Tel Aviv University and the University of Lisbon researchers have synthesised and identified a small molecule that will be a less expensive and more effective alternative to an antibody that can treat various types of cancer.
Researchers published their findings in the Journal of ImmunoTherapy of Cancer, taking an existing antibody to the next level.
“In 2018, James Allison and Tasuku Honjo were awarded the Nobel Prize in Medicine for their contributions to the study of immunotherapy, the treatment of cancer through immune system activation,” Prof. Satchi-Fainaro says. “Honjo discovered that T cells, which are immune cells, express the protein PD-1, which disables T-cell own activity when it binds to the protein PD-L1 expressed in cancer cells. Actually, the interaction of PD-1 and PD-L1 allows cancer cells to paralyse T cells, preventing them from attacking cancer cells. Honjo created antibodies that neutralise either PD-1 or PD-L1, allowing T cells to fight cancer more effectively.”
A smaller yet smarter alternate
While the Nobel Prize winners’ 2018 discovery is extremely promising in the fight against cancer, there are some drawbacks to consider. To begin with, antibodies are expensive to produce, so they do not appeal to all patients. Second, antibodies are too large to penetrate a solid tumour; as a result, treatment falls behind, affecting all parts of the cancer.
Researchers, on the other hand, have combined bioinformatic and data analysis tools to come-up a smaller but smarter alternative.
“Post-doctoral researcher Dr. Rita Acrcio started with thousands of molecular structures, and by using computer-aided drug design (CADD) models & databases, we narrowed the list of candidates until we reached the best structure,” says Prof. Satchi-Fainaro.
“In the second stage, we confirmed that the small molecule controls tumour growth as effectively as the antibodies—it inhibits PD-L1 in animals engineered to have human T cells. In other words, we created a molecule that can inhibit PD-1/PD-L1 binding while also reminding the immune system that it needs to attack the cancer. Furthermore, the new molecule has several significant advantages over antibody treatment.”
“To begin with, because the antibody is a biological rather than a synthetic molecule, it necessitates a complex infrastructure and significant funding to produce, costing approximately $200,000 per patient per year. We, on the other hand, have already synthesised the small molecule using simple equipment in a short period of time and at a fraction of the cost. Another benefit of the small molecule is that patients will most likely be able to take it at home, orally, with-out the need for IV administration in the hospital.”
The experiments show that the new small molecule helps activate immune cells within the solid tumor mass.
“The surface area of a solid tumour is heterogeneous,” explains Prof. Satchi-Fainaro. “If there are fewer blood vessels in a specific area of the tumour, the antibody will not be able to get-inside. The small molecule, on the other hand, diffuses and is thus not entirely dependent on the tumor’s blood vessels or hyperpermeability. I believe that in the future, the small molecule will be commercially available, and make immunotherapy more affordable for cancer patients.”
