WuXi Advanced Therapies (WuXi ATU), the advanced therapies business unit of WuXi AppTec, is a Contract Testing Development and Manufacturing Organization (CTDMO) that offers integrated platforms to transform the discovery, development, testing, manufacturing and commercialization of cell and gene therapies. The company offers its customers an end-to-end solution for cell and gene therapy development, spanning early pre-clinical discovery to GMP manufacture and commercial lot release.

WuXi ATU’s headquarters are located in Philadelphia’s Navy Yard. In recent years, the CTDMO has expanded to add plasmid, viral vector and cell therapy manufacturing and testing facilities in Wuxi City and Shanghai, a research facility in Oxford through the acquisition of OXGENE in 2021, and it also recently entered a collaboration with the A*STAR Biotechnology Institute in Singapore.

In this Q&A, WuXi ATU’s chief executive officer, David Chang, discusses some of these key recent events, as well as cultivating a culture of success and general market trends impacting contract organizations operating in the cell and gene space.

Contract Pharma: How would you characterize the culture of WuXi ATU?

Chang: At WuXi ATU, we’re passionate about improving and accelerating patient access to the cell and gene therapies that could change, or even save, their lives, which we do through long-lasting and meaningful partnerships with our customers. We’re a fast-paced and dynamic organization that is extremely ambitious in pursuit of our goal, and always putting the needs of the patient and customer first.

We have an excellent team at WuXi Advanced Therapies, who are all working hard to help us achieve this ambition. As CEO, I believe that people do their best work when they’re enthusiastic about the company they work for, so I try to make WuXi ATU an employee centric organization that our team enjoys working for, where a friendly, inclusive and supportive environment empowers them to do their best work for our customers to deliver more accessible ground-breaking therapeutics to patients as quickly as possible.

CP: It’s been a little more than a year since you closed the OXGENE acquisition deal. Tell us a little about OXGENE, what they bring to the table and what it means for WuXi ATU moving forward?

Chang: OXGENE specializes in manufacturing innovations and discovery research. They have significant in-house expertise in viral vector design and engineering and cell line development, as well as in the development of innovative and scalable manufacturing solutions. Combining OXGENE’s discovery and pre-clinical expertise with WuXi ATU’s GMP manufacturing and testing platforms allows us to offer our customers an integrated, end-to-end solution all the way from construct optimization to commercialization.

Furthermore, bringing OXGENE’s scalable manufacturing solutions—like TESSA technology for plasmid-free AAV manufacture or LentiVEX producer cell lines—onto WuXi ATU’s GMP manufacturing platforms will ultimately reduce the high manufacturing costs currently associated with cell and gene therapies, which we hope will start to make these treatments more cost effective for patients and health authorities.

CP: You recently opened a new cell and gene therapy testing facility. What can you tell us about how it enhances your capabilities as an advanced therapy services provider? What about the facility is unique and sets it apart from other cell and gene therapy service providers?

Chang: Our new advanced therapies testing facility in Philadelphia’s Navy Yard gives us an additional 140,000 square feet for cell and gene therapy testing, tripling our overall testing capacity, and ensuring that we are ready to support the growing demand within the cell and gene therapy industry. WuXi ATU has significant expertise in assay development, biologics safety testing, viral clearance and commercial lot release assays, and we are proud to bring that knowledge to our customers; R400 significantly enhances our ability to do just that.

CP: On the technology front, WuXi ATU recently launched an AAV vector suspension platform for advanced therapy companies. What can you tell us about this technology and how it enhances your capabilities?

Chang: AAV based gene therapies are increasingly being developed for systemic indications and those with large patient populations, in addition to localized conditions and rare diseases. But these indications require larger quantities of AAV, which means that employing a scalable manufacturing process is key. Switching from adherent to suspension culture is an important step in scaling up the manufacturing process, and we’ve developed a platform for this, that is designed to provide all components, processes, and testing requirements to support customers from regulatory filing through to clinical development. 

The advantage of a platform approach is that every step of the manufacturing process, from use of a high-producing HEK293 clonal cell line and OXGENE’s high-performance reconfigured AAV plasmids, to pre-validated upstream and downstream processes, has been carefully optimized to increase viral titers and quality. The process is predictable and the results reliable; each step is noted in the batch record, ensuring transparency throughout all manufacturing steps. The platform approach also saves significant time and costs when it comes to staff training and technology transfer, since manufacturing staff are well versed in the platform process. Furthermore, Bills of Material, batch records, technology transfer documentation and sample and testing plans are integrated into the platform, streamlining the GMP manufacturing process considerably.

CP: What are some other company highlights from the past 12 months?

Chang: We recently published a paper in Nature Communications about our Tetracycline-Enabled Self-Silencing Adenovirus (TESSA) technology, which we are very excited about. This is a method for manufacturing rAAV using gene modified adenoviral vectors instead of plasmids—solving many of the scalability challenges and manufacturing bottlenecks for the gene therapy industry in a single stroke. With TESSA technology, all the genetic elements needed to produce rAAV encoding the gene of interest are integrated into two separate adenoviral vectors. These have been modified so that they can provide all the help necessary for AAV replication but can’t produce adenoviral structural proteins. This results in high yields of very infectious rAAV.

At the same manufacturing scale, TESSA technology produces significantly higher yields of more infectious rAAV than plasmid-based manufacturing processes (the exact fold change depends on serotype, but in most cases the yield is at least ten-fold higher than using standard AAV plasmids). However, the additional scalability advantage is that as well as producing higher yields, TESSA technology doesn’t limit rAAV manufacture to hundreds of Liters. In fact, we believe it will be possible to manufacturer AAV at thousands of Liters or more using TESSA technology, which will greatly amplify the number of patients that can be treated with a single batch of rAAV.

