New protein-based therapeutic tool could change the way we treat diseases

A team of scientists at Kyoto University's Institute for Integrated Cell-Material Sciences (iCeMS) has created a protein-based therapeutic tool that could change the way we treat diseases caused by harmful or unnecessary cells. The new tool, published in Nature Biomedical Engineering, involves a synthetic protein called Crunch, short for Connector for Removal of Unwanted Cell Habitat. Crunch uses the body's natural waste removal system to clear out specific target cells, offering hope for improved treatments for cancer, autoimmune diseases, and other diseases where harmful cells cause damage.

Every day, billions of our body's cells naturally die as part of normal processes. These dead cells are quickly cleaned up by immune cells called phagocytes. Phagocytes act like microscopic vacuum cleaners, spotting dying cells by detecting an "eat me" signal on their surface. Once they recognize that signal, they surround and digest the dead cells in a process called "phagocytosis" or more specifically "efferocytosis".

What we've done is take that natural cleaning system and reprogram it to target living cells that shouldn't be there. We built Crunch by modifying a protein called Protein S, which normally helps phagocytes recognize dead cells. But instead of binding to dead cells, we gave Crunch the ability to recognize specific living cells we want to remove, like cancer cells or overactive immune cells in autoimmune diseases."

Mr. Yuki Yamato, study's first author, Graduate School of Biostudies, Kyoto University

To do this, the researchers replaced the part of Protein S that detects dying cells with a kind of sensor that can recognize unique surface proteins found only on the unwanted cells. These sensors can be designed in an order-made way to target almost any type of cell. Once Crunch binds to its chosen target, it connects that cell to the phagocytes, which then engulf and break it down.

Crunch works like a high-precision delivery tag. It doesn't kill the cells directly. Instead, it labels them in a way that tricks the immune system into thinking they are ready for removal. This makes the body itself clear them out, using processes it already relies on every day.

Professor Jun Suzuki, from iCeMS at Kyoto University, who led the study, describes how they tested the new system. "In mice, we used Crunch to get rid of cancer cells that were made to express specific cell surface protein, so we could track them," says Suzuki. "We also used it to eliminate certain immune cells in a model of lupus, a disease where the immune system attacks healthy tissue. In both cases, the harmful cells were successfully cleared, and signs of disease were reduced." 

The new tool could prove to be helpful for treating certain illnesses. Many current treatments, like CAR-T cell therapy or antibody-based drugs, are useful, but they also have certain limitations. In the case of CAR-T, blood cells are collected from the patient, modified in the lab, and then put back. Crunch, on the other hand, is a protein-based therapy that could potentially be delivered through a simple injection.

Because Crunch's targeting sensor can be modified depending on the disease, it acts like a customizable platform. "We think this could become a new kind of therapy that can be adapted to many conditions. We can also adopt the targeting sensors from antibodies and CAR-T. It's the ecosystem for the various therapeutic tools" says Suzuki. 

The team is now working to make Crunch safer, easier to produce, and more effective in real-life settings. With further research, this technique could open the door to a new generation of treatments that help the body clean up harmful cells in a precise and natural way.