Memorial Sloan-Kettering and Eureka Go After ‘Undruggable’ Targets
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it’s hard to make small molecule chemical compounds that will specifically target the internal proteins that are cancer culprits, Scheinberg says. Many of these protein targets lack distinctive folds and pockets where a small drug could fit, bind, and therefore block the proteins’ harmful actions.
Scheinberg, however, thought he could take advantage of a common cellular mechanism that brings telltale traces of the WT1 protein to the cell surface. Molecules of WT1, like other proteins, are eventually broken down into fragments by the cell’s internal garbage disposal unit, the proteasome.
The trash-clearing system in human cells also includes macromolecules called HLA, which carry the broken fragments of WT1 to the outer cell membrane. The HLA carrier wraps itself around the fragment, a peptide containing only nine amino acids.
“The HLA is like a hot dog bun—the peptide is the hot dog,” Scheinberg says. HLA molecules are in the business of exposing these peptide morsels to the immune system—which may recognize them as a foreign invader that needs to be struck down.
To foster that immune response, Scheinberg asked Liu to use Eureka’s human antibody drug discovery platform to make an antibody to the “hot dog-bun” combination of HLA/WT1 that moves to the cell surface. In theory, the antibody would stick to the complex and flag the cell for destruction by immune system cells.
“He asked me if I would take on this highly adventurous project,” Liu says. “I said, ‘Let’s go for it.’ ”
Their experimental human monoclonal antibody, ESK1, killed cancer cells in test tube studies, and also triggered the death of two different types of human leukemia cells in mouse models of the disease, Liu and Scheinberg reported in Science Translational Medicine’s March 13 issue.
If ESK1 shows good results in human trials, Scheinberg says, the drug discovery strategy he developed with Eureka could become a wider platform that could yield antibody drugs against many other cancer-promoting molecules inside cells.
“I think this could be a general approach,” he says.
David Loeb, a cancer researcher at Johns Hopkins, says the novel tactic is worth pursuing. By choosing WT1 as a first focus, the Scheinberg team may be able to produce a drug that is broadly useful across various cancer types, says Loeb, who has studied the WT1 protein for years. And because WT1 is seldom found in normal cells, the drug might selectively kill cancer cells while causing few side effects, Loeb says.
“I think that they picked an awesome target,” says Loeb, director of the Musculoskeletal Tumor Program at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.
Scheinberg says that in the mouse studies so far, ESK1 showed no evidence of toxicity or of binding to normal tissues.
As drug targets, internal cell proteins may have advantages over cell surface molecules, Scheinberg says. Cancer-promoting proteins inside cells are more likely to carry out work needed to keep the cell alive, while some cell surface antigens may merely be markers that identify a cell as potentially cancerous, he says. In addition, internal proteins are more likely to be unique to the tumor, rather than being common in healthy cells as well.
“There’s very little on the outside of a cell that is tumor-specific,” he says.
The exact role of WT1 in cancer is still mysterious, but vaccine studies have shown that its peptides can raise an immune response. Scheinberg has already tried WT1 peptide fragments as an experimental cancer vaccine, which is now in Phase 2 trials in acute myeloid leukemia as a pipeline product of Formula Pharmaceuticals of Berwyn, PA.
Loeb says groups other than Scheinberg’s have also used the peptide vaccine approach to WT1. But the challenge for those drugs is that they depend on sufficiently activating the immune systems of patients whose immune systems may have been weakened by previous rounds of chemotherapy, he says. The advantage of Scheinberg’s new tactic, Loeb says, is that it supplies the body with a pre-made antibody, ESK1, which recognizes the WT1 fragment. This leaves less work to do for a suppressed immune system.
That said, the success of ESK1 in human trials would depend on the health of another aspect of the patient’s immune system, Loeb says. There must still be enough of the circulating immune system cells that can respond to the antibody’s signals and destroy cancer cells. Scheinberg’s team could test levels of these immune cells, called “effector cells,” in patients as it chooses participants in the ESK1 clinical trials, Loeb says.
Before beginning a Phase 1 trial, Scheinberg’s team still needs to do animal toxicity studies and scale up manufacturing of ESK1. But the drug has an advantage that may speed its path to the clinic—it’s already a human form of the antibody rather than an antibody generated from animal tissue that would need to be humanized.
Creating fully human antibodies is the specialty service of Eureka, which was founded in 2006 with venture firm backing of about $4 million to $5 million, Liu says. The small private company draws revenues from biotechnology companies, big pharmaceutical partners, and research institutions, including Memorial Sloan-Kettering. It funded its own part of the work on ESK1.
Eureka finds drug candidates by screening antigens (substances that provoke immune reactions) against a library of 50 billion varieties of antibodies, using a decades-old method called phage display. The company, which has about 20 employees, also creates cell lines to crank out copies of antibody drugs. Liu and Scheinberg say they’ve been creating antibodies for a range of internal cancer-related proteins, in addition to WT1, that have also been seen as inaccessible targets of drug therapy.
If the technique proves successful in the ESK1 trials, it might be worth trying on internal proteins that result from chromosome translocations—an element common in childhood cancers, says Loeb, who specializes in pediatric oncology.
Scheinberg says his team is prepared to conduct the initial round of human safety studies of ESK1 on its own, and is looking for partners to help it advance into the more rigorous, and expensive, series of mid-stage trials that come next. The work on the WT1 antibody has been supported so far by “several million” dollars from the Sloan-Kettering Institute’s Experimental Therapeutics Center and Technology Development Fund, the National Institutes of Health, and six non-profit disease foundations, Scheinberg says. Progress on the experimental drug could speed up if a pharmaceutical company steps in to finance the program before it advances to the second phase of clinical trials, he says.
“We’re in discussions with corporate sponsors,” Scheinberg says. Eureka and Memorial Sloan-Kettering share equal rights to ESK1, Liu says. Scheinberg is one of multiple inventors with a financial interest in the compound.
Liu says he’s excited about the results of the WT1 work, but he also sees it as a general proof of concept that antibodies can work against intracellular proteins. A success in human trials for ESK1 could validate that strategy for a broad class of cancer-promoting proteins inside tumor cells, he says.