A small molecule that can successfully treat a spectrum of cancers in place of an antibody has been found and synthesised by researchers from Tel Aviv University and the University of Lisbon. Prof. Ronit Sachi-Fainaro leads an international team of researchers, who is the Director of the Center for Cancer Biology Research and the Laboratory for Cancer Research and Nanomedicine at the Sackler Faculty of Medicine, Tel Aviv University, as well as Profs. Rita Guedes and Helena Florindo, both from the Research Institute for Medicines at the Faculty of Pharmacy, University of Lisbon, made the ground-breaking discovery.
The clinical use of antibodies against the PD-1/PD-L1 proteins has already been authorised, and they are regarded as holding the greatest promise for the fight against cancer. Without the severe side effects that come with treatments like chemotherapy, this immunotherapy can significantly improve patient outcomes. However, since the antibodies are expensive to produce, not all patients can access them. Additionally, because the antibodies are too large to penetrate and reach less accessible and less exposed areas of the tumour, the treatment does not completely affect the solid tumours. Now, scientists at the Universities of Lisbon and Tel Aviv have used bioinformatic and data analysis tools to discover a more compact and intelligent replacement for these antibodies.
Prof. Satchi-Fainaro said, “Post-doctoral researcher Dr. Rita Acúrcio started with thousands of molecular structures, and by using computer-aided drug design (CADD) models and databases, we narrowed down the list of candidates until we reached the best structure.” She added, “In the second stage, we confirmed that the small molecule controls tumor growth as effectively as the antibodies – it inhibits PD-L1 in animals engineered to have human T cells. In other words, we have developed a molecule that can inhibit PD-1/PD-L1 binding and remind the immune system that it needs to attack the cancer. Moreover, the new molecule has some major advantages over the antibody treatment.”
Prof. Satchi-Fainaro underlines, “In addition to accessibility considerations, our experiments show that the small molecule improves the activation of immune cells inside the solid tumor mass. The surface area of a solid tumor is heterogeneous. If there are fewer blood vessels in a particular area of the tumor, the antibody will not be able to get inside. The small molecule, on the other hand, diffuses, and is therefore not entirely dependent on the tumor’s blood vessels or on its hyperpermeability. I believe that in the future, the small molecule will be commercially available and will make immunotherapy affordable for cancer patients.”