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5:48 PM
Jul 25, 2019
 |  BC Innovations  |  Product Development

Institute for Protein Design's de novo revolution

How a Seattle hub is overhauling protein- and cell-based therapies by breaking free of evolution's constraints.

Seattle's Institute for Protein Design is growing an army of spinouts that build proteins from the ground up. With applications ranging from multivalent vaccines and synthetic cytokines to precision cell therapies, these companies could put de novo designed proteins on the map and bring forth a new generation of biologics.

"If we're successful, then the whole way biologics are made could change a lot in the next ten years. But I think currently, we're kind of on the fringe," said David Baker, who directs University of Washington’s Institute for Protein Design (IPD) and is a professor of biochemistry and a Howard Hughes Medical Institute investigator.

IPD's core technology is Rosetta, a computational platform for modeling, predicting and designing protein structures.

Rosetta's lowest hanging fruit are in optimizing the structures of existing proteins. But the platform is increasingly being used for de novo protein design: making fit-for-purpose proteins that are completely unrelated to any proteins that have evolved in nature.

Using Rosetta, researchers can identify a structure corresponding to a desired function, then find an amino acid sequence that readily and stably folds into that structure because it is the lowest free energy state for that sequence.

"Almost all biologics design that's done is by selection. Either you identify a naturally occurring protein, or an antibody that you elicited in a mouse. There's almost no design based on things like the concept that proteins fold to the lowest energy state," Baker told BioCentury.

De novo protein design can tailor biologics to exact size and polarity specifications, enabling researchers to create finely tuned agonists and antagonists, drug delivery vectors, vaccines, macrocycles, diagnostic sensors and synthetic biology circuitry.

The biggest risk is immunogenicity, since the proteins are foreign by definition. But according to Baker, animal models suggest the issue can be avoided by staying within certain biophysical parameters. "So far, it seems like if you're really stable, really soluble and not too big, you kind of go under the radar, but they haven't gone into a human yet."

At least nine companies have spun out to commercialize drug development technologies developed or co-developed at IPD. Two of these are single-asset companies, three are tools companies and four are therapeutics platform companies exploiting de novo protein design. The most advanced is PvP Biologics Inc., whose single asset is in Phase I testing for Celiac's disease.

"IPD is this platform in a basic research sense for de novo protein design, and then you have investigators that pursue more narrow applications of that and spin out companies, which can be platforms unto themselves," said Bryan White, founder of Sahsen Ventures and a member of IPD's advisory board.

De novo translation

According to Baker, the biggest hurdle for translating de novo protein designs is going from prototype to product. The iterative nature of the protein design process and lack of anchor to existing proteins means there is more uncertainty in the hit-to-lead optimization process than is typically the case...

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