Aggregation Analysis

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Many opportunities for aggregation can sidetrack the job of a therapeutic antibody. [Protein Data Bank]

Although bioprocessing relies on lots of teamwork, that’s not always a good thing when it comes to proteins. As I’ve reported over the past few months—Assessing Antibody Aggregation and Keeping IgG2s Apart—various steps in bioprocessing can cause proteins to aggregate, which can adversely impact function and even safety. Working on these stories made me wonder: What is the status of this problem?

With certainty, protein aggregation is not a new issue in bioprocessing. In 1996, Genentech scientists noted the need to watch for aggregation. Then, in 2001, scientists at the Universitat Autònoma de Barcelona pointed out that intracellular protein aggregates created during over-expression in bacteria have “a major economical impact in protein production bio-processes.”

The second certainty is that the problem continues. At Cambridge Healthtech Institute’s 8th Annual Rapid Methods to Assess Quality & Stability of Biologics—a virtual meeting planned for August 24–25, 2020—will include several talks about aggregation. For example, proteomics expert Michael B. Goshe of North Carolina State University will talk about how “alterations in the meta-stable three-dimensional structure of large protein therapeutics can lead to aggregation, decreased efficacy, unwanted side effects, and/or immunological responses, and therefore must be reliably detected.”

So, bioprocessors continue to deal with protein aggregation, but how big is the problem? According to a recent search of PubMed of bioprocessing and “protein aggregation”—a strategy that won’t find every related article but should reveal any trends—shows increasing interest since around 2010. It’s no explosion of articles but more of a slow increase. Adding in the many other ways to describe these phenomena would likely increase the number of articles.

As an example, searching for aggregation and “therapeutic protein” produced a PubMed high of 21 articles in 2015—and more than 14 articles a year for 2011–2019.

In short, aggregation remains a problem in bioprocessing, and companies must contend with it during manufacturing and storage.

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