Working with macrophages, Resolution Therapeutics faces a “unique” manufacturing challenge. They progressively lose cells as they move towards their final product. Damian Marshall, PhD, VP, analytics, and Steve Howe, PhD, VP, process development, talk to GEN about how they’re tackling the move towards commercialization.

GEN: What products are you developing?

Steve: We’re developing a macrophage therapy to treat end-stage liver disease in adults. Macrophages can communicate with the rest of the immune system. We manipulate them to utilize their natural pro-restorative phenotype to actively reduce inflammation and scar tissue.

GEN: Why are macrophages harder to develop into a medicine?

Steve: Unlike T-cells, which can be induced to divide, macrophages are terminally differentiated and don’t multiply. We obtain cells from patients but, as they differentiate and polarize into the macrophages we want, rather than growing more cells we naturally lose a proportion of them.  As we can’t compensate for this by expanding our cell population, we need to develop high-yield operations.

GEN: How are you overcoming that challenge?

Steve: Part of the solution is through control of the process and part of it is through analytical understanding. More than any other cell therapy, there’s a critical interplay between processes and analytics. We need to understand what’s happening to the cells at every step to keep them healthy and ensure the quality of our medicine.

GEN: What are the challenges to analytics?

Damian: With a CAR-T therapy, the pathway for applying analytics to support manufacturing is relatively well developed, but our product is a pioneering therapy, so there’s no script on how to measure and control the manufacturing process.

Also, Steve has the challenge of being ready to scale up to manufacturing therapies for thousands of patients each year, and–if the analytics don’t follow–there’s a risk of creating a bottleneck in quality control.

GEN: How are you aiming to supply therapies to this huge patient population?

Damian: We’re looking to build analytics into our processes to allow us to collect real-time data. We’re also thinking outside of the box around automation, liquid handling and robotics because many of the technologies we need aren’t necessarily available [off-the-shelf].

Steve: We are already thinking: How can we scale out to manufacture thousands of batches a year? How can we effectively deliver these cells to that many patients? And what would our wider manufacturing and supply-chain strategy look like to manage this?

GEN: Do you know how you’ll answer those questions?

Steve: We have solutions, but they’re not fully tested yet. We’re working with a single CDMO to manufacture for our planned pilot clinical trial, but to go to the next stage and scale requires a complete shift in thinking.

Damian: It’s the same for quality control. Our plans are there—we just need to translate them into reality.

Resolution Tx spoke at the Terrapinn conference on Advanced Therapies earlier this year.

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