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Expanding Single-Cell Technology, GigaGen Moves Forward in Drug Development Market


NEW YORK (GenomeWeb) – Single-cell analysis firm GigaGen has made a sharp turn in its business plans over the last several years from early intentions in the genomic diagnostics instrument space to now seeking to establish itself in drug development and target discovery.

The company's CEO and Co-founder, David Johnson, spoke with GenomeWeb last week about the firm's turnabout in focus and the progress it has made over the past several years in adapting its platform to support collaborations with large pharmaceutical companies, as well as its own internal target discovery and drug development efforts based on immune repertoire sequencing enabled by its droplet-based single cell microfluidic technology.

Early in its inception, Johnson said, GigaGen was aiming to advance its platform as a tool for sequencing immune cells to monitor and diagnose disease. But, he said, the company realized that "even though we had some interesting clinical directions for that, it just wasn’t going to be worth developing in that way … It's too hard to get diagnostics paid for," he said.

Shifting focus, the firm began to develop primer sets built around applications that customers or partners would pay for, he said, zeroing in on the use of immune repertoire sequencing — an analysis of the genomic diversity of T- and B-cells in a patient's overall immune system — as a tool for discovery of novel drug compounds that act on known targets, or for uncovering new targets to support the development of whole new classes of molecularly targeted therapies.

An important step for the company in this shift, Johnson said, was the expansion of its platform from a focus on single-cell sequencing, to a system that now takes the genomic data from that immune repertoire sequencing and uses it to create a synthetic system of matched protein expression.

"We've set up our platform so we can capture entire immune systems as DNA, and then we have a pipeline to express them as recombinant proteins, so we are essentially making synthetic immune systems, taking the entire immune system and copying it as an expression library," Johnson said.

"We get the coding sequences from the immune system and then make protein expression constructs, and go into yeast cells or mammalian cells, and the recombinant cells express the proteins as either a cell surface protein or a secreted protein depending on what you want to do," he explained.

All of this is still supported by the company's initial droplet-based single-cell sequencing technology. "We've kept our initial droplet methods because they are really fast," Johnson said. "It's the only way we could find to do a few million cells per hour."

"A Fluidigm chip can do a few thousand per chip I think now, but immune repertoires are so diverse, and you want to copy it quickly, so droplets was the best way for us to do that," he explained.

Although GigaGen does sell its services to partners in the pharmaceutical industry — with collaborations in the immune disorders, infectious disease, and oncology spaces — the company took an interesting step in also putting its technology to work in house for its own drug development efforts.

One arm of this, Johnson said, is using the platform for target discovery. "The value is relatively low for 'me too' drugs, especially if you look at what's already on the market … With PD-1 antagonists, for example, if you make another one of those it might be on the market in 2025, and it'll be the 13th one."

"That's not stopping anyone," he said, "but if you want to make a bigger impact, there are still something like 2,000 cell surface receptors that are uncharacterized orphans."

Currently, researchers have other tools, like RNA-seq, which allow them to compare tumor and normal tissue, and use bioinformatics analyses to mine for new drug targets, but Johnson said that these approaches miss out on the added complexity of the post-transcription environment where proteins can have different epigenetic modifications.

"Our technology allows you to take an immune system from a patient, sequence it, and make a synthetic version, and then screen against libraries to see what comes up," he said.

In that vein, GigaGen is using its platform to make synthetic versions of dozens of cancer immune systems, trying to get as many samples as possible and screen against libraries of potential targets.

"Once we get hits, we pick out the T-cell receptors and targets and start to characterize them functionally in vitro with the hope that we discover essentially a new checkpoint inhibitor pathway, or whatever it is that comes up," Johnson said.

"It's a bit of a fishing expedition," he admitted. But the company is balancing the risk and uncertainty of that process with a second arm of drug development that is more of a sure thing.

The firm's first actual pipeline candidate is a new form of recombinant intravenous immunoglobulin, IVIG, developed using the company's immune sequence and replication platform.

Patients with primary immune disorders are currently treated with IVIG created by collecting and pooling plasma samples from human donors, isolating IgG antibodies from the plasma pool and processing them to remove impurities and protect against contamination.

By generating genetic immune repertoire maps from over a thousand human donors, GigaGen has been working to isolate and manufacture the IgG sequences to produce the first recombinant form of this therapy.

According to Johnson, GigaGen is currently trying to finance clinical studies for this product with some interest from the plasma suppliers for traditional IVIG.

Also supporting its more exploratory work are partnerships with larger pharma companies, in which Johnson said the company is using its platform both for target discovery, similar to its own internal efforts, and in drug candidate discovery.

"For a long time people were looking at big random libraries of sequences that are not derived from nature at all. … You'd pull down things that bind to the therapeutic target, but then once you do functional assays, they're garbage. They kill the mouse, or they don't work, or something else," Johnson said.

Technologies like GigaGen's allow companies to screen for binders against targets within a narrower context of molecules that are actually active in the body, which makes the process a little more likely to succeed, he said.

Beyond current partnerships, Johnson said that GigaGen recently got a small grant from DARPA to use its platform to support research on the Zika virus. "In a rapid response effort, they essentially want to take the best responders, grab the B-cells, copy them, and find the antibodies that are going to be efficacious against the virus," he said.

As GigaGen advances its own efforts and partnerships, immune sequencing is blossoming as the focus of a number of other companies. Some, like Sequenta, are pursuing the diagnostics applications that initially drew GigaGen into the field, and others, like Abvitro or Atreca are focusing on drug development.