The "mask" cancer drug activates as soon as it reaches the tumor to reduce side effects

The “mask” cancer drug activates as soon as it reaches the tumor to reduce side effects

Many cancer treatments are notorious for brutalizing the body; They attack healthy cells at the same time as they attack cancerous cells, causing a large number of side effects. Now, researchers at the University of Chicago’s Pritzker School of Molecular Engineering (PME) have designed a way to prevent a promising cancer drug from wreaking such havoc. The team has engineered a new “disguised” version of the immunotherapy drug interleukin-12 that is activated only when it reaches a tumor. The research on the molecule, also known as IL-12, is described in the journal The nature of biomedical engineering.

“Our research shows that this masked version of IL-12 is safer for the body, but it has the same anti-tumor efficacy as the original,” said Aslan Mansurov, a postdoctoral research fellow and first author of the new paper. The IL-12 engineering work was conducted with Jeffrey Hubel, the Eugene Bell Professor of Tissue Engineering, who co-led the immunoengineering research topic at PME with Professor Melody Schwartz.

Overcoming toxicity

Researchers know that IL-12 activates lymphocytes and immune cells that have the ability to destroy cancer cells. But in the 1990s, early clinical trials of IL-12 were halted due to severe toxic side effects in patients. The same immune activation that started a chain of events killing cancer cells also led to severe inflammation throughout the body. IL-12, at least in its natural form, has been shelved.

But Mansurov, Abel, Schwartz, and their colleagues had an idea to activate the potential of IL-12. What if the drug infiltrated through the body without activating the immune system? They designed a ‘masked’ molecule with a cap that covers the section of IL-12 that normally attaches to immune cells. The cap can only be removed by tumor-associated proteases, a group of molecular scissors found near tumors to help them degrade surrounding healthy tissue. When the protease cuts the cap, IL-12 becomes active, able to stimulate the immune response against the tumor.

“Masked IL-12 is largely inactive everywhere in the body except at the tumor site, where these proteases can unmask,” Mansurov explained.

take off the mask

The researchers conducted a series of experiments that showed that the masked molecule did not cause the inflammation attributed to unmodified IL-12. In fact, when they tested the effect of engineered IL-12 in colon cancer, they found that the drug completely eliminated the cancer cells. In breast cancer models studied in vitro, masked IL-12 was more effective than anti-PD1 antibodies, an immunotherapy commonly used in humans.

To further explore the new drug’s potential benefit in treating humans, Mansurov and colleagues turned to melanoma and breast cancer biopsies collected and donated from patients. The team wanted to make sure that human cancers contained high enough levels of tumor-associated proteases to detect IL-12. Indeed, when the engineered IL-12 was exposed to biopsy samples, its molecular mask took off, unleashing its full immune power.

“For decades, the field has hoped that IL-12 might one day become a viable treatment in the fight against cancer, and we have now shown that it is possible,” Mansurov said. “We’d like to translate this molecule into the clinic and are now talking with a number of potential partners to make that happen.”

While introducing this new development to patients will take some time, it is clear that a new treatment is on the horizon.

“Our goal at the Pritzker School of Molecular Engineering is to provide solutions to some of humanity’s biggest challenges. Immunological engineering is taking an interdisciplinary approach to research, allowing us to develop new ways to fight disease,” Hubel said. “This is a very promising development for those battling cancer.”

Reference: Mansurov A, Hosseinchi P, Chang K, et al. Masking the immunotoxicity of interleukin-12 by incorporation into a domain of its receptors via a cleavable tumor–protease linker. Nat Biomed M. 2022. doi: 10.1038/s41551-022-00888-0

This article has been republished from the following Materials. Note: The article may have been modified for length and content. For more information, please contact the mentioned source.

2022-06-06 08:30:00

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