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Avalon GloboCare Using Exosome Isolation Platform to Pursue Oral Cancer Dx, Rx Applications

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NEW YORK – Avalon GloboCare seeks to launch a diagnostic tool based on its extracellular vesicle (EV) isolation system, which it believes can extract and separate exosomes from liquid samples in a variety of cancerous conditions.

The company's initial diagnostic application is in oral cancer, for which it is combining its exosome isolation tech with a microRNA biomarker that may be able to predict progression from a potentially precancerous condition to malignancy.  

In parallel the firm is attempting to apply its exosome technology in oral cancer therapy by administering the same biomarker via bioengineered exosomes to minimize the chances of cancer progression or even revert the tissue to a pre-cancerous state. 

Exosomes – a subset of EVs – are membrane-bound bodies produced by cells and shed into the bloodstream and other liquids in the body. Researchers believe that they can potentially measure proteins or nucleic acids much easier by examining exosomes derived from cancer cells than searching for the molecules circulating freely in the bloodstream. 

Founded in late 2016 by CEO David Jin, Freehold, New Jersey-based Avalon has since expanded, acquiring Beijing GenExosome Biotech in late 2017 and later establishing a US-based subsidiary called GeneExosome. The firm partnered with Da An Gene in 2018 to optimize exosome technology, clinical development, and product commercialization. 

Commercialized through GenExosome, Avalon's isolation system applies an ultrafiltration method that uses the size and charge of exosomes to capture them. After collecting a liquid sample such as saliva, plasma, or urine, the firm's researchers incubate it with targeted reagents and perform low-speed centrifugation in order to preserve the exosomes, followed by immunomagnetic separation. 

Jin explained that the platform contains a proprietary semipermeable filter membrane that allows water and other small molecules to pass through, while retaining large molecules such as exosomes and large proteins. The membrane can bind exosomes ranging in size from 30 nm to 200 nm.

Jin also noted that the platform can filter a few drops of a liquid-based sample in 10 to 15 minutes. In addition, he claims that the tool has over a 95 percent purification rate for exosomes and that the filtration mechanism minimizes damage to exosome products. 

"We have developed a series of tube sizes that are commercially available for serum and whole blood, and our kits can hold that small amount and still isolate the cells for biobanking and [downstream] analysis," Jin said. 

Emphasizing that the exosome isolation system is highly scalable, Jin explained that researchers can centrifuge between 30 μl and 1 L of a liquid sample. To process volumes larger than 1 L, Avalon researchers exchange out the centrifuge tool for a vacuum filter to separate the targeted exosomes. 

GenExosome currently markets research-use-only products for serum and plasma, cell culture mediums, and stem cells. 

Avalon is also developing a liquid biopsy assay that uses real-time PCR on harvested EV content to analyze potential disease-specific nucleic acid biomarkers. Jin said that the firm has partnered with Gene Plus and BGI to analyze biomarkers for five conditions, including oral cancer, NASH, leukemia minimal residual disease, colorectal cancer, and macular degeneration. 

Having performed multiple studies looking at oral cancer and miR-185 — an miRNA that has shown potential as a predictive biomarker — Jin explained that his team could potentially use the method on patients to monitor cancer progression.   

If a patient's miR-185 expression level is higher than normal, it might mean that the patient's condition is stable or precancerous. If the level "drops precipitously however," Jin said that "the patient may need to undergo surgery or biopsy immediately to check if the condition has progressed to oral cancer."   

Jin explained that Avalon is targeting EVs instead of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) due to the latter sample types' overall low reliability and stability over time. Arguing that methods that look at CTCs have low sensitivity and specificity, Jin said that many tools also cannot distinguish between CTCs, epithelial cells, and normal cells. 

While acknowledging that ctDNA can be a powerful diagnostic tool, Jin argued that its instability can often lead to inconsistent results. Since ctDNA is derived from dying cells, Jin believes that ctDNA liquid biopsy platforms may not provide a complete picture of the molecular "make-up of a patient's tumor." 

"If you repeat a test using ctDNA within a specific timeframe, you might get different answers," Jin said. "The reason is that once ctDNA is in a patient's bloodstream, it is subject to integration."  

In contrast, Jin believes that using exosomes as starting material produces higher sensitivity and specificity. In addition, he noted that EV-derived nucleic acids can allow researchers to detect RNA expression levels, splice variants, fusions, copy number variations, and epigenetic changes. 

A number of other companies and researchers are applying exosome extraction protocols to develop diagnostic tests. 

