By Jocelyn Kaiser Mar. 1, 2021 , 11:00 AM
Researchers have shown in mice that designer antibodies can curb the growth of tumors by targeting two of cancer’s most infamous offenders—the proteins RAS and p53, which are mutated in many tumors but have largely defied drug development efforts. If their promise holds up in clinical trials, such drugs could make it possible to unleash the body’s immune system on hard-to-treat cancers including pancreatic and ovarian.
“It’s exciting,” says immunologist Jon Weidanz of the University of Texas, Arlington, who co-founded a company that works on similar immunotherapies, called bispecific antibodies. The new drugs can lock onto a few snippets of p53 or RAS jutting out from a tumor cell’s surface—and then trigger immune cells to attack them. “The therapies have the potential to work when there’s a really low number of the target on cells. That is 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 can’t be fixed. When p53 is turned off in tumors, they can grow unchecked. But targeting p53 with drugs is difficult, because restoring its activity is much harder than inhibiting its activity or turning off its production—more typical drug strategies against misbehaving proteins.
RAS, which signals cells to grow uncontrollably when mutated, has been hard to target with inhibitors because of its smooth shape and lack of obvious binding sites.
And both proteins function inside cells, making them hard to fight with engineered antibodies, versions of the Y-shaped proteins our immune system uses to tag foreign invaders for destruction. Antibodies can’t easily get inside cells, so drugs based on them work best against cancer proteins that poke out from a tumor cell’s surface.
But even though RAS and p53 stay inside tumor cells, the cell’s surface carries traces of them, snippets that can be sensed by the immune system. To target these fragments of mutant p53 and RAS, known as neoantigens, cancer geneticist Bert Vogelstein’s lab at Johns Hopkins University turned to bispecific antibodies. Standard antibodies have two identical arms, but bispecifics are crafted to have one arm that binds to immune soldiers called T cells, and another that links to a cancer cell surface protein, bridging the cellsand activating the immune cell to attack its new, cancerous partner.
The challenge was that the bits of mutant p53 and RAS that an antibody could target are extremely scarce on tumor cells—fewer than 10 copies per cell, the researchers found. Discovering a bispecific antibody that would bind to them, but not to healthy cells, took Hopkins graduate students Emily Hsiue and Jacqueline Douglass and their team more than 5 years. First, they tested a library of antibody fragments to find those that stuck to the p53 and RAS neoantigens. Next, they converted these fragments into different bispecific antibody designs and tested which were best at coaxing T cells to kill cancer cells in a dish. The strategy was “informed trial and error,” says molecular biologist Shibin Zhou of Hopkins, who co-led the work.
In the end, the team came up with a p53-targeting “diabody,” a compact, two-armed antibody lacking the stem of a typical Y-shaped antibody. In mice with tumor cells bearing a specific mutation in the p53 gene, this bispecific dramatically curbed tumor growth, the researchers report today in Science. Two separate RAS diabodies worked well on lines of cultured cells with two different cancer-promoting mutations and modestly slowed the growth of tumors in mice, the team writes today in Science Immunology. In a third study led by research fellow Suman Paul, the same type of pared-down, double-target antibody also worked in mice against a type of leukemia that involves T cells, they report in Science Translational Medicine. Its target was yet another hard-to-drug type of cancer.
The studies come with caveats. To treat patients, researchers would have to develop a panel of bispecific antibodies tailored to both a person’s immune proteins and the particular p53 or RAS genetic mutations in their tumor. (The leukemia bispecific would also have to be matched to a patient’s T cell cancer.) Because they lack the Y stem of normal antibodies, the diabodies disappear faster from the bloodstream, so they would have to be infused continuously for weeks with a pump carried by the patient. “There’s quite a ways to go for many reasons,” says Vogelstein, who describes the work today at the online Advances in Genome Biology and Technology meeting.
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 directed to mutant P53, a critical tumor suppressor,” says physician-scientist David Scheinberg of Memorial Sloan Kettering Cancer Center, who consults for biotech companies working in this area. (Hopkins has filed patent applications related to the treatments.)
And although researchers are making progress developing other drugs for RAS cancers, those drugs don’t enlist the immune system and will likely stop working within 1 year as tumors become resistant, Weidanz predicts. Bispecific antibodies, which can rally a broad immune response, offer “the potential for a more large-scale war that hopefully the immune system could win.”
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