-Fc-Dxd (DAR3.9) outperformed T-Dxd (DAR8) in both the subcutaneous and intracranial tumor models. Moreover, IHC staining and RNA-seq analysis of the treated tumor tissues revealed the involvement of the cGAS-STING-IFNs pathway in mediating the drug activity. Gene expression and protein function were more profoundly modulated by VHH3-Fc-Dxd than T-Dxd. Unlike the higher tumor distribution, the mouse serum PK study revealed a faster clearance (T1/2), reduced exposure (AUC), and higher volume distribution (Vz) for VHH3-Fc-Dxd relative to T-Dxd. Our results provide an example for the next generation HER2-NDC with substantially differentiated pharmacokinetics and pharmacodynamics profiles that will further benefit treatment outcomes and therapeutic windows.

DOI: 10.1038/s41401-025-01634-3

Source: https://www.nature.com/articles/s41401-025-01634-3