Drugs that infiltrate cancer cells and destroy them from within become extra effective after passing through the hands of a group of chemical scientists.
The world has seen major advances against cancer in recent years in the form of a new group of drugs to treat cancer which can best be described as medicine’s answer to Trojan horses.
As small and harmless ‘packages,’ the drug circulates in the patient’s bloodstream until it meets a cancer cell. It is then invited inside. Inside the cancer cell, the innocent guest completes its real—and for the cancer cell malicious—mission: It releases its toxic payload, killing the cancer cell.
Illustration of a drug that is harmless when circulating in the bloodstream. But when it encounters a cancer cell and is taken up by the cell, the drug's toxic cargo is released, killing the cancer cell. Illustration by Claus Lunau / DTU
It may sound simple, but it’s not. Because sometimes the Trojan horse-type cancer drug is invited into healthy cells, which then die, which is undesirable.
Other times, the drug is released prematurely, i.e. while it is still circulating in the bloodstream, and thus the effect of the treatment is reduced as smaller amounts of medicine are delivered to their actual destination, the sites of the cancer. Last but not least, very few drugs can be attached to the Trojan medicine horses due to certain chemical challenges.
This new group of drugs is known as antibody-drug conjugates, or ADCs. An ADC consists of an antibody that will recognize the cancer cell and a substance designed to kill the cancer cell. The two substances are conjugated by a chemical molecule called a linker. Today, there are only about a dozen ADCs in the world.
For an ADC to work as intended, it is crucial that the linker is stable in the bloodstream and effectively releases the active substance that is supposed to kill the cancer cell. Over the past couple of years, chemist and DTU Associate Professor Katrine Qvortrup has been researching possible ways of improving the linker molecule.
“In research circles, the general consensus was that a new linker design could improve the ADCs in several ways: We would be able to increase the selectivity of the ADC, i.e. make sure that it gets better at targeting only the cancer cells, and we would be able to avoid inefficiencies, for example by making sure that the medicine is not released prematurely, and finally, we may be able to achieve improvements that would make it possible to connect more types of drugs to the linker than has been possible so far,” says Katrine Qvortrup.
Associate Professor Katrine Qvortrup (left) and Postdoc Katja Egeskov Grier are both employed at DTU Chemistry, where they are developing a new drug that can find cancer cells inside the body and kill the cells from the inside. Photo credit: Bax Lindhardt / DTU
Linker must be cleaved
The antibody is a key part of the ADC as it makes sure that that chemical package recognizes the cancer cell and is invited in. This happens via an antigen on the outside of the cancer cell. The antigen is unique in being present on cells that grow rapidly, which is the case for many cancer cells.
The antigen acts as a receptor, so when the ADC antibody meets the cancer cell’s antigen, recognition occurs, and our Trojan friend is ‘invited’ inside. Unfortunately, similar antigens are found in certain healthy cells that by nature grow rapidly, such as hair, nail and bone marrow cells, and these cells will perish if the ADC is let in.
So Katrine Qvortrup and her colleagues started looking at ways of ensuring that the toxic payload is only released in cancer cells and not in the other fast-growing cells. This involved taking a close look at the inside of the cancer cell, and how it differs from the inside of healthy cells. Perhaps they could spot a difference that could be used to make sure that the ADC is only activated in the cancer cell.
“For a linker to release the drug inside the cell, it must first be cleaved. Something needs to trigger the cleaving. Linkers can be cleaved in several ways, one method involving the use of enzymes. Encountering a certain enzyme, the linker opens up, and the drug is released,” explains Katrine Qvortrup.
Special enzyme in certain cancer cells
This led the researchers to take an interest in an enzyme called sulfatase, which is found in higher concentrations inside certain cancer cells. High sulfatase concentrations are usually seen in hormone-dependent cancers such as prostate cancer and certain types of breast cancer. Based on this knowledge, the research group designed a linker that is cleaved only when it meets sulfatase.
During the development of the linker, the researchers worked closely with the Finsen Laboratory, which is the cancer research department at Rigshospitalet in Copenhagen. The Finsen Laboratory was involved in testing the various versions of the linker that were developed until DTU researchers succeeded in achieving the desired properties.
“With our new linker, we have added a kind of extra level of security, which means that the ADC is first taken up by a fast-growing cell and can then only be triggered if sulfatase is present. This means that should the ADC enter a fast-growing, healthy cell, nothing happens because there is not enough sulfatase present. In this way, we target the drug even more precisely at the cancer cells, resulting in greater efficacy and fewer side-effects, because healthy cells are not targeted,” says Katrine Qvortrup.
Changing antibody size
The researchers have also succeeded in improving the linker in several ways by changing its chemical functionalities, for example by increasing its water solubility. This helps to stabilize the ADC design, which in turn increases the efficacy of the drug. In addition, they succeeded in designing a linker capable of conjugating several types of drugs, which makes it possible to use ADCs to attack far more diseases.
Last but not least, they started changing the size of the antibody, so you can use a smaller molecule to deliver the toxic drug.
“An antibody is a fairly large molecule, and it prevents the ADC from penetrating metastases, where the cancer cells are very densely packed. We have therefore developed ‘nanobodies’, which are significantly smaller molecules than the antibodies used so far in ADCs. In this way, we can sneak the ADC into metastases,” says Katrine Qvortrup.
The solution was inspired by the scientific literature, which describes a special receptor on cancer cells that has not been exploited before. The researchers made sure that their ‘nanobodies’ would recognize this receptor, so that an ADC can now enter the metastatic cancer cells.
DTU researchers have had the new linker technology further analysed by Abzena, a private company specializing in this field. The technology has been patented.
“We’re now in the process of fine-tuning our linker, while also having more tests done in order to gather more knowledge about its functionalities. Having published all our research in spring 2023, we will soon be ready to sell the technology so that it can be used in the fight against cancer,” says Katrine Qvortrup.
Source: DTU