NEW YORK – Swiss startup QGel has developed a series of synthetic extracellular matrices (ECMs) based on biological, biophysical, and biochemical parameters that it believes researchers can use to mimic organs and tumors to test cancer drugs on a variety of cell types outside the human body.
The Lausanne-based firm is in the midst of a $60 million financing round to enter the clinical testing phase and eventually commercialize its technology to offer organoid-based services to pharmaceutical companies to help accelerate drug development.
In order to grow human cells ex vivo, researchers typically use gels derived from animal-based cells. While different animal-derived cells exist for research use, QGel CEO Colin Sanctuary explained that QGel's technology is comparable to a gelatinous protein mixture called "Matrigel." Marketed by Corning Life Sciences and Beckton Dickinson Biosciences, Matrigel is secreted by Engelbreth-Holm-Swarm mouse sarcoma cells and rich in growth factors and other proteins that induce growth of different cell types.
While researchers can use organoids grown in Matrigel for lab work, Sanctuary noted that doctors choose not to apply it to clinical situations because of ethical concerns related to its animal-derived nature and its unreliable reproducibility from batch.
According to Sanctuary, the idea to create non-animal derived biomaterial matrices for cell culture stemmed from his time working at Straumann Group, a Swiss firm that supplies dental instruments and equipment. Originally hired to drive development of the technology for bone regeneration, Sanctuary worked with Jeffrey Hubbell, now a tissue engineering professor at the University of Chicago and lead inventor of the technology, to examine potential research and clinical applications using the gel.
Noticing how several types of cells could grow in the artificial medium, Hubbell and Sanctuary saw that they could manufacture and scale the system to test new drugs on patient tissues. The team cofounded QGel in 2009 with Swiss Federal Institute of Technology professor Matthias Lütolf.
According to Hubbell, the researchers originally sought to mimic how a natural ECM works with completely synthetic components. He explained that ECMs have 3D mesh-like adhesion domains that bind to the target cell's receptors, allowing the cells to migrate by enzymatically degrading the network. By building a synthetic information-poor gel scaffold network, the team wanted to include biomolecules that would bind to the cell's surface.
Hubbell also highlighted that ECMs have certain mechanical characteristics, such as stiffness, that differ depending on the type of tissue.
"Through chemistry, we were able to control gel properties, mechanics, the cell surfaces, and the ability of the cell to degrade or remodel the matrix in three dimensions," Hubbell explained.
Hubbell said that researchers can use the technology to learn if one cancer cell type is more invasive than another type, which he believes will inform researchers how to potentially treat the cancer cell. In addition, researchers can analyze the cells to understand what adhesion receptors they produce, or what enzymes they use to migrate.
"When we first developed them in the context of surgery and bone repair, we were making materials the length of centimeters for lesions and tissues" Hubbell noted. "But when we started looking at cell culture experiments, we scaled the technology down to look at about 1,000 samples in one well that's a few millimeters in length."
QGel is therefore partnering with hospitals to develop curated organoids, as it is encouraging the groups to move away from Matrigel to a fully synthetic, defined, and regulated product that researchers can scale and use for a large amount of patients in a short period of time with improved reproducible results.
Because QGel has hundreds of unique ECMs, Sanctuary emphasized that the firm's technology is not a "one-size fits all solution." He said that QGel asks interested parties to provide information about the types of cells they are working with (such as stem cells or cancer cells), in addition to the type of Matrigel they are using.
QGel then sends the researchers about 100 different gels to test out. Sanctuary noted that his team sometimes requires trial and error to achieve the best combination of mixtures to find an ECM gel for cell development, especially for new cell types.
"If [the researchers] are not working on a strategic interest, such as bone regeneration, we'll give them a gel that we think might work, but they'll need to test it first," Sanctuary said. "When the gels work, [the researchers] send us the results, which we can include in our database of viable ECMs."
On the other hand, QGel usually offers two to three different gels to a partner with a known cell type and performs a "mini trial," which involves a process that incorporates liquid handling robotics.
Sanctuary noted that research groups QGel has partnered with usually request ECMs to grow a variety of cancers for therapeutic testing. While QGel has developed targeted products and protocols to establish patient-derived organoids for pancreas, colon, prostate, breast, and lung tissue, Sanctuary said that several more organs are in its pipeline and that the firm has also developed drug response testing protocols for all organoid types.
