February 24, 2024

Scientists have redesigned the cancer-fighting protein so that it does not cause side effects

Researchers at the University of Washington have redesigned a protein that stimulates the immune system to fight cancer. By doing so, they eliminated dangerous side effects that occurred when using the protein. In tests on mice, the new compound strongly inhibited tumor growth, and in some animals even led to the removal of tumors.

For patientóin with aggressive kidney cancer or skóry protein that stimulates the immune system to fight – interleukin-2 (IL-2) may be the only salvation. However, the doses at whichórych is most effective, have side effects serious enough to pose a threat to the patient’s life.

Scientists, thanks to computer modeling, have designed this protein once again from scratch. The new protein mimics IL-2’s ability to stimulate the immune system’s response, but without the dangerous effects of theóin side. The protein has so far been tested only on animals, but wkrótce clinical trials can begin on humans as well.

Interleukin-2 plays a key role in directing the body’s immune response to an intruder. It’s a cytokine. Increases lymphocyte activityóIn T cells by binding simultaneously to their IL-2 receptorsβ and IL-2γ. In the comórkach, in whichówhich the third type of receptor, IL-2, is presentα, binds collectively to all three, but the latter binding, in comórks that build blood vessels, can cause them to leak – life-threatening condition.

– For 30 years, people próbowali change IL-2 to make the protein safer and more effective, said Daniel Adriano Silva Manzano, a biochemist at the University of Washington in Seattle (UW) and head of theówny author of the study. But IL-2 is unstable and stops working when it loses its swój normal shape, and many mutations further destabilize its structure.

To engineer IL-2 from scratch, UW researchers joined forces with colleagues from Portugal, Spain and the UK. The work began by analyzing howów binding of the protein to receptors β i γ, and also with the receptor α. IL-2 is a single long chain amino acidów. When it folds into an active 3D shape, it forms four segments, które twisted into spirals called alpha helixes. There are two sites in the helix structure thatóre binds to receptors β i γ. With receptors α However, parts of one of the helixes and two other spots in the helix are connected.

The researchers used software developed by David Baker, a protein designer at the UW. A program called Rosetta is being used just to design proteins. With this, the researchers in the new protein maintained the needed interactions with receptors β i γ, But they eliminated a part thatóra binds to receptors α. The Rosetta program proposed 40 options. After analyzing them, the teamół has synthesized and tested 22 of them.

In the end, the researchers established a version thatówhich they named Neo-2/15. It shares only 14 percent of. of their amino acid sequenceóin IL-2. Laboratory studies have shown that Neo-2/15 binds to receptors β i γ, but not with receptors α. In mouse models of colorectal cancer and melanoma, the compound reduced receptor-related side effects α, strongly inhibited tumor growth, and in some animals even eliminated tumors.

The results of the team’s work appeared in the journal „Nature”.

– This is a brilliant study – said James Olson, an oncologist at the Fred Hutchinson Cancer Research Center in Seattle, który was not involved in the research. Olson added that if Neo-2/15 reduces dangerous side effects in human tests, doctors will gain a new agent thatóry can provide patients with a longer treatment time, which will help the immune system remove tumorór.

A UW-affiliated company, Neoleukin Therapeutics, is currently working to bring Neo-2/15 to testóIn clinical. The company’s scientists are studying howób antibodies can target proteins in tumors but not in healthy cellsóhelices, so as not to trigger an autoimmune reaction,.

Baker acknowledged that a similar approach to selectively seeking specific receptorsów, may prove useful in boosting the immune response against other types of cancersóin, as well as in suppressing the immune response to autoimmune diseases.