One well known example is Bio-Techne, which currently markets a urine-based test called ExoDx Prostate IntelliScore. The technology extracts exosomes and identifies three exosomal RNA biomarkers to help doctors assess whether a patient is a greater risk for high-grade prostate cancer. The firm is also pursuing tests to guide therapy in lung cancer. 

In addition, proteomics firm Tymora Analytical Operations has developed a workflow for isolating EVs and analyzing their protein contents via mass spectrometry, which the company is now using to develop a urine-based test for bladder cancer.

University of Kansas researchers have also developed a microfluidic chip to isolate and analyze tumor-associated exosomes, applying the method on ovarian cancer in a study published earlier this year to identify potential protein biomarkers for early detection. 

Jin believes that Avalon's extraction kits stand out due to the tool's high purification during the proprietary centrifugation step, as well as its ability to isolate and purify exosomes within minutes. In contrast, he argues that other extraction kits damage up to 70 percent of cells during the centrifugation process and require an additional step for purification. Jin also noted that tools developed by other companies require between one to two days to perform the extraction processes. 

Jin said in an email that not only does the exosome isolation system and analysis platform enable researchers to efficiently extract and analyze EV contents such as mRNAs, miRNAs, circular RNA, DNA, and metabolites, but that Avalon also provides nanoparticle tracking analysis of the harvested particles, as "the number and the size of exosome/EVs may impact the specificity and sensitivity of the diagnosis." 

Overall, Jin envisions a convergence will occur in the next two to three years in the liquid biopsy space, where researchers will apply more exosome-based methods to analyze potential biomarkers linked to cancers. Rather than replacing ctDNA-based methods however, Jin believes that exosomes will instead complement ctDNA as an additional material that researchers can use to detect the presence of cancers and other conditions.

Therapeutic possibilities 

Another thing that may set Avalon apart from potential competitors is its parallel pursuit of therapeutic applications for exosomes, starting with the miR-185 molecule in oral cancer. For this application, Avalon is building off recent research that has shown that EVs derived from mesenchymal stem cells may promote therapeutic activity that is comparable to MSCs themselves.

The firm currently has multiple collaborations with academic centers in the US and China. In the US, the firm has begun a codevelopment program with Weill Cornell Medicine to apply its exosome extraction system in a program called Avalon Clinical-Grade Tissue-Specific Exosomes (ACTEX). The firm aims to standardize the bioproduction of stem cell-derived, tissue-specific exosomes as a novel tool to promote tissue remodeling, angiogenesis, and cell proliferation and differentiation. 

The firm also established a joint venture with Nanjing BenQ Hospital for GMP bioprocessing, bioproduction of stem cells, CAR-T, and exosome bio-banking. 

Essentially, Avalon is using stem cells as a "factory" to continually pump out exosomes and collect the intact exosomes for regenerative medicine and to promote wound healing, Jin said. Cells of origin include mesenchymal stem cells (MSCs), endothelial progenitor cells, hematopoietic stem cells, endothelial cells, and neural stem cells. 

Last month, the firm published a study in the journal Artificial Cells, Nanomedicine, and Biotechnology that demonstrated that exosomes derived from MSCs could be used to deliver miR-185 to inhibit progression of potentially malignant oral disorders.

Jin also noted that Avalon completed and later submitted a study this year to an undisclosed research journal on oral cancer in a cohort of 200 Chinese patients. In the study, the researchers monitored patients that either had oral cancer or oral leukoplakia, a premalignant lesion that can lead to oral cancer. 

"Although the etiology of oral leukoplakia is not fully understood, these lesions are often associated with carcinogenic exposures, such as from use of tobacco, alcohol or chewed betel nuts," Jin explained. 

The researchers bioengineered MSCs overexpressing miR-185 in exosomes and then treated both cohorts with the cells. The team found that exosomal miR-185 deterred progression of oral leukoplakia to oral cancer, as well as reversed some cases of oral cancer to a precancerous state. 

Following the publication of the new oral cancer study later this year, Avalon plans to apply for regulatory approval of the miR-185 treatment with the Chinese Food and Drug Administration, followed by an application for full 510(k) commercialization from the US Food and Drug Administration in mid-2020. 

According to Jin, his team filed for IP with the US Patent and Trademark Office for the exosome isolation system — specifically using saliva-derived exosomes to identify miR-185 for oral cancer early diagnosis — in 2017. 

According to Avalon CFO Luisa Ingargiola, the firm has raised a total of $26 million in funding since 2016. The firm raised capital from angel and large Chinese investors, as well as a $6 million financing round led by Roth Capital earlier this year. Ingargiola said that the firm is using the funds to expand GenExosome and other subsidiaries.

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