Clarity in cell line development

A bright future ahead for cell line development in China

Andy Tsun
Dr Andy Tsun, Co-Founder & VP of Discovery Biology at Biotheus Inc

China has experienced rapid economic growth over the last ten years. Thanks to economic reforms in 1978, the country has experienced an explosion in productivity, capital investment and in the upskilling of its workforce[1]. Per capita GDP for each Chinese citizen has nearly tripled since 2008, according to a recent report[2], while college admissions have risen by more than 10% over the same period[1].

The life science sector in China has also seen dramatic growth. According to the same report[2], venture capital investment in life sciences had risen to 53 times its 2008 level by 2018. M&As, partnership and other activity also rose by record amounts over the same period.

A key emerging market is biologics, which includes monoclonal antibodies (mAbs) designed to treat conditions, such as autoimmune diseases and cancer. MAbs use clones of the same cell, called cell lines, to manufacture the drug product. With Chinese companies rushing to manufacture new therapeutics as well as copies of existing off-patent drugs (biosimilars), developing new cell lines and having them accepted for use in products is increasingly important.

A key part of bringing a biologic to market is convincing the National Medical Products Administration (NMPA), formerly known as the Chinese Food and Drug Administration, that each cell line is derived from a single cell origin. It’s here that Solentim’s VIPS™ (verified in-situ plate seeding) system has an important role to play.

A future of innovation

Among the earliest landmarks in the growth of Chinese life science was WuXi PharmaTech, which in 2007 completed a $70 million IPO on the New York Stock Exchange. By late 2018 the Company, now known as WuXi AppTec, had raised $1 Billion in its Hong Kong listing and had market capitalisation of $17.5 Billion[2].

WuXi PharmaTech IPO’d as a contract research organisation (CRO) providing low-cost chemistry-based services to international pharmaceutical companies. Today, however, the focus has moved onto biology-based products, especially biosimilars. According to Dr Andy Tsun (pictured), Co-Founder and VP of Discovery Biology at Biotheus Inc, these copies of existing off-patent drugs were the traditional focus of Chinese biotech, but today companies are moving towards finding new drug targets as well as developing novel biomolecules.

“There are still large local companies who are interested in developing biosimilars,” he explains, “But that’s slowly changing.” In the future, he expects companies to move towards developing novel drugs and modalities, such as cell and gene therapies, and finding new drug targets, to remain competitive. Funding for new start-ups, for example, has cooled over the last year as investors wait to see how the market develops. “We’re in a contraction period because many companies are developing similar programs and investors want to see how everything will pan out,” he explains.

In contrast, Biotheus Inc., founded in 2018, was fortunate with their initial financing because they are working on novel antibody-based products and hope to look at novel targets in the future. As Dr Tsun explains, “we secured two investment rounds in one year because investors were comfortable with our strategy. We have the right team and a record of discovering and developing drugs in China.” The company officially commenced operations in April 2018 and secured 15 million US dollars of seed funding a month later.

Expanding the reach

Another key trend, according to Dr Tsun, is that international pharmaceutical companies are increasingly seeking a strategic presence in China. Companies, such as Sanofi, have moved R&D labs to China to benefit from the relatively untouched market, as well as for drug development and commercialisation. While at the same time some Chinese companies have moved research labs to the USA to benefit from scientific talent. For example, WuXi AppTec has established a large site in Philadelphia for gene therapy and interestingly purchased a Solentim VIPS system very early on for stable producer cell lines. “The best translational scientists and clinicians are in the US,” Tsun says. “They collaborate [with Chinese companies] to produce the best possible protocols for clinical trials.”

Within China, the rapid growth of life sciences has saturated the biotech capacities of the first-tier cities, such as Shanghai and Beijing. Shanghai was the first city in China to have a biotech hub, and benefits from excellent universities and a skilled workforce, but Dr Tsun explains the focus is now turning to a wider range of areas, such as the biotech park built in Guangdong province.

The Government’s Thousand Talents plan to attract Chinese scientists back to China is also helping to build biotech opportunities in second-tier cities, explains Dr Tsun. “In a large city, such as Shanghai and Beijing, there’s been a huge push for these initiatives, and they’ve attracted some very good scientists from overseas. And, because of second-tier cities turning into first-tier cities and wanting to build up their biotech presence and parks, there is still an enormous space for biotech to expand in China.”

Accelerating Commercialisation

Traditionally, Chinese biotech was hindered by slow drug approval and barriers to start-ups commencing manufacture, according to a 2018 report by investment bank Goldman Sachs[3]. However, the NMPA has now made huge efforts to follow US FDA practices to ensure a more efficient drug approval process, the report claims.

Among the key reforms are shorter approval times for clinical trials and accelerated review for therapies that address an unmet medical need. The CDFA has also introduced faster approval for drugs already approved in the USA.

Critical to getting NMPA approval for biologics is providing the assurance of clonality of cell lines. This involves ensuring that cells used to generate biologically-derived drugs are of clonal origin to guarantee the consistency, efficacy and safety of the finished product. In the US, the FDA will approve a cell line for manufacturing mAbs or other biologics based on a single round of cloning combined with imaging, rather than a statistical expectation based on two rounds of limiting dilutions.

In China, Dr Tsun explains, no company has yet filed an Investigational New Drug (IND) application for a clinical trial based on a single round of cloning. However, he believes the regulatory environment is changing and plans for Biotheus Inc. to be among the first to submit an application with one cloning round.

“I think it’ll become more common in the future,” he says. “The NMPA will observe what’s happening around the world and the US FDA is often seen as a barometer for assessing the risks and approvability of biologics projects. So, if one round of cloning gives the necessary assurance and is satisfactory elsewhere, then there is a higher likelihood this will be adopted in China; the first company to test the waters would accelerate this adaptation.”

The Solentim difference

Out of five mAbs approved to date by the NMPA, four of these use the Solentim Cell Metric® or Cell Metric CLD whole-cell imaging systems to provide assurance of clonality. Dr Tsun himself used Cell Metric imaging systems at a previous company and views them as the best on the market.

“A lot of companies are using imagers, but – for cell seeding – the alternatives are limited dilution or fluorescence-activated cell sorting (FACS),” he says. “Rapid throughput and high efficiency are a challenge when ensuring clonality” When he co-founded Biotheus Inc., they decided to purchase a Solentim VIPS and, he adds, “the high efficiency single cell seeding function of the VIPS helps with throughput.”

He likes the VIPS system due to reliability, cost and because VIPS is unique in that it fully integrates single cell isolation and whole-well imaging into a single convenient system. “Before we bought the VIPS, we were using a VIPS demo unit. And, before we used the demo unit, we didn’t have cell-line generation capabilities in house,” he explains. “A company like us doesn’t have the luxury of multiple liquid handlers and robotics, so having one system that can carry out both these tasks and combine the images into a Clonality Report, helps us a lot.”

NMPA – new changes

The NMPA will be replaced by the State Drug Administration in a new proposal submitted for final approval. According to Biocentury, the new entity will not be responsible for food administration, allowing the regulator to focus more on medical technologies. The proposed changes are designed to raise China’s drug regulations to international standards.

References

[1] https://www.forbes.com/sites/peterpham/2018/03/06/is-there-a-secret-growth-hormone-added-to-chinas-economy/#6b628eb23f13

[2] China life science investment and partnering activity: A 10-year retrospective 2008-2018. ChinaBio® Group.

[3] China Biotech Primer: Equity Research. The Goldman Sachs Group Inc. June 15, 2018