Xpressions Blog

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Using CHO "Omics" to Address Production of Increasingly Complex Biotherapeutics

Feb 1, 2018 10:54:21 AM

Increasingly, solutions for complex human diseases are being addressed with increasingly complex protein therapeutic modalities. These include molecules such as bi-specific proteins, DARPins, triabodies and novel scaffolds decorated with peptides, enzymes or growth factors, to name a few. Many, if not most, of these proteins do not exist in nature and producing them presents a range of production and secretion challenges such as ensuring appropriate folding and subunit pairing.

At Selexis, we have spent a lot of time interrogating and characterizing our propriety CHO-K1 cell line (CHO-M); we were one of the first companies to fully sequence the CHO-M’s genome and transcriptome. From this data, we have built a comprehensive understanding of the transcriptional and genomic landscape of our cells and where there are mutations or unexpected increases or decreases in host gene transcription levels. This has provided us with detailed insight into potential secretion bottlenecks within our CHO-M cell line, particularly as it applies to difficult-to-express proteins and we have developed technologies to address these bottlenecks, such as our SURE CHO-Mplus libraries.

 As we stress the secretory machinery of our CHO-M cells with these non-natural proteins, we now have the data, as well as the tools to address a myriad of issues including improper folding or pairing, metabolic overload or backlog in protein translocation or vesicle trafficking.

As an example of how we are using our CHOomics to address non-natural protein production, we were working with a client on an exciting new therapeutic minibody, but were hitting roadblocks in producing sufficient levels of secreted protein. The minibody gene was readily transcribed within our system, however, the high levels of transcription did not translate into high productivity levels. Detailed evaluation of the cell line determined that one of the molecular chaperones was binding the minibody too tightly, trapping it within the ER. Using the data from the SURE CHOomics, and by overexpressing key auxillary secretory proteins determined by our CHOomics, we were able to boost minibody production by 6X, allowing us to salvage the program and help our partner move the drug into the clinic.

In Summary

At Selexis, we believe in the promise of these newer biologics and have committed significant resources to ensure our SUREtechnology Platform can meet the new expression challenges that these non-natural proteins present. We are very proud of our history of empowering scientists and biopharmaceutical companies around the world to realize the full potential of their research and we work hard every day to maintain that legacy.