Monoclonal antibodies revolutionized cancer immunotherapy, where Nobel laureates James Allison and Tasuku Honjo developed drugs capable of modularizing PD-1/PD-L1 interactions against all forms of cancer. Despite this significant progress, cancer immunotherapy based on monoclonal antibodies still has its limitations. In addition to being unable to fully enter and treat solid tumors, this method of treatment remains very expensive for the vast majority of patients. However, researchers have found a promising way to overcome these problems by creating reduced versions of the PD-L1 inhibitor molecule. The first advantage is that they are capable of penetrating solid tumours. Second, because they are synthetic, their production is much cheaper than the production of conventional monoclonal antibodies. For many patients, it is a ray of hope.
In 2018, James Allison and Tasuku Honjo discovered that T-cells express PD-1 proteins that deactivate them when associated with another PD-L1 protein, which expresses on the surface of cancer cells. This modularization system is naturally present in our body to reject any alien and pathogenic body, PD-1
In a phenomenon called tumor clotting, the interaction between PD-1 and PD-L1 gives tumor cells the ability to completely paralyze T cells. This mechanism allows tumors to grow freely and the body is not protected.
Two Nobel Prize winners then developed antibodies that inhibit PD-1 or PD-L1, which have already received clinical approval, and the advantage of such treatment is that it can target a wide range of cancer tumors and will be much less invasive; it has few side effects compared to alternative methods such as chemotherapy; it is also noted that the chances of patients getting remission are higher.
These inhibitors are currently available only in the form of monoclonal antibodies; however, their production is expensive, so they cannot be made available to all patients; nor can they fully cure solid tumors because the antibodies are too large to reach the least exposed areas where very few blood vessels exist.
"", explains Ronit Sachi-Finaro, Director of Research and Research Centre for Cancer Biology and Nanomology, University of Tel Aviv. ", he explains.
Then researchers at the University of Tel Aviv and University of Lisbon developed a family of synthetic, smaller inhibitors, partly based on computer simulations. According to the preliminary results presented in the journal, molecules will significantly improve the immune response within compact tumors.
To develop a family of small molecules, the research group analysed thousands of molecular structures using models from drug computer design databases. ", explains Sachi-Finaro.
A family of synthetic molecules was then tested on animal models that were pre-infected with cancer forms and genetically modified to produce the same type of T-cells as humans, and then researchers found that they were able to control tumor growth as effectively as monoclonal antibodies.
Since new structures are more flexible and less cumbersome, they do not depend on blood vessels to deliver them to tumor cells, so they can enter deep into tumors effectively into tumor microbes.
New molecules are also beneficial in terms of production costs because they require more simple equipment than antibodies, namely, the production of monoclonal antibodies will cost about $2,000 per year per patient, and synthetic molecules can be produced faster and ordered orally, without the patient having to go to hospital.