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

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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.