A new kind of medicine that destroys specific proteins on the surface of cells could lead to better therapies for conditions such as cancer.
The approach, devised by at the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues, involves using modified antibodies they call TransTACs to join a surface protein to another common protein that is involved in transporting iron into cells. The first protein then gets dragged inside the cell and destroyed.
This resulted in the destruction of more than 90 per cent of the target protein in different cell culture experiments. One of the proteins Zhou鈥檚 team targeted helps cancer cells evade the immune system.
Advertisement
鈥淭his strategy is highly innovative and seems to have tremendous potential for the treatment of various cancers,鈥� says at the University of California, Los Angeles.
Almost all drugs work by interfering with the functions of proteins, usually by binding to key sites on them. Most drugs also consist of small molecules that can move from the bloodstream into cells.
However, for many target proteins, researchers have failed to find small molecules that bind to key sites well enough to block their activity. So, back in 1998, at Yale University came up with the idea of creating drugs that destroy proteins, rather than blocking their activity.
His team made drugs, dubbed PROTACs, that effectively add a 鈥渞ecycle me鈥� label to the target protein, resulting in its destruction by the cell. In 2020, and there are now more than 70 in development.
But to get inside cells, PROTACs have to be small-molecule drugs, and finding safe and effective ones is hard. So, more recently, several teams around the world have started to apply the idea of destroying proteins, rather than blocking them, to the proteins that straddle the membranes of cells.
Because these proteins protrude from the cell surface, they can be targeted with large molecules, such as antibodies, that are easier to develop and much more specific than small-molecule drugs. And with around a third of all human proteins being on membranes, there is still plenty of scope for treating a huge range of conditions.
Most methods tried so far work only for specific cell types, but the approach developed by Zhou鈥檚 team should be more universal because it relies on a membrane protein called the transferrin receptor. This is involved in iron uptake and is found on almost every type of cell in the body. What鈥檚 more, there are usually much higher levels of this receptor on cancer cells, as they need more iron than normal cells.
The transferrin receptors take up iron with the help of the protein transferrin. This is released into the blood by the liver, binding first to iron and then to a transferrin receptor. This causes the cell membrane around the receptor to bulge inwards and pinch off to form a little bubble inside the cell.
Next, the cell releases digestive enzymes into the bubble so the iron can be absorbed, and the transferrin receptor returns to the outer membrane. Across the whole surface of a cell, this process can happen 500 times every second.
When a TransTAC binds a target protein to the transferrin receptor, the target protein ends up in the bubble too, where it gets destroyed by the enzymes. The modified antibody is designed to release the transferrin receptor at this point.
To test if the idea works, Zhou鈥檚 team created TransTACs that target three different membrane proteins and tried them on cancer cells growing in culture.
For instance, many cancers have a protein on their surface called PD-L1 that sends a 鈥渄on鈥檛 attack me鈥� signal to the immune system. The team鈥檚 TransTAC that targeted PD-L1 reduced the level of this protein on breast cancer cells by 98 per cent.
The team has yet to test the effectiveness of TransTACs in animals, but mice dosed with one kind of TransTAC didn鈥檛 show any ill effects.
鈥淚t鈥檚 a very cool idea and an exciting advance,鈥� says at Stanford University in California. Like Daniels-Wells, he thinks this approach may prove most suited to treating cancers.
bioRxiv
