Department of Biotechnology and Bioengineering, Interdisciplinary Program in Biohealth-machinery Convergence Engineering, College of Art, Culture and Engineering, Kangwon National University, South Korea.
Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine, Tucson, AZ, USA.
Biomaterials. 2021 Jun;273:120817. doi: 10.1016/j.biomaterials.2021.120817. Epub 2021 Apr 19.
Heat shock protein 90 (HSP90) plays a crucial role in the survival of cancer cells. When an inhibitor blocks the signaling pathway of HSP90, its client proteins are degraded, destabilized, and inactivated. Although HSP90 inhibitors are in various clinical trials, there are no HSP90 inhibitor-immunoconjugates due to the difficulty in chemical modification of HSP90 inhibitors. Here we show that biological affinity binding enables the incorporation of HSP90 inhibitors to an antibody without the need for chemical conjugation. We constructed a recombinant fusion protein composed of an anti-HER2 scFv and an HSP90 inhibitor-binding domain (HER2 scFv-HBD). The HBD spontaneously captures a HSP90 inhibitor, resulting in the formation of an HER2 scFv-HBD/HSP90 inhibitor complex. In an HER2-positive cancer mouse model, targeted delivery of HSP90 inhibitors was confirmed and improved anti-cancer efficacy was observed. We have proven the promise of tumor-directed HSP90 inhibition as a new form of targeted therapy.
热休克蛋白 90（HSP90）在癌细胞的存活中起着至关重要的作用。当抑制剂阻断 HSP90 的信号通路时，其客户蛋白会被降解、失稳和失活。尽管 HSP90 抑制剂正在进行各种临床试验，但由于 HSP90 抑制剂的化学修饰困难，目前尚无 HSP90 抑制剂免疫偶联物。在这里，我们表明生物亲和力结合使 HSP90 抑制剂能够无需化学偶联而掺入抗体。我们构建了一种由抗 HER2 scFv 和 HSP90 抑制剂结合域（HER2 scFv-HBD）组成的重组融合蛋白。HBD 自发捕获 HSP90 抑制剂，导致形成 HER2 scFv-HBD/HSP90 抑制剂复合物。在 HER2 阳性癌症小鼠模型中，证实了 HSP90 抑制剂的靶向递送，并观察到了改善的抗癌疗效。我们已经证明了针对 HSP90 的肿瘤导向抑制作为一种新的靶向治疗形式的前景。
