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Cancer-Fighting Protein Designed to Cut Adverse Effects

Computational biology illustration

(Lawrence Livermore National Lab)

11 Jan. 2019. A computational biology lab designed a synthetic protein that works like natural cancer-fighting proteins, but in lab mice kills cancer cells with few adverse effects. A team from University of Washington in Seattle published its findings in yesterday’s issue of the journal Nature (paid subscription required), and started a company to take the technology to market.

Researchers from the lab of medical school and biochemistry professor David Baker are seeking better treatment options for solid-tumor cancer patients. Potential weapons against cancer recognized for some time are interleukin-2 and interleukin-15, natural signaling proteins called cytokines, that bind to and regulate the actions of white blood cells. Thus, these cytokines can stimulate the immune system to fight tumor cells, but are also blunt instruments in the body, becoming toxic to other cells and functions, particularly in the immune system. Because of these limitations, natural interleukin-2 and -15 are used sparingly, only in last-ditch cases, and where the patient is otherwise healthy enough to withstand the effects.

Earlier attempts to engineer changes to interleukin-2 and -15 proteins to make them less toxic, say the authors, resulted in weaker or less stable variations of the natural proteins. The team from Baker’s lab, in UW’s Institute for Protein Design that Baker also directs, took a different approach, designing a new protein from scratch. Institute for Protein Design is the developer and home of Rosetta software for molecular modeling of proteins that  makes it possible to design large, complex molecular structures, such as cytokines, from scratch, without starting from a known natural protein. The new protein in this case would need to bind only to immune system targets for fighting cancer cells, like natural interleukin-2 and -15, but ignore other cells to minimize adverse effects.

Using Rosetta, the team led by postdoctoral researcher and first author Daniel Adriano Silva, designed a new protein to meet these specifications they call neoleukin-2/15, or Neo-2/15. The new protein is built around a chemical scaffold, with components that bind only to the desired target receptors in immune system cells. In further iterations, they optimized the amino acid sequences to enhance their binding properties, while remaining stable. “Neo-2/15 is very small and very stable,” says Silva in a university statement. “Because we designed it from scratch, we understand all its parts, and we can continue to improve it making it even more stable and active.”

Tests in lab mice induced with melanoma, an aggressive skin cancer, and colon cancer show that Neo-2/15 stimulated the immune system to kill these tumor cells. But the test mice also exhibited few toxic effects and little, if any, unwanted immune system responses. The authors conclude the technology has promise for developing a new class of immunotherapies.

Several of the paper’s authors, including Baker and Silva, founded a spin-off enterprise, Neoleukin Therapeutics, to commercialize the technology. Silva is also the company’s vice-president and research chief. The university applied for a provisional patent, essentially an intent to file for a patent, on the technology, with several of the authors listed as inventors.

Baker tells more about their discoveries in the following video.

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