However, Sanctuary highlighted that conditions like prostate cancer present issues because the cells develop too slowly for clinicians to develop actionable, effective, and personalized treatment.
According to Sanctuary, the speed to process a customized ECM for a new cell type depends on two major criteria: how quickly or freshly obtained the cells are from a patient, as well as the team's ability to retain the viability in synthetic gels of a biopsy sample. On average, he believes that time needed for his team to identify the right gel formation for a new cell is about two to four months.
In a 2016 study published in Nature, Lütolf and his team at SFIT used QGel's artificial ECMs tool to design intestinal organoids from mouse and human intestinal stem cells. Finding that the technology acted as a well-defined alternative to animal-derived matrices for culturing the organoids, the team noted that researchers could use ECMs to identify designer matrices for long-term culture of other types of stem cells and organoids.
QGel has also encountered issues related to accessing patient samples as it attempts to successfully recreate ex vivo environments for cell survival and growth. Initially looking at pancreatic cancer, Sanctuary's team reached out to hospitals and began requesting access to pancreatic cancer cells.
"It can take 6 to 18 months to collect direct patient specimens, but we need to have approximation models to start doing preliminary testing," Sanctuary said. As such, the firm purchased and worked with patient-derived xenografts, since the material was commercially available and could be tested on right away. "When we finally got our human patient samples, we [therefore] weren't starting from scratch," he said.
According to Sanctuary, QGel has partnered with multiple international hospitals and academic groups that give QGel access to patient samples for research and development purposes. One such partner is Charles Rivers Laboratories, but Sanctuary declined to disclose additional partners due to contractual obligations.
Sanctuary said that QGel follows one of three routes to get its technology in the hands of pharmaceutical customers. The company has signed service agreements where it first receives the customer's cells of interest in a specific ECM. QGel then tests the partner's proprietary drugs and mails back the results.
QGel has also supplied large contract research organizations with its technology so they can in turn offer services to pharmaceutical firms. Sanctuary noted one early partner is Novartis, where it is sending them its gels, which Novartis then sends along with their drug libraries to an academic institute and have them use the gels in drug screens.
Sanctuary said that QGel met with the US Food and Drug Administration in April during a roundtable discussion on regulating in vitro medical diagnostics technology for downstream drug-response applications. While both the US FDA and European Medicines Agency agree that diagnostic test done on live patient cells from the patients must be regulated, Sanctuary said that current market players are figuring out how to interpret and integrate the technology into clinical usage.
"While it's not completely relevant, we [now] have an existing guideline based on genetic sequencing," Sanctuary said. "We are able to leverage off Foundation Medicine's and Tempus' groundwork to see what needs to be included to make sure that sort of diagnostic test and predictive testing is more comprehensive and beneficial to the patient."
QGel currently has nine patent families protecting the biochemistry and formation of the hydrogels, manufacturing methods, and use of gels for testing drugs with the European Patent Office and US Patent and Trademark Office.
Since QGel began in 2009, the firm has raised a total of $20 million to support global expansion, with its most recent $12 million funding round in 2017. Sanctuary said QGel has been funded by angel investors and an undisclosed "high-net worth individual who's been active in the pharma and biotech space their whole career."
Now the firm is looking to raise an additional $60 million to enter the clinical testing phase and work with pharmaceutical firms to help develop and accelerate drug development.In the long term, QGel will use the funds to achieve regulatory approval and have its tests reimbursed by insurance companies to predict drug response.
While declining to comment on the actual price of the QGel's gels for research use, Sanctuary believes the synthetic ECMs are competitive to the prices of gel derived from animals. Noting that the clinical uses for ECMs are still several years away, he compared an eventual cell-based drug screening assay based on the ECMs to current companion diagnostic technology on the market. Sanctuary therefore envisions final pricing as how much the firm would theoretically save the payor in terms of reimbursement.
"It's a lot of money to treat individuals who might not have needed [potential cancer] treatment in the first place, as it's paid for by the healthcare system and will drive up costs exponentially up," Sanctuary argued. "If we can save money and give ethical reasons not to treat a patient and instead give them an alternative treatment, that could save unimaginable amounts, and this is where the clinical data will be so important."
QGel also plans to soon launch a US operation by establishing its own facility in the states.
"Right now, we ask some of our partners to mail samples overnight over the Atlantic," Sanctuary said. "However, we want to take down those barriers and eventually work with an American team."