University of Illinois Chicago scientists have redesigned a treatment for the most common pediatric leukemia to eliminate its severe side effects, like blood clots and liver damage. If approved, the new drug may be tolerated by a broader range of leukemia patients and even be used to treat other cancers.
The team led by UIC's Arnon Lavie created a new form of asparaginase, an enzyme approved clinically for acute lymphoblastic leukemia, the most common blood cancer in children. Using protein engineering, the team designed a new biologic compound that tries to maximize the therapeutic effects of the enzyme while reducing toxicity and harmful responses in the patient.
In a paper in Cancer Letters , Lavie and co-authors from UIC and Ghent University in Belgium reported that their compound successfully destroyed leukemia cells in mice without the common side effects of asparaginase. The new treatment also shrank tumors in laboratory models of additional cancers, such as melanoma and liver cancer.
These encouraging results boost the ongoing efforts of Lavie's research group to bring their novel enzyme to clinical trials. In 2023, the National Cancer Institute Experimental Therapeutics Program chose his company, Enzyme by Design , to perform the preclinical work needed for approval to test the drug in humans.
"I am excited for the opportunity to translate my academic research into a potential treatment that addresses an unmet need," said Lavie, UIC professor of biochemistry and molecular genetics and a member of the University of Illinois Cancer Center. "The reality is that the pharmaceutical industry is primarily interested in de-risked molecules, and our goal is to de-risk our novel asparaginase sufficiently so that it becomes an interesting therapeutic for a company."
Remodeling and humanizing an enzyme
Asparaginase depletes an essential amino acid called asparagine, which some cancer cells — unlike normal cells — can't make. As a result, treatment starves the cancerous cells and kills them, while most normal cells remain healthy, at least in theory.
The FDA approved asparaginase in the 1970s. But its severe side effects mean the drug can only be used in a subset of leukemia patients. Because the drug is derived from bacterial sources, it can cause a strong immune response in some patients, forcing treatment to be stopped. The drug's short half-life also means it must be infused intravenously multiple times per week during treatment to maintain the effective dose.
To solve these issues, Lavie and his research group went back to the animal where asparaginase was originally discovered in the 1950s: the guinea pig. Because the enzymes in mammals are similar to those in humans, the researchers hoped that the guinea pig enzymes would not provoke an immune response in patients.
"We characterized several different asparaginases from the guinea pig to identify the one with highly unique anticancer properties," said Amanda Schalk , a research assistant professor at UIC who has been involved in the project since it started in 2011. "Then we re-engineered it to see if we could make that enzyme even better."
After determining the enzyme's protein structure, the team set out to "humanize" it, substituting components to make it more like the human version.
"The molecular structures told us where we can make changes that would not interfere with the structure, stability or activity of the enzyme," Lavie said. "Then we leveraged the fact that the body is tolerant to human-like proteins, which would allow kids and other patients to successfully complete their cancer treatment."
In making the changes, they serendipitously extended the half-life of the enzyme, which would mean less frequent treatments when used against cancer and reducing the burden on patients receiving the treatment.
"It was a very happy accident, which turns out to be extremely important," Lavie said. "Ultimately, it means that you can treat the patient with a lower dose, and with a longer interval between treatments."
Success in leukemia, potential beyond
The Cancer Letters paper is the strongest evidence yet of their novel enzyme's promise. In an animal model of acute lymphoblastic leukemia, mice treated with the new compound recovered as well as those treated with traditional asparaginase. But asparaginase treatment caused a dramatic loss of body weight — a common sign of toxicity — while the new compound did not.
The team also tested their modified enzyme with models of melanoma and liver cancer subtypes that, like acute lymphoblastic leukemia, produce tumor cells that can't make their own asparagine. In both cases, the redesigned enzyme effectively killed the cancer cells, suggesting its potential to treat certain solid-tumor cancers as well.
The research team is already on track to pursuing clinical trials. After establishing Enzyme by Design with support from the UIC Office of Technology Management , the project has received nearly $4 million in funding, Schalk said.
"It has been incredible to see the progress made from discovery to drug development over the past 13 years," Schalk said. "It's so exciting the further along we get on the path to the clinic to provide life-changing benefits to patients."
Through that support, the group is conducting the toxicity, pharmacokinetic and manufacturing studies necessary for permission from the FDA to begin their first clinical trials.
"After more than a decade, we will finally get the chance to see how the drug performs in humans," Lavie said. "The university has been very supportive of this project, and of me as a faculty member, to try to realize this dream of translating an academic discovery to something that could help patients."
Additional UIC co-authors on the paper included Ying Su, Ashley De Loera, Alyssa Garcia and Hui Chen. The research was funded in part by grants from the National Institutes of Health and the U.S. Department of Veteran Affairs.
