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Mammoth Biosciences Enters New Phase of Business Strategy With Horizon Deal, $45M Fundraise

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NEW YORK – Less than two years after coming out of stealth mode, biotech startup Mammoth Biosciences is aiming to take the CRISPR-Cas nucleases in its portfolio and turn them into products.

Earlier this month, the company — which was cofounded in 2018 by University of California, Berkeley CRISPR researcher Jennifer Doudna — signed a collaboration deal with Horizon Discovery to identify and optimize novel proteins owned by Mammoth in order to develop engineered cell lines.

The companies are planning to a create a new generation of genetically engineered CHO cells for the production of biotherapeutics such as therapeutic antibodies. Horizon's bioproduction business unit currently offers a CHO cell line and customized services to the biopharmaceutical industry to facilitate the development and identification of best-performing gene-edited cell lines. Under the terms of the agreement with Mammoth, Horizon will have access to Mammoth's CRISPR platform, and the companies will collaborate to optimize certain CRISPR tools to rapidly develop proprietary CHO cell lines in which selected genes will be knocked out to improve performance parameters such as productivity or purification.

In the wake of that deal, the company announced that it had closed an oversubscribed $45 million Series B financing round. Mayfield, NFX, Verily, and Brook Byers participated in the funding round, which was led by Decheng Capital. Mammoth has raised more than $70 million in funding to date.

Not long after coming out of stealth mode, Mammoth spoke about its plans to create a CRISPR-based disease detection platform that could have both at-home and hospital-use versions, using Cas12 and Cas13 to look for DNA and RNA to detect various diseases. In March 2019, the company was able to add the newly discovered Cas14 nuclease to its portfolio, giving its disease detection platform a putative edge over similar technologies, thanks to Cas14's exceptionally small size and lack of need for a specific protospacer adjacent motif (PAM) in order to bind or cleave a target DNA sequence.

The company's early focus seemed to be on diagnostics. At the time the company licensed Cas 14, Mammoth CEO Trevor Martin noted that the platform would be able to utilize any CRISPR-Cas protein with a purpose, and that Cas proteins could be multiplexed to detect several nucleic acids, or even DNA and RNA, simultaneously.

However, in addition to developing its own disease detection platform, the company has also been actively engaged in protein discovery efforts to look for new and novel Cas nucleases that it can use or engineer. Those efforts have started to pay off, with the Horizon deal as an example.

"This is the first public announcement we've made around leveraging these novel nucleases we have access to, like Cas14, for areas outside of diagnostics — in this case, cell manufacturing lines," Martin said in an interview. "From the very beginning, we knew that many of our novel nucleases had really interesting and useful properties outside of diagnostics, in areas like therapeutic and gene editing. And of course, our protein discovery pipeline is constantly producing proteins with uses in both diagnostics and therapeutics."

The firm's protein discovery process utilizes an in-silico approach to search metagenomic databases and analyze them with machine learning algorithms to search for CRISPR or CRISPR-like systems. High-throughput in vivo screens are then used to identify the CRISPR protein characteristics and functions.

According to Martin, the discovery of Cas14 is the most obviously successful example of that discovery and characterization pipeline — the first author on the Science study on the discovery of Cas14 was Lucas Harrington, who was then a researcher in Doudna's lab and is now a Mammoth cofounder and the firm's chief discovery officer. But Martin also noted that the company's pipeline has produced many other proteins that can't currently be made public.

"We think [these proteins] are really enabling those next-generation novel uses," he said. "To use the example of Cas14, there one of the properties was, of course, that it has this diagnostic capability that's very useful. … But also, from the moment that we had characterized and developed it, it was clear that this would be extremely exciting for therapeutic applications."

'Have your cake and eat it, too'

The deal with Horizon is likely not the last one Mammoth will make in the therapeutics space. A big part of its protein discovery and development pipeline involves the ability to tailor nucleases for specific applications.

"We definitely aren't as interested in just random parameters that might exist in a vacuum," Martin said. "But anytime we're looking at a partnership, for example, we're looking at what are the product requirements, and then we can tailor the discovery process to those requirements."

In diagnostics, for example, that would require looking at whether a nuclease would need a certain time of activity or a specific temperature in which it would need to operate. And in therapeutics, the company is looking to focus on finding or engineering nucleases that would facilitate in vivo editing.

Right now, most gene editing-based therapeutics are applied ex vivo, which has implications in time, cost, and risk to the patient, Martin said. And while Cas9 has many advantages as a possible therapeutic agent, it has limitations for in vivo editing, such as its size.

"Novel nuclease like Cas14 can have distinct advantages. The most immediate one is the size — it can be around a third the size of Cas9 or less," Martin said. "So, that's extremely exciting in terms of enabling delivery techniques that either weren't as efficient or weren't even possible at all before."

He also noted that novel nucleases can have PAM requirements that are different than Cas9, allowing for more precise targeting of DNA, or fewer off-target effects.

"What's really exciting is that we've identified nucleases that have increased targeting ability so you can target more places in the genome, but it doesn't come at the cost of having more off-targets," he noted. "It's not just going everywhere in the genome, and that's why you can target more places. You can kind of have your cake and eat it too.

"On that front, I think it goes back fundamentally to our strategy, which is starting an unbiased search through all sorts of metagenomic data really looking for new CRISPR or CRISPR-like proteins, " said Martin. "And when you have that kind of as your starting point for your development, you can really start to build proteins that have these really interesting functions where you're not robbing Peter to pay Paul, which is kind of what you have to do when you're doing just standard protein engineering starting with something like Cas9 and you want to target more places but maybe you get more off-target effects."

Because of the seemingly obvious benefits the company expects to keep reaping from its protein discovery and characterization pipeline, Mammoth plans to spend some of the proceeds from its recent fundraising to continue and expand that effort, and then pursuing partnerships similar to the deal with Horizon to find the best ways to use whichever nucleases they may discover.

"[CRISPR protein discovery is] what we're the world's best at. I think we'll continue to be," Martin said. "Partnering with a company like Horizon, or other partners that we'll be announcing over the next few years, really allows us to actually pursue this strategy, because there's no way that as a startup we'll be able to bring products to market in all these different areas by ourselves. What's exciting about the Horizon deal is that they are world leaders in this specific vertical that we're not experts in."

Mammoth doesn't have a specific timeline for rolling out further partnerships with other companies, Martin added, but he noted that the company is in active conversations with firms in both the diagnostic and therapeutic spaces.

The company is also planning to use part of the funding it just raised to continue the development of its disease detection platform and push it into clinical trials.

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