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

增强内体逃逸以改善抗 PSMA 免疫毒素对前列腺癌的细胞毒性

• 批准号: 407307550
• 负责人: Professor Dr. Philipp Wolf
• 金额: --
• 依托单位: Arbeitsgruppe Antikörper-basierte Diagnostik und Therapie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/407307550?language=en
• 关键词: Enhancing; endosomal; escape; improved; cytotoxicity

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.

前列腺癌是最常见的癌症，也是工业国家男性癌症死亡的第二大原因。虽然发病率和死亡率正在下降，但目前还没有针对晚期的治愈性治疗。因此，晚期前列腺癌的治疗需要新的、创新的概念，以增强疗效。我们的抗PSMA免疫毒素为前列腺癌开发了一种新的、强大的、有效的治疗选择。免疫毒素特异性结合前列腺癌细胞表面上的前列腺特异性膜抗原（PSMA），并且能够直接诱导细胞凋亡-独立于在肿瘤发生或化学激素治疗期间可以改变的信号传导途径和上游元件。免疫毒素的人源化/去免疫化对于在患者中的安全应用是必要的。然而，它也导致细胞毒性降低。本课题采用重组乙型肝炎病毒表面抗原（TLM）的PreS 2结构域，或加入肥皂草（Saponaria officinalis L.）通过避免经由内质网的有损（蛋白酶体和溶酶体降解）途径，应导致免疫毒素的增强的内体逃逸。这两种方法将在体外和体内进行检查，并应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新的治疗选择，并减少剂量限制性副作用。此外，我们的研究将提供有价值的见解，未来使用的内体逃逸增强剂的免疫毒素，抗体药物偶联物或肽，蛋白质和siRNA为基础的治疗增强细胞内输送。