Enhancing endosomal escape for an improved cytotoxicity of anti-PSMA immunotoxins against prostate cancer

前列腺癌是工业国家男性最常见的癌症，也是癌症死亡的第二大原因。虽然发病率和死亡率在下降，但目前尚无治疗晚期的根治方法。因此，晚期前列腺癌的治疗需要新的和创新的概念，以提高疗效。通过我们的抗PSMA免疫毒素，我们开发了一种新的、强大和有效的前列腺癌治疗方案。免疫毒素与前列腺癌细胞表面的前列腺特异性膜抗原(PSMA)特异性结合，能够直接诱导细胞凋亡-不依赖于在肿瘤发生或化疗激素治疗过程中可能改变的信号通路和上游元件。免疫毒素的人源化/去免疫对于患者的安全应用是必要的。然而，它也会降低细胞毒性。在本项目中，整合乙肝病毒表面抗原(TLM)的PreS2结构域或添加来自防风的植物皂苷SO1861应该会通过避免内质网中的损失(蛋白酶体和溶酶体降解)途径来增强免疫毒素的内体逃逸。这两种方法都将在体外和体内进行测试，应该会导致更有效地杀死前列腺癌细胞和更高的抗肿瘤活性。在临床上，我们的策略可能会为无法治愈的晚期前列腺癌患者带来一种新的治疗选择，同时减少剂量限制性副作用。此外，我们的研究将为未来使用内体逃逸增强剂来增强免疫毒素、抗体药物结合物或基于肽、蛋白质和siRNA的疗法的细胞内输送提供有价值的见解。

Prostate cancer is the most common cancer and the second most leading cause of cancer deaths in men of industrial countries. Although incidence and death rate are on the decrease, there is currently no curative treatment available for advanced stages. Therefore, treatment of advanced prostate cancer requires new and innovative concepts with enhanced efficacy.With our anti-PSMA immunotoxins we developed a new, strong and effective therapeutic option against prostate cancer. The immunotoxins specifically bind to the prostate specific membrane antigen (PSMA) on the surface of prostate cancer cells and are able to directly induce apoptosis - independently of signaling pathways and upstream elements that can be altered during tumorigenesis or chemo-hormonal treatment. Humanization/de-immunization of the immunotoxins is necessary for a safe application in patients. However, it also leads to a reduced cytotoxicity. In the present project, the incorporation of the PreS2-domain of hepatitis-B virus surface antigen (TLM) or the addition of the plant saponin SO1861 from Saponaria officinalis L. should lead to an enhanced endosomal escape of the immunotoxins by avoidance of lossy (proteasomal and lysosomal degradation) pathways via the Endoplasmatic Reticulum. Both approaches will be examined in vitro and in vivo and should cause a more effective killing of prostate cancer cells and a higher antitumor activity. In the clinic, our strategy could lead to a new therapeutic option in patients with incurable, advanced prostate cancer with reduction of dose-limiting side effects. Moreover, our study will provide valuable insights with regard to the future use of endosomal escape enhancers for an enhanced intracellular delivery of immunotoxins, antibody drug conjugates or peptide-, protein- and siRNA-based therapeutics.