The cell therapy industry has expanded significantly in recent years. The approval of Kymriah, a gene modified cell therapy according to the FDA, as well as Yescarta prompted a wave of R&D investment.

Advances in manufacturing technology have also played a part in driving growth, according to Spencer Fisk, senior vice president & chief technical operations officer, Rubius Therapeutics.

“Companies often struggle to scale up manufacturing as necessary in clinically and commercially viable ways, and the process can prove time consuming, costly, and complex,” he says.

Fisk cites Rubius’ candidate cancer therapy RTX-321 as an example of how technology is addressing such issues. RTX-321 is an allogeneic artificial antigen presenting cell (aAPC). It is made from red blood cells that have been modified to express proteins from HPV-16 virus—to present them to the immune system.

Priming the immune system allows it to fight cancers caused by the HPV-16 virus, more effectively. According to recently released preclinical data, RTX-321 induces CD8+ T cell and innate NK cells to attack tumors.

Manufacturing innovation

Like Rubius’ other candidates, RTX-321 is made using its “Red Platform,” which brings together single-use processing technology and automated control to ensure flexibility and scale-ability, says Fisk.

“This allows us to quickly advance new updates to our platform from concept to supply and rapidly deploy our products. Our approach also provides for process robustness through simplified operations while providing immediate operational cost savings.”

Production is a three-week process. It begins with CD34+ hematopoietic precursors collected from a healthy O negative donor. These cells are engineered with a lentiviral vector, or gene cassette, to express the viral protein prior to culturing.

The cells are then exposed to media and growth factor in a bioreactor to promote further expansion and differentiation until the nucleus is ejected.

The production system is designed to support supply as needed, notes Fisk, who adds, “Use of these scalable systems allows for accelerated small-scale modeling and development of process improvements which can then be transitioned right-first-time into manufacturing. This, coupled with semi-automated approaches to capture and analyze data enables us to quickly and repeatedly assess process performance for improved process understanding.”

Allogeneic cell therapies, such as the company’s Red Cell TherapeuticsTM can be readily available, compared to a manufacturing time of three to four weeks for a custom, patient-specific product, explains Fisk, pointing out that this is a major advantage because a patient’s disease may progress while awaiting autologous cell therapy manufacture.

“With the added benefit of freezing drug substance, product is available ‘on demand’ for patients enrolled in our clinical trials,” he says.

Shelf life

Rubius first shared details of how it makes RTX-321 in its third quarter filing explaining the process involves a freezing step that gives it a “potential shelf life of several years based on preliminary stability data.”

“Freezing the drug creates more flexibility, supply chain consistency, and continuity by having an on-demand and truly off-the-shelf product for patients participating in our clinical trials,” explains Fisk.

“Additionally, frozen drug alleviates the burden on our clinical development and manufacturing teams to match each dose to each patient enrolled in our trials. Finally, it extends the product’s shelf life for up to several years, and once thawed, can be used within 52 days.”

Rubius has also invested in standardized analytical platforms designed to accelerate process development and improve quality control and manufacturing.

“This enables improved analysis and analytical platform development, further supporting the technical life cycle development of our products and speeding our ability to deliver additional value to patients,” notes Fisk.

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