NEW YORK – University of Edinburgh spinout BioCaptiva is getting ready to test its novel cell-free DNA isolation technology for the first time in human studies. The approach is designed to work with apheresis machines, a technology traditionally used to treat blood disorders by extracting, manipulating, and reintroducing blood in a continuous, closed loop.
The company believes its BioCaptor device can isolate orders of magnitude more cell-free DNA than what current methods get from a standard blood draw, offering an increased chance of detecting tumor DNA fragments at low concentrations.
Developed by Tim Aitman, director of Edinburgh's Center for Genomic and Experimental Medicine, and chemical biology professor Mark Bradley — both now members of the company's board — the BioCaptor device is an apheresis column, "similar to the fuel filter in the fuel line of a car," according to BioCaptiva CEO Jeremy Wheeler.
Inside is a substrate with a large surface area that is coated with a polymer that captures cell-free DNA through electrostatic forces and hydrogen bonds. This material is "tuned" towards unbound DNA of a certain size, such that the device captures only cell-free DNA and no other blood components.
The company is not alone in experimenting with apheresis in the context of liquid biopsy. Investigators from the UK's Institute for Cancer Research, for example, have explored the approach to overcome the low prevalence of circulating tumor cells in prostate cancer.
But Wheeler said that both BioCaptiva's polymer technology and the application of apheresis for capturing cfDNA are IP protected.
From the early days of liquid biopsy research, investigators have bemoaned the fact that early-stage cancers and even advanced cases of certain tumor types shed only minute amounts of DNA into the blood.
"The scarcity of mutant cfDNA in circulation is a real challenge … especially when we are talking about detection of early-stage, localized disease," said Victor Velculescu, a professor at Johns Hopkins Medicine and cofounder of liquid biopsy startup Delfi Diagnostics, in an email.
This means that with the amount of cfDNA obtained from a standard blood draw, it can be difficult, even impossible, to detect ctDNA mutations in early-stage or otherwise low-DNA-shedding tumors. "Reliance upon a 10-milliliter blood draw as the source of your cell-free DNA [means] an absolute hard stop about how far you can go," Wheeler added.
To overcome these challenges, companies like Delfi and others have worked on methods for more sensitively detecting cancer, either through error correction and signal boosting techniques, or by targeting different analytes, like DNA methylation, rather than DNA mutations.
BioCaptiva hopes to provide a boost from the opposite side, by isolating a much larger amount of cfDNA upfront, which presumably would include a larger number of tumor DNA fragments — making their detection and characterization easier.
"Right now … we have companies spending billions and billions of dollars of sharpening the razor blade of what to do with the tiny, tiny amounts of ctDNA; finding the needle in the haystack. But the idea that we've taken forward is, 'what if we changed the rules? What if we took a bucket of needles and threw them in the haystack so that if you put your hand into that haystack, you come out looking like a porcupine?'," Wheeler said.
In terms of applications, the company doesn't see BioCaptor being implemented in cancer screening, even though that is one area where low levels of ctDNA are known to confound liquid biopsy tools, because performing apheresis in a screening population just wouldn't be practical.
However, Wheeler said the device might find use in follow-up testing for individuals with a positive screening result. Or, the company believes, in the post-treatment setting for monitoring patients treated with curative intent for recurrence of their tumors.
BioCaptiva hasn’t published any data in the peer-reviewed literature, but Wheeler said that tests run in its lab and in vivo work in animals has demonstrated an ability to capture significantly more cfDNA than a single blood draw.
"We're looking at 100 times more cell-free DNA than you would typically get," he said.
The company plans to begin its first human trial this year and has had early discussions with the US Food and Drug Administration about regulatory clearance. The company hasn't disclosed what institutions it will work with but the study will be in healthy subjects, designed to verify that what investigators have seen in animal studies can be replicated in humans.
The company doesn't intend to develop BioCapture as a cancer diagnostic, but will pursue clearance for the device itself, which hopefully would then be taken up by liquid biopsy companies.
Wheeler said he has been busy discussing the technology with diagnostics firms, commercial labs, and others. Once the first in-human data is available later this year, the plan is to identify specific indications the firm might target in future clinical trials for regulatory purposes.
Another path forward could be catching the attention of apheresis companies, where the BioCapture device would become part of a larger platform menu.
Compared to a syringe and phlebotomist, apheresis is obviously "a bit more expensive," Wheeler said, with a similar price point to CT scans, and a several-hour time requirement. But if the device stands to improve early cancer detection, the overall economics are still favorable, he argued, considering the savings to the healthcare system in reducing the need for expensive late-stage cancer treatments.
For any of this to be realized, BioCaptiva will need to show not only that BioCapture can isolate large amounts of cfDNA, but also that this leads to better detection of tumor fragments within that sample.
Considering how far investigators have been able to push ctDNA detection using regular phlebotomy and advanced sequencing techniques, it's possible the field might not recognize enough added value by boosting cfDNA amounts.
Velculescu said Delfi believes its fragmentation-based method can overcome a large degree of the ctDNA signal challenge on its own.
Other leaders in the liquid biopsy field also expressed caution, saying that absent published data, while having more cfDNA molecules is inarguably a good thing, it's unclear whether an apheresis capture technology would be practical or transformative.
Wheeler said the company expects to have data in hand from its initial trial of the device in healthy volunteers by the end of this year.