Scientists from The Scripps Research Institute (TSRI) have developed a new method for connecting healing molecules to antibodies, and this is to improve the medical treatments that exist today.
![Schematic description of the method: linking of thiol groups found in antibodies/proteins with heterocyclic rings associated with drug/dye compounds (the yellow part). In the picture you can see the stability of the new connections (blue arrow) compared to the disintegration over time of the known connections (red arrow). [from the original article]](https://www.hayadan.org.il/images/content3/2013/11/mcontent-500x102.gif "Schematic description of the method: linking of thiol groups found in antibodies/proteins with heterocyclic rings associated with drug/dye compounds (the yellow part). In the picture you can see the stability of the new connections (blue arrow) compared to the disintegration over time of the known connections (red arrow). [from the original article]")
Scientists from The Scripps Research Institute (TSRI) have developed a new method for connecting healing molecules to antibodies, and this is to improve the medical treatments that exist today.
Drug-antibody conjugates, as they are called, form the basis for new medical treatments on the market that harness the ability of antibodies to recognize their unique and selective target in order to deliver a multitude of drugs to specific cell types, for example - delivering toxic chemotherapy drugs into cancer cells without harming the healthy cells around them or on the way to them. The new method allows drug developers to create more stable pairs than those that exist today. "A more stable link between the drug molecule and the antibody means better healing - the chance that the toxic drug will detach from the antibody before it reaches the target site is much lower," explained the lead researcher.
The findings of the new study have long been published in the scientific journal Angewandte Chemie.
The new method of creating more stable drug-antibody pairs follows the first generation of similar powerful therapeutic methods that have recently entered the market. Two pairs of this type are now in clinical trials: Brentuximab vedotin (Adcetris®), approved by the US Food and Drug Administration back in 2011, demonstrated significant effects in clinical trials against cancers resistant to other treatment methods. The combination uses an antibody to transfer a compound (monomethyl auristatin E) that destroys cells into cells containing a receptor (CD30) which is a main marker for lymphoma type cancer. The second combination, called ado-trastuzumab emtansine (Kadcyla®), which was approved last year for the treatment of breast cancer, manages to transfer the toxic compound mertansine into the cancer cells that overexpress the HER2 receptor.
The success of these duos and the great potential inherent in this technology have made them popular among pharmaceutical companies, especially those trying to develop new anti-cancer drugs. Although the method is effective, it also has serious limitations. The method involves the use of compounds derived from the compound maleimide, which can be easily added to small drug molecules. The maleimide is used as a connector or bridge that forms strong bonds with amino acids of the cysteine type that can be added to the antibody, which is composed of amino acids. In this method, a single antibody can be labeled with drug molecules containing one or more maleimide groups. The main problem lies in the fact that these maleimide-cysteine bonds go through several forms of decomposition while in the bloodstream. When such a breakdown occurs, the charge of the drug molecules, which are often extremely toxic compounds, may cause unwanted peripheral damage to the body's healthy cells. This instability of these bonds is part of the reason for the multiple toxicity of these well-known pairs.
A more stable link means lower toxicity and higher efficiency of the antibody-drug conjugates, a goal that chemical research laboratories around the world have been looking for for many years. It seems that the researchers from the Scripps Research Institute have now succeeded in finding a new and more effective method in the form of a click reaction of a thiol group. In their new article, the researchers describe their method for preparing improved bonds between drug and antibody using compounds based on heterocyclic rings substituted with a sulfonyl group, instead of the maleimide compound. The new method makes it possible to obtain more stable bonds between the drug and the antibody and also more selective ones, so that the drug binds to the most appropriate positions in the desired protein, notes the lead researcher. The large chemical company Sigma-Aldrich will begin selling these compounds and allow the pharmaceutical companies to begin developing more stable combinations with their help.
Although linking drug molecules to target-directed antibodies is the best-known medical application of the new method, the researchers emphasize and say that the method has great potential in other areas as well. "Our method should also be useful for many other types of protein pairs," claims the lead researcher. Among these - the conjugation of proteins to light-emitting molecules (fluorescence) for laboratory experiments and medical diagnosis, as well as for linking drug compounds to polyethylene glycol groups (pegylation) to accelerate their excretion from the body.
The news about the study
