BPI 2026：BMS 的 Jacqualyn Schulman 谈加速克隆细胞系开发

By Tyler Menichiello, Chief Editor, Bioprocess Online

In many ways, biopharma development is a race against time, not only to bring medicines to patients faster, but also as an operational necessity. After all, time is money, and reducing timelines is one of the greatest cost-saving levers in biopharma development.

Clonal cell line development (CLD) is a critical step in therapeutic protein production that can take months, and as such, it’s one where gains stand to be made in terms of speeding up overall development.

At this year’s BioProcess International conference in Boston, I attended a session by Jacqualyn Schulman, Ph.D., a cell line development principal scientist at Bristol Myers Squibb (BMS). Her presentation, titled, “Fast-Tracking CHO Cell Line Development Using Integrated Engineering Strategies,” was a case study about mitigating post-translational modifications (PTM) using a multiplex gene knockout strategy.

Instead of making edits to the lead clone, Schulman’s team performed edits directly in an enriched bulk CHO cell population and then screened these clones for both titer and the knockout genotype.

This approach not only mitigated the PTM in question, but it expedited the process, avoiding months of potential work through traditional methods.

I was fortunate enough to catch up with Schulman after her presentation to ask a few questions for Bioprocess Online.

The following transcript has been edited for clarity and readability.

Tell me about the case study you presented and what you hope the audience took away from your talk.

Schulman: We had a problematic PTM that we were able to eliminate through multiplex genetic engineering, performing a triple knockout to prevent this hydroxylysine modification from occurring.

Typically, when people are looking to do multiplexing knockouts, whether it’s to eliminate a PTM or even to increase titer, usually you’re doing it to the lead clone. You’re already waiting five or six months to get that lead clone, so we really wanted to take a risk and see if we could skip that step to get it done a lot faster.

So, we decided to take an enriched bulk — take that transfected population, enrich for it, and then use that as the starting material instead of the lead clone.

By doing that and performing a two-step screening process where we screened for both high titer and our triple knockout, we were able to simultaneously get the lead clone that had the triple knockout without spending an additional five months to get there.

That was really exciting, but it was a risk. I’ll be honest, I thought there was a chance that I was going to do this and still be repeating it in the lead clone, but it was high risk, high reward.

How did this method differ from traditional screening?

Schulman: Typically, when you’re waiting for that lead clone, you already know that it’s producing your antibody well and that it has all the characteristics you like. When you proceed forward with making a knockout, you’re really screening to see if the clone is a knockout. It’s a one-step screen.

However, when you’re doing this with an enriched bulk, you still have a heterogenous population. So, even though you can be pretty confident that all those cells are expressing your antibody, they’re expressing it at a bunch of different levels.

Another challenge was this was a bispecific antibody, which are notorious for making a lot of impurities, so we also wanted to screen out any clones that were making those impurities.

By first screening the clones for both titer and product impurities, we were able to reduce 50% of the clones. We started with 200 clones and eliminated half of them. Then, from those 100 clones, we were able to screen forward and determine which ones were knockout and pick 24 to go into our production studies with.

You mentioned how this was a high-risk experiment. Were you encouraged to take that risk?

Schulman: I would say we were encouraged! I think a lot of people were skeptical, but I made it clear that I’d be willing to repeat this all over if needed.

My thoughts were, “Sure, we’re spending time, and time is money, but at the same time, there’s no negative impact. It’s not adding anything to the timeline, and if anything, it’s such a win if it works out. So, why not?”

Maybe other companies are doing this, but if they are, they haven’t shared, so I like to think we were the first.

Which sessions that stood out to you in the cell line development track? What are you excited by, and what seem to be the general sentiments you’re hearing?

Schulman: I feel like everyone’s really pushing the limits and looking at how we can produce titer. A lot of people are working on complex molecules, and they’re just getting harder.

Basic mAbs are really a thing of the past, and even bispecifics, because now you’re getting into trispecifics. We’re getting into these really difficult-to-express molecules where maybe you’re not getting the five to 10 grams you want; you might be pushing it at one to two grams.

So, what can we do?

One company I thought was interesting made their own CHO cell line, which I thought was really innovative. Traditionally, cell lines are made through iterations of some parental cell line, but they went back to the hamster cell, and the doubling time was like 10 hours. In a production study, they were getting to a viable cell density of almost 60, and they actually harvested their production on day seven. They were getting higher titer in less time.

I never thought of going back to the hamster; I thought that was really unique and creative. We keep trying to make something work, and maybe we get small increases, but I think going back right to the source and making something your own was really cool.

How would you summarize the themes of this year’s BPI?

Schulman: A lot of people are pushing the limit with engineering, whether it’s over-expressing or doing knockouts. We’re pushing the limits on how many genes we can edit. It’s always impressive to me that you can knock out so many genes and the cells are still living.

Transposases are another hot topic.

Tell us about your upcoming panel discussion on precision cell line engineering for biologics.

Schulman: I’m sharing a stage with Andy Racher, Ph.D., and Laura Greenfield, and we’ll mostly be talking about various modalities we’re seeing, difficult-to-express proteins, the challenges we’re seeing, and how we’re working to overcome those.

 We’ll also talk about the different kinds of Cas proteins. Everyone’s used to Cas9, but there are other complexes and similar things coming out, so we’ll discuss the trends we’re seeing, the advantages of using them, and what’s next.

We’re the last session, but they saved the best for last!