How engineered protein patches could improve immunotherapy

Scientists at the University of Washington and the U.K.’s Medical Research Council Laboratory of Molecular Biology have designed a flat, two-pronged protein to improve cell signaling. (Ian Haydon, UW Medicine Institute for Protein Design)

Scientists at the University of Washington and the U.K.’s Medical Research Council Laboratory of Molecular Biology have designed a new protein material they say could improve the efficacy of immunotherapies by influencing cell signaling.

The new flat material, formed with two types of protein as building blocks, could thwart the intrinsic ability of cells to control signaling, which could in turn prevent a natural process that limits the effect of immunotherapies, as described in a study published in Nature.

The findings could inspire new treatments for infectious diseases and inflammatory disorders and could also inform the design of future multiprotein materials to modulate cell responses, the researchers said.

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Cell signaling occurs when a cell’s protein receptors on its surface bind to molecules such as drugs, hormones and neurotransmitters. But to ensure the response triggered by the signaling is transient, so it can still work at a later time, cells normally cut off signaling by engulfing the activated receptor and the stimulating molecule in a process called endocytosis.

“This tendency of cells to internalize receptors likely lowers the efficiency of immunotherapies,” Emmanuel Derivery, Ph.D., co-corresponding author of the study, explained in a statement. “Indeed, when antibody drugs bind their target receptors and then become internalized and degraded, more antibody must always be injected.”

To overcome this problem, the researchers designed two protein components that can self-assemble into large, flat patches. Signaling molecules can then be further engineered into the protein scaffolds. Using two or more genetically modified materials made the structure more controllable than those made from one component, they said.

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The team showed that the protein patches can latch onto living cells, activate surface receptors and induce a downstream signal. Changing the signaling molecules would allow the patch to target different surface receptors to work on different cell types, the researchers said.

More importantly, the patch appeared to have resisted being absorbed by cells, and the extent of the inhibition could be adjusted so that it would last for hours or even days by modulating the patch size, according to the bioengineers.

Modified proteins have been tested as solo treatments themselves or as combinations with drugs. The University of Washington’s David Baker, Ph.D., the other co-corresponding author of the current study, co-invented an artificial protein that could be switched on and off to degrade a protein of interest as it responded to cues from the cell’s environment. The team suggest that the technology, called degronLOCKR, could enable treatments to be delivered at just the right time in the right amount.

The ability of new, 2D protein patches to shut down endocytosis could help extend the efficacy of signaling-pathway antagonists, the researchers suggested. And, “the ability to assemble designed proteins around cells opens up new approaches for reducing immune responses to introduced cells, for example in therapy for Type 1 diabetes,” they wrote in the study.