Scientists at Tel Aviv University and the University of Lisbon have discovered and synthesized a small molecule that could be a more accessible and effective alternative to antibodies that have been successfully used to treat a range of cancers. The results of this study were published in the Journal of Cancer Immunotherapy.
An international team of researchers is behind this groundbreaking development. They are led by Prof. Ronit Sachs-Fanaro, Director of the Cancer Biology Research Center and Director of the Laboratory of Cancer Research and Nanomedicine at Tel Aviv University’s Sackler School of Medicine, and Prof. Helena Flindo and Prof. Rita Gerdes of the Institute of Pharmaceutical Research at the University of Lisbon’s Faculty of Pharmacy.
“In 2018, the Nobel Prize in Medicine was awarded to James Allison and Benjamu for their contributions to research on immunotherapy, the treatment of cancer by activating the immune system,” said Professor Sach-Fanaro, winner of the 2020 Kadar Family Prize.” Honjo discovered that immune cells called T cells express the protein PD-1, which, when combined with PD-L1, a protein expressed in cancer cells, disables the activity of the T cells themselves. In fact, the interaction between PD-1 and PD-L1 allowed cancer cells to paralyze T cells and prevent them from attacking the cancer cells. Masayuki Motsu has developed antibodies that neutralize PD-1 or PD-L1, thereby freeing T cells to fight cancer effectively.”
Clinical use of antibodies against PD-1/PD-L1 proteins has been authorized by regulators, and they are considered to have the greatest potential in the fight against cancer. Such immunotherapies could dramatically improve patient outcomes without the serious side effects associated with treatments such as chemotherapy.
However, such antibodies are expensive to produce, so they are not available to all patients. In addition, this treatment does not affect all parts of solid tumors, as the antibody is too large to penetrate and reach areas of the tumor that are not easily accessible and exposed. Now, using bioinformatics and data analysis tools, scientists from Tel Aviv University and the University of Lisbon have found a smaller and smarter alternative to these antibodies.
“Starting with thousands of molecular structures, postdoctoral researcher Dr. Rita Acúrcio narrowed down the list of candidates by using computer-aided drug design (CADD) models and databases until we found the best structure,” said Prof. Satchi-Fainaro.” In the second phase, we demonstrated that this small molecule can control tumor growth as effectively as an antibody – it can inhibit PD-L1 in animals designed to have human T cells. in other words, we have developed a molecule that inhibits PD-1/PD-L1 binding, alerting the immune system to the need to attack the cancer.”
“In addition, this new molecule has some major advantages over antibody therapy. The first is cost: because the antibody is a biological rather than a synthetic molecule, it requires a complex infrastructure and considerable capital to produce, at a cost of about $200,000 per patient per year. In contrast, we have synthesized small molecules in a short time with simple equipment and at a very low cost. Another advantage of small molecules is that patients will likely be able to take them orally at home without the need for intravenous injections in the hospital.”
In addition to accessibility considerations, experiments have shown that small molecule drugs improve the activation of immune cells within solid tumor masses.
“The surface area of solid tumors is heterogeneous,” explains Professor Satchi-Fainaro.” If there are fewer blood vessels in a particular area of the tumor, antibodies will not be able to get inside. On the other hand, small molecules will diffuse and therefore are not entirely dependent on the tumor’s blood vessels or its high permeability. I believe that in the future, small molecules will be available on the market and make immunotherapy affordable for cancer patients.”
