Stable Cell Line Development at Aragen – Accelerating speed to IND
Efficient cell line development is critical in bringing biologics to market and requires a team of experienced scientists, a portfolio of well validated cell line platforms, and state of the art facilities. Aragen delivers this combination and has completed more than 200 cell line development projects, with over 100 of those cell lines in the clinic following an investigational new drug (IND) application. More than four of Aragen’s cell lines are producing marketed products.
Support for a broad range of host cell lines and expression vectors
Aragen’s researchers are specialists in handling a wide range of host cell lines (CHO, SP2/0, and NS0) and expression vectors (DHFR, Glutaminebiologics Synthetase (GS), and antibiotics).
CHO cell line platforms tailored to specific development requirements
Aragen currently offers CHO DG44, Sigma CHOZN GS, and Asimov CHO GS cell line platforms.
Our internal CHO DG44 platform is an essentially free-to-own (royalty-free) and is a high- productivity CHO cell line option that can deliver >4g/L in 5 months for a range of biologics. The DG44 platform has an extensive regulatory track record and uses commercially available media and feeds.
Sigma’s CHOZN platform is based on deletion of the CHO glutamine synthetase (GS) gene with Talon gene editing technology. The resulting GS-/- CHO host and expression vector with GS selection is a great combination for companies with an interest in an established GS selection system. Regulators are familiar with its efficacy and operation, and its expression vector produces titers equivalent to the DG44 platform.
Asimov is a more recent platform that also employs the GS knockout in the CHO host. Asimov uses artificial intelligence (AI) to optimize the expression cassette, which is especially useful for new formats or proteins that are anticipated to be difficult to express.
Mitigating risk with parallel cell line development
Deciding which CLD platform would work best a priori is challenging. Therefore, Aragen’s cell line development service provides cost-effective approaches to test different platforms simultaneously without losing time on the way to IND.
A poor expressing product is a suitable candidate for testing on multiple platforms. Simultaneous testing provides a mitigation strategy to the risk of having to repeat CLD due to low titers or poor product quality that results in high material costs (COGS). If two platforms have comparable titers, then the superior product quality or reduced milestone costs can drive the platform decision. We have optimized breaks in the CLD process so that parallel work can be stopped as soon as data is available to determine which platform is the most effective.
Optimized cell line development services for therapeutics, diagnostic and research reagents
Our cell line development laboratories, based in Morgan Hill, California, combined with our team’s 28 years of expertise enable unrivaled cell line creation, resulting in research cell banks (RCBs) ammenable to IND and BLA filings. All of our platforms are well-documented, regularly reviewed by global regulatory agencies and extremely competitive with respect to titers obtained and speed of delivery. Our service supports μg to g scale protein expression levels, and are continually optimized to meet the specific requirements of human therapeutic cell line development as well as diagnostic and research reagents.
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Cell line development is a process by which a large population of identical cells is created, containing the gene that, on translation, encodes the biologic (recombinant proteins, monoclonal antibodies, bi-specific monoclonal antibodies, fusion proteins, vaccines). Chinese Hamster Ovarian (CHO) cells and Human Embryonic Kidney (HEK) cells for example, are among the most effective and prolific biological factories, and their cultures are utilized to produce novel cell lines. Apart from biologic production stable cell lines are also used in drug screening and gene functional studies.
To ensure the successful insertion of the vector in the host cell line several transfections are performed. When the transfected cultures are pooled together, it is called bulk transfection. To identify the best transfected cells or hot spots the bulk transfection is divided into several tiny populations called minipools and the leftover is referred as the bulkpool. Minipools help identify the high producing cells. Bulkpool is used for a fed-batch production run to generate materials that is purified and analysed as an analytical standard or benchmark against the expected product quality.
Clone screening is a process by which the transfected pools is analyzed for the cells those carrying the desired genomic changes and expressing the target protein. clone screening is a complex process because the performance of the clones is unpredictable in different culture conditions therefore the higher the number of clones screened the greater are the chances of discovering the high producing clone. Once a few efficient clones have been identified, multiple assays should be carried out to build a thorough picture of the features of each before selecting the best performing clone.
Clonality is one of the most crucial steps in guaranteeing cell line quality and safety. The FDA currently require evidence that each cell line used in manufacturing has been generated from a single cell. Single cell cloning (SCC) is a method in which single cells are separated from the pool of transfected pool such that final MCB is generated from the single cell and produces identical product. SCC is currently achieved using two commonly used methods i.e., single cell sorting using FACS and limiting dilution.
Research cell bank is a small cell bank produced under research conditions used for the production of a biotherapeutic for research purpose only. A master cell bank (MCB) is generated from a research cell bank (RCB) when cell line development is completed. Cells from a RCB are thawed and expanded, and when cell counts reach the desired number, a MCB is prepared and stored in a LN2 freezer.
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