Peter O’Callaghan, Ph.D.
Rachel Da Rosa, Ph.D.
In this interview, Lonza’s Peter O’Callaghan, Ph.D. (Senior Director, Head of Expression System Sciences) and Rachel Da Rosa Ph.D. (Product Manager, Licensing and Early Access Services), address questions on the importance of DNA vector design in determining bioproduction outcomes, in addition to the benefits of using high performing, validated materials early in the development process to pave the way to IND and beyond. They also cover what expression solutions that Lonza have developed to help ensure high titer and stable bioproduction.
Q: At a high level, why is the expression vector important in bioproduction?
PO’C: The first and very important step in recombinant protein expression is the design, synthesis, and assembly of a DNA expression vector that encodes the product gene(s). The expression vector acts as a critical set of genetic instructions that effectively tells host cells (in our case, Lonza’s CHOK1SV GS-KO® cell line) how to make a therapeutic protein, so the quality of this genetic instruction manual can play a key role in determining the overall success of a biomanufacturing process by influencing not only how much product the host cell produces, but also how well this product meets quality, regulatory and commercial needs.
Q: What are some of the early considerations that biologic drug developers must make to ensure a successful biomanufacturing process, and where can optimized vector design help address these?
RDR: Biologic drug developers face growing pressures from the early stages of development to accelerate programs as efficiently as possible while managing risk. Timelines, and importantly, efficiency, are particularly pressing in early development, where the generation of clinical material and progression to IND filing is a major milestone that may be linked to securing additional funding. The use of optimized vectors at an early stage can reduce time spent on early material generation for tox studies, cell line development and process development by streamlining vector construction (which is especially advantageous when considering the increasing prevalence of complex, difficult-to-express and multi-chain proteins such as bispecifics and fusion proteins), reducing post-transfection recovery times and enabling higher and more stable expression levels alongside robust product quality that meets regulatory requirements. These early gains in efficiency not only accelerate the path to clinic, but also lay the foundations for commercially viable biomanufacturing. Therefore, selecting an expression system and vectors that can demonstrate these attributes early in development can increase the likelihood of long-term success for drug developers.
Q: What expression vector solutions have Lonza developed to help maximize the chances of success for their customers?
PO’C: At Lonza, we continuously innovate our expression systems to support the evolving needs of biologic drug developers. The GS Gene Expression System® offers a comprehensive toolbox of advanced vectors, scalable cell lines, and technologies designed to optimize and de-risk the development of biotherapeutic proteins.
We’ve made DNA vector design a major focus area in recent years. In 2019, Lonza acquired exclusive rights to use the hyperactive piggyBac® transposon technology in bioprocessing. Integration of GS piggyBac® into our vector platforms has consistently improved titers across a range of molecules, including more complex multi-chain formats. Building on this, we introduced the GSquad® vector system in 2022, offering streamlined workflows for constructing multi-gene vectors capable of expressing products with up to four genes. Most recently, we launched the GSquad® Pro vector system, which incorporates LHP-1, a novel, high- strength, synthetic gene promoter developed in-house. The GSquad® Pro vector system drives significant improvements in titer for a broad range of molecules, including more difficult-to-express proteins, while delivering excellent expression stability and product quality. These advanced vector technologies, combined with our proven CHOK1SV GS-KO® cell lines and deep process expertise across the global Lonza network, help to optimize and accelerate the path from early development, through IND submission and scale-up, to commercial manufacturing.
Figure 1: Customer example: difficult-to-express bispecific antibody format was expressed using standard mCMV promoter and LHP-1 promoter as part of Lonza’s new GSquad® Pro vector system. The new promoter enabled a ~>40% uplift in titer to approximately 5 g/L.
To learn more about the science behind the new GSquad® Pro vector system and how it can boost titers, read the technical note here.
Q: How can drug developers best leverage Lonza’s advanced technologies and expertise to maximize their chance of success?
RDR: It’s never too early in the development journey to adopt proven, scalable technologies that are familiar to regulators. From both scientific and commercial perspectives, initiating early-stage development with the GS Gene Expression System® can help to de-risk the path to IND and beyond. Leveraging a GMP-ready system from the outset can help to:
- Eliminate the need to switch to another cell line later in development, minimizing the risk of having to repeat development work, improving cost and resource efficiency and reducing the risk of delays
- Establish early confidence in critical attributes such as product quality, which may be more consistent when using the same platform throughout all development stages, and scalability
- Reduce regulatory risks by having a strong track record with GMP-compliant manufacturing
- Potentially increase investor confidence – biotherapeutic candidates developed using technologies with proven scalability, and a strong regulatory track record may be viewed more favorably by investors
- Ensure compatibility with CDMO platform processes for an easier transition to later-stage development when you’re ready to scale up
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