The typical scheme employed when designing site saturation variant libraries
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The best kept secret in drug discovery has a Twist

The importance of protein engineering for a variety of applications, from food ingredients to health care, is no secret. Using synthetic biology tools, we can create increasingly precise and elegant enzymes optimized for countless new and useful functions. Antibody engineering is one of the most critical and promising technologies made possible in recent years, and has the potential to change the lives of millions of people suffering from diabetes, cancer, and other debilitating conditions.

Yet current approaches to designing libraries of engineered antibodies — variants — in an effort to identify those perfectly suited for the disease or cell of interest suffer from a lack of control, lack of coverage, and imprecision, in addition to being time consuming. After spending months creating and testing variants, researchers may come out no further along in their quest because the technology they used failed to produce the key variant they needed. And this means that those most in need of novel drugs must continue to wait for relief.

There is a better approach — one that the community at large isn’t aware of yet. But that is likely to change soon. The lid is about to come off of the best-kept secret in drug discovery.

Precise, unbiased, and rapid antibody variant libraries

The owner of that secret is Aaron Sato, CSO of Twist Biopharma and Vice President of Protein Engineering at Twist Bioscience.

Aaron Sato

You’re probably already familiar with Twist’s revolutionary high throughput silicon DNA synthesis platform, which has decreased the time and cost of gene synthesis for researchers in academia and industry worldwide. Yet the power of the genetic code is realized in the final product: protein. Building upon Twist’s existing technology, Sato’s protein engineering group has, in only a year, grown to a close-knit team of twelve people that have shown proof of concept with a number of technologies — a testament, says Sato, of the speed that they can produce antibody libraries and make a real impact. Much of this success is due to the multiple resources available at his team’s fingertips — such as a large automation team and bioinformatics and software support — not available in traditional biotech companies of Twist’s size.

Their antibody variant library technology is unique in that it is precise, provides unbiased, full coverage of antibody variants, doesn’t introduce stop codons/sequence liabilities, and like all Twist products, uses NGS to confirm and guarantee the antibody sequences. Separate from Twist Biopharma, one of Twist Bioscience’s library proof-of-concept studies, led by David Ӧling and colleagues at AstraZeneca’s Innovative Medicines and Early Development Biotech Unit (and with collaborators at Imperial College London) demonstrated that Twist’s library technology produced 99.9% of the predicted maximum number of amino acid variants compared to ePCR, which yielded only 35%. Several of those identified by the Twist library but not the ePCR-produced library were found to be critical as candidates for potential drug development.

“I think it’s the generation of what we can do [in protein engineering],” says Sato. “I always find the Twist library technologies enable these cool libraries that we’ve always dreamed of making that we could never do because we didn’t have the ability to precisely define each of those sequences. Now we can because we can synthesize so many. In the future, [our] technology will allow scientists to be the creative people that they are, to create new libraries and types of discovery technology that they just couldn’t do in the past.”

Show me the data

It is risky business, to be sure, as the technology is still so new and in the process of being proven out. Sato says that the biggest feedback they receive isn’t criticism so much as lack of confidence in their technology.

“People want to see more data; in order to sell the technology people need to have confidence that it’s going to work, and they get that confidence by seeing the results of what we’re doing,” says Sato. “We just need to continue to do proof of concept studies to show the value of what we do, and I foresee that people are going to get so excited about the technology just like I do that [the feedback] will just address itself when people really understand the value that this brings.”

For now, many of the proof-of-concept studies are being done in collaboration with academic groups, like the Vanderbilt University Medical Center, and smaller companies. According to Sato, small companies are the ideal partners because they are willing to take a bit of risk to try out a revolutionary new technology like Twist’s protein variant library technology. They view Twist as a partner they can work with to find a solution to a problem they don’t know how to solve — whether that be a specific target or a specific cell therapy — which makes such partnerships extremely fruitful.

Empowering life-changing therapies

Yet it’s only a matter of time until big pharma companies begin to recognize the power of their technology, too, Sato says, and their recently announced collaboration with LakePharma will help propel them forward in the space. Through this partnership, Twist and LakePharma will use synthetic antibody libraries to discover novel antibodies that target GPCRs, which are involved in multiple disease classes from inflammation and pain to cancer. In the near future, Twist Bioscience will have additional synthetic libraries for other target classes and LakePharma will use them against other target classes.

This is only the beginning of a new era in medicine, and Twist plans to lead the way.  For example, Twist is uniquely positioned to help companies in the CAR-T therapy space, because the approach depends on antibodies to work. Such companies can use Twist’s synthetic antibody libraries to rapidly discover targeting molecules that they can simply integrate into their CAR T platform. In other words, Twist’s technology is likely to be the engine behind life-changing therapies — and maybe even cures.

Emily Leproust, Twist’s CEO, suggests that her CSO’s best-kept secret for drug discovery will soon be let out of the bag — it’s already on its way out.

“Soon,” she says, “people will realize the power of the technology, which we believe will change the way drug discovery is done and may change for the better the lives of many people.”

Aaron Sato and Emily Leproust will be speaking at SynBioBeta 2019, October 1-3 in San Francisco. Meet the innovators and companies, find new opportunities, partner up and discover the potential of the biological industrial revolution.

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Embriette Hyde

Embriette Hyde

A trained microbiologist with over 7 years of experience in microbiome research, Dr. Embriette Hyde is passionate about bringing science to the public. She is currently working as Managing Editor at SynBioBeta and mentors K-12 students through Schmahl Science Workshops, fostering passion for science from a young age.

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