We’re also making great strides in developing lentiviral producer cell lines for scalable, plasmid free lentiviral production. These have all the genetic elements needed to produce a gene-of-interest expressing lentiviral vector stably integrated into the cells’ genome. This system therefore requires nothing more than cell culture and expansion prior to harvesting the lentiviral vectors. Our GFP expressing producer cell lines produce similar yields of lentiviral vectors to the transient system prior to any process development, and we expect similarly positive results from a producer cell line we’re currently developing with a therapeutically relevant transgene.

We’re also extremely excited to have recently launched a new collaboration with the A*STAR Biotechnology Institute in Singapore to bring our proprietary TESSA technology to the Asia-Pacific region. This partnership aims to foster scientific innovation in cell and gene therapy, and establish a joint professional development program to train and develop the next generation of scientists and engineers in GMP manufacturing for the cell and gene therapy industry.

CP: In general, how would you characterize the current state of the cell and gene therapy market? What are your predictions for the space 5 years from now?

Chang: The cell and gene therapy space is booming now, in a way that we haven’t seen since the early 90s, when the promise of these types of therapeutics was really energizing the market. The difference is that now we know so much more about them, and we’re so much closer to actually realizing that promise. We understand more about the genetic basis of disease, and the development of CRISPR / Cas technology has given us another hugely important weapon to fight it with. This has and will continue to revolutionize the cell and gene therapy field as gene editing starts to move from ex-vivo to in-vivo therapies, and gene therapies move from being treatments that are only developed for rare diseases with localized impact to systemic indications with large patient populations.

CAR-T cell therapies have had enormous success in hematological cancers, and now we’re making great strides towards understanding how we can adapt this technology to work in solid tumors too—I think we can expect to see breakthroughs in this area in the next few years, as well as in the transition from autologous to allogeneic cell therapies, which will allow more scalable and cost-effective manufacture of these treatments. I think that we can certainly expect more cell and gene therapies to be approved by the FDA, and as scalable technologies bring manufacturing costs down, I think we can also expect to see these treatments become more accessible for the patients who need them.

CP: What are 3 key trends and challenges impacting cell and gene therapy CDMOs?

Chang:

1. Plasmid quality and availability: while plasmid-based transfection remains the standard for viral vector manufacture, securing a supply of high-quality plasmids that can be delivered rapidly will continue to be key to accelerating the development of cell and gene therapies. We’ve addressed this by bringing plasmid manufacture and supply in house, where we can manufacture, test and deliver OXGENE’s high-quality packaging plasmids and custom plasmids within extremely short time frames. Packaging plasmids are available off the shelf at research, clinical and commercial GMP grades, and custom plasmids can be delivered within 5 months depending on grade.
2. Scaling up cost-effective manufacture: this is still a hot topic for viral vector manufacture. The switch from adherent to suspension cell culture made it possible to produce more viral vector in the same physical footprint, but transfection efficiency continues to be the limiting factor in manufacturing scale up. Removing the industry’s reliance on plasmids will be the only way to address this. We’ve addressed this by developing plasmid free manufacturing technologies—TESSA technology and LentiVEX producer cell lines—for both AAV and lentiviral manufacturing.
3. Testing and regulatory requirements: raw materials, drug delivery and mechanism of action are all more complex for cell and gene therapies than for traditional drugs. This means that the testing and regulatory requirements are also complex. The relative immaturity of the field also means that these requirements are still evolving as developers, manufacturers and regulators learn and respond to new developments in the field. Our expertise in testing and regulatory services for advanced therapies can help developers keep ahead of the curve.

CP: What services do sponsors seek in the development of cell and gene therapies? How do they differ from traditional drug development services?

Chang: Advanced therapies often have complex mechanisms of action compared with small molecules and other drugs, so testing requirements are also more complex. It can take significant expertise to develop in vitro assays to evaluate the biological activity of a cell or gene therapy. For example, multiple assays may also be needed to evaluate different aspects of a drug’s potency. This means that testing services are absolutely critical.

In addition to the inherent complexity and variability of advanced therapies, the relative youth of the cell and gene therapy field means that testing and regulatory requirements are still evolving. This is a result of a responsive industry learning and adapting, but poses substantial challenges for getting new therapies from bench to clinic as quickly as possible, so access to regulatory consultancy services can be really beneficial to developers. This is where WuXi ATU provides a really turn-key solution, with an integrated Contract Testing, Development and Manufacturing Organization (CTDMO) model to address all the complexity involved in developing a cell or gene therapy in house.

CP: What’s next for WuXi ATU in the near- and long-term?

Chang: This is a very exciting time to work at WuXi ATU. The cell and gene therapy market is growing rapidly, and so are we. We’re an organization driven by a team of staff who are passionate about what they do. I think the next few years are going to be very interesting for us as more and more cell and gene therapies get close to, and reach, commercialization and FDA approval. We hope this is going to contribute to growing interest in our scalable manufacturing technologies and platform services, because customers know that they can get reliably high yields of high-quality viral vectors or cell therapies when they manufacture with us. This is an extremely fast paced industry, and speed to clinic or market is crucial. So true to our ethos of putting the customer first, we will continue to build out our technical capability and capacity ahead of industry need, so that our customers can always rely on us to be ready when they need us, without requiring extensive wait times for services.