New immunotherapy drugs target two elusive proteins that cause cancer | Science

By Jocelyn KaiserApple. 1, 2021 at 11:00 a.m.

Researchers have shown in mice that design antibodies can slow tumor growth by targeting two of cancer’s most infamous offenders – the RAS and p53 proteins, which are mutated in many tumors but have largely defied development efforts. drugs. If their promise holds in clinical trials, such drugs could help unleash the body’s immune system on difficult-to-treat cancers, including pancreatic and ovarian cancers.

“It’s exciting,” says immunologist Jon Weidanz of the University of Texas at Arlington, who co-founded a company that is working on similar immunotherapies, called bispecific antibodies. The new drugs can lock onto a few fragments of p53 or RAS exiting the surface of a tumor cell – and then trigger immune cells to attack them. “Therapies have the potential to work when there are a very low number of targets on the cells. It’s a big deal, ”says Weidanz, who wrote a commentary accompanying the papers.

P53 is a tumor suppressor, and the intact protein helps healthy cells repair DNA – or self-destruct if the damage cannot be repaired. When p53 is turned off in tumors, they can grow unchecked. But targeting p53 with drugs is difficult, because restoring its activity is much more difficult than inhibiting its activity or stopping its production – more typical drug strategies against misbehaving proteins.

RAS, which signals cells to uncontrollable growth when mutated, has been difficult to target with inhibitors due to its smooth shape and lack of obvious binding sites.

And both proteins work inside cells, making them hard to fight off with modified antibodies, versions of the Y-shaped proteins that our immune systems use to mark foreign invaders for destruction. Antibodies cannot easily get inside cells, so drugs based on them work best against cancer proteins that come out of the surface of a tumor cell.

But even if RAS and p53 remain inside tumor cells, traces of it are left on the surface of the cell, fragments that can be detected by the immune system. To target these fragments of mutant p53 and RAS, known as neoantigens, the laboratory of cancer geneticist Bert Vogelstein at Johns Hopkins University turned to bispecific antibodies. Standard antibodies have two identical arms, but bispecifics are designed to have one arm that binds to immune soldiers called T cells, and another that binds to a surface protein of a cancer cell, connecting the cells and activating the cell. immune cell to attack its new cancer partner. .

The challenge was that pieces of mutant p53 and RAS that an antibody could target are extremely rare on tumor cells – less than 10 copies per cell, the researchers found. The discovery of a bispecific antibody that would bind to them, but not to healthy cells, brought Hopkins graduate students Emily Hsiue and Jacqueline Douglass and their team over 5 years. First, they tested a library of antibody fragments to find those that stuck to the p53 and RAS neoantigens. Then they converted these fragments into different bispecific antibody designs and tested which ones were best at persuading T cells to kill cancer cells in a box. The strategy was “informed trial and error,” says molecular biologist Shibin Zhou of Hopkins, who co-led the work.

Ultimately, the team came up with a “diabody” targeting p53, a compact two-armed antibody lacking the stem of a typical Y-shaped antibody. In mice with tumor cells carrying a specific mutation in the p53 gene, this bispecific significantly inhibited tumor growth, researchers report today in Science. Two separate RAS diabodies performed well on cell lines cultured with two different cancer-promoting mutations and slightly slowed tumor growth in mice, the team writes today in Scientific immunology. In a third study by researcher Suman Paul, the same type of purified double-target antibody also worked in mice against a type of leukemia involving T cells, they report in Scientific translational medicine. Its target was yet another type of cancer that was difficult to treat.

The studies come with caveats. To treat patients, researchers would need to develop a panel of bispecific antibodies tailored to both a person’s immune proteins and the p53 or RAS genetic mutations particular to their tumor. (Bispecific leukemia is also expected to be associated with a patient’s T cell cancer.) Because they do not have the Y stem of normal antibodies, diabodies clear the bloodstream more quickly, so they should be infused. continuously for weeks with a pump worn by the patient. “There is a long way to go for many reasons,” says Vogelstein, who describes the work today at the online meeting on Advances in Genome Biology and Technology.

Still, outside researchers are enthusiastic. Although other groups are also working on bispecific antibodies that target intracellular cancer proteins, “this appears to be one of the first agents against mutant P53, a critical tumor suppressor,” says physician-scientist David Scheinberg from Memorial Sloan Kettering Cancer Center, which consults with biotechnology companies working in this field. (Hopkins has filed for patent applications related to the treatments.)

And although researchers are making progress in the development of other drugs for RAS cancers, these drugs do not call on the immune system and will likely stop working within a year as the tumors become resistant, predicts Weidanz. . Bispecific antibodies, which can rally a broad immune response, offer “the potential for a larger-scale war which, hopefully, could win over the immune system.”