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Horizon Aims to Build Unique Portfolio of Gene Editing Tools While Avoiding IP Woes


NEW YORK – Horizon Discovery is used to making deals for interesting technology. The gene editing firm has built a varied portfolio that includes assets such as recombinant adeno-associated virus editing technology, a license from Sigma-Aldrich for the use of zinc-finger nuclease technology to engineer in vivo disease models, and the exclusive rights to a transposon-based platform with applications in bioproduction, reference standards, and therapeutic development.

Most recently, the company signed two licensing and commercialization deals — with Rutgers University for a CRISPR base editing technology and with biotech startup Mammoth Biosciences for the use of its protein discovery platform — that were meant to provide its customers with access to new and unique technologies and fill in some gaps in its own service offerings.

But unique technology wasn't the only consideration when Horizon was looking for new partnerships — the company was also acutely aware of the intellectual property battles that have become a cause of uncertainty and distraction in the gene editing space, and was looking to make the deals for the best technology with the clearest IP.

In January 2019, Horizon and Rutgers announced that they had signed an agreement to commercialize a gene editing technology developed in the lab of Rutgers Robert Wood Johnson Medical School pharmacology associate professor Shengkan Jin. The base editing platform — which modifies genes by creating single-point mutations in DNA without making double-stranded breaks — has potential applications in the development of new cell therapies and would augment Horizon's research tools and services, the company said at the time.

Horizon planned to collaborate with Rutgers to further develop the technology and work toward commercializing it.

A year later, Horizon said it had exercised its option to exclusively license the base editing technology for use in therapeutic, diagnostic, and service applications. Rutgers has granted the company an exclusive license to the technology, which includes the right for Horizon to sublicense the technology to entities seeking to use it for therapeutic development.

The company is seeking early-access customers to assess the technology and lead its development, which could enable the development of therapeutics that rely on engineering cells either directly in the body or externally before transplanting back into the patient. The technology could also be used in cell therapy programs that require more effective multi-gene knockouts such as CAR-T cells with an improved safety profile.

According to Horizon's Head of Business Operations Paul Brooks, this is the first base editing technology the company has licensed or offered to its customers as a tool or part of a service.

"Horizon has a longstanding interest in gene editing technologies starting with AAV, moving on to zinc finger nucleases, and moving on to CRISPR. And we try and stay abreast of all the technologies which are coming through," he said. "What has caught our attention in the last couple of years was the emergence of base editing. In terms of the way we look at our customer base, we work across the entire drug discovery workflow — we start with customers at the research stages and work with them all the way through bioproduction. And, so, because we are engaging with both biotechnology companies and pharma companies, base editing was a natural technology for us to take to our customer base."

Of course, Rutgers isn't the only university or research institution with base editing technology for which Horizon could have sought a license. The Broad Institute's David Liu pioneered the technique in 2017. But according to Brooks, Rutgers' Jin and his team had what Horizon needed most: a technology with the clearest path to licensing and commercialization.

"During our discussions [with various potential partners], it just became apparent that the Rutgers technology was something which met our needs in terms of what we intend to do with it. Also, they shared a lot of our views on the way this technology should be taken to market and addressing the customer base that we were looking at," Brooks said. "Some of the other technology was not as clear cut in terms of how we could actually commercialize it. Rutgers was the clearest way through licensing and commercializing the technology."

He also noted that the technology's development was at a stage where Horizon will be able to lend its expertise to complete it, keeping in mind the needs of the firm's customers and using its own expertise in the gene engineering space.

Horizon believes that the natural first iteration of the base editing platform, named Pin-point, is as a tool aimed at the cell therapy space. The company is aiming to partner with companies that are developing CAR T therapies, T cells, and other similar products, to validate the platform's performance.

"At some point in the future, we may go after more of the gene therapy space, but in the first iteration, it's staying more in that cell therapy space," Brooks said. "There may be some initial partnerships with select key partners, almost like a beta test for some of the technology, kind of like validating it in the hands of our customers. That probably could take place in about 12 to 18 months, with a view to developing that validation dataset to support it to go out to a wider market thereafter."

On the bioproduction side, Horizon announced in December 2019 that it has signed a deal with Mammoth to develop new CRISPR tools, with the aim of generating new engineered cell lines for the biopharmaceutical industry.

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 protein discovery 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. Horizon will have exclusive rights to utilize this novel bioproduction approach and will also be allowed to sublicense it to other companies for purposes of modifying their own proprietary cell lines.

CHO cells are epithelial cells derived from the ovary of the Chinese hamster and are often used in biological and medical research and commercially in the production of therapeutic proteins. They're also the most commonly used mammalian hosts for industrial production of recombinant protein therapeutics.

According to Brooks, Horizon is hoping that this deal will allow it to provide something new for existing customers and to reach out to new customers as well. The company will use Mammoth's platform to find or engineer new proteins that will allow it to optimize its own CHO cell lines with specific targets to improve productivity, protein production, and other metrics.

"But what you do find with a lot of pharma and biotech companies in the bioproduction space is that they've already got their own CHO cell lines in-house," Brooks added. "And, so, what they will be interested in is potentially modifying their own cell line to improve their performance. We will probably be there for both."

Again, however, when it came time to choose a company to partner with, the legalities of commercialization and IP were a factor for Horizon in making this deal, in addition to Mammoth's unique offerings and the value of its technology.

CHO cell lines "are a standard model, and what the market really needs is the next generation of models," Brooks said. "For the next generation of models you really need to start using gene editing and gene engineering. The challenges you face when you begin to do that is that the IP becomes very murky."

If a company licenses a CRISPR-based technology to engineer a cell line and then sells that cell line, it may become liable for a lot of royalty fees, he added. Instead, Horizon wanted a technology with clear IP, and so it set out to look for a company with just that kind of clarity, "so we could take it to our customers and give them a very clear understanding of what their fees would be surrounding the IP," Brooks said.

The IP issue is the "biggest sadness" in the CRISPR space today, he added. The obscurity of who owns which patent makes it very hard to operate. Brooks noted that the number one item he sees on many wish lists of pharma and biotech companies is to find an alternative to CRISPR-Cas9 in gene editing technology, solely because of the constant back-and-forth IP battles.

Most recently, the Broad and ERS Genomics each had hearings in front of the European Patent Office, in which some of the Broad's CRISPR patents were revoked while some ERS patents were upheld. But the story has gone the other way around in the US, with the Broad rising victorious from numerous court battles, and UC Berkeley vowing to continue the fight.

Though it may seem that companies operating in both the US and Europe may be able to take advantage of the differing rulings to do business with as many patent holders as possible, Brooks said the continued murkiness surrounding the IP has the opposite effect.

"I think at the moment, because of a lot of it is being overturned, everyone's playing it safe," he said. "People don't know what the climate is and it's causing people to hold back."

So, Horizon's strategy remains clear for now, he added. The company wants to add as many unique and cutting-edge gene editing and gene engineering tools and services as possible into its portfolio. It plans to continue engaging with universities, tech transfer offices, and small biotechs to look for those people and companies driving those next technologies.

But it also wants to make sure that it can tell its customers that those tools and services are being offered without the worry of retroactive royalty fees or IP problems.

"If [Horizon] can develop tools and technologies that are cleaner for customers, then I think that's going to resonate," Brooks said. "And, obviously, we're going to benefit from that in terms of growing the business."