BioPharm

www.biopharminternational.com April 2019 BioPharm International eBook 19 Outsourcing Resources Manufacturing industry is undeniable, but with new antibody formats, there is renewed interest in non-mamma- lian expression systems, including Escherichia coli and Pichia pastoris. As discussed in this article, mAbs with modulated effector functions have altered glycosylation profiles that may not require the post-tran- scriptional modification appara- tus in a mammalian cell and may actually benefit from its absence. For e xa mple, du r va lu mab a nd atezolizumab have been protein engineered to remove the N-linked glycosylation site and could there- fore be produced in microbial sys- tems. Many new m Ab formats also require linker proteins; for exam- ple, many of the bsAb fragments require linkers between the dif- ferent domains. These non-native p r o t e i n s m ay b e d i f f ic u lt t o express in mammalian cells but may be produced in mic robia l systems instead. The rapidity and reduced cost of goods of micro- bial manufacturing compared to mammalian systems makes them potentially attractive platforms for some formats. Another approach to altering the glycosylation profiles of mAbs is to use knock-out cell lines that lack enzymes, such as fucosyltrans- ferase. Lonza has partnered with BioWa, a US-based biotech com- pany, to create the POTELLIGENT CHOK1SV cell-line technolog y, which produces antibodies with enhanced ADCC even when their t a rget a nt ige n de nsit y is low, resulting in improved efficacy. Flexible bioprocessing at the right scale As many new molecular formats with higher potency or smaller target patient populations move toward approval, traditional large- scale commercial assets may not be appropriate. Multiplexing in sin- gle-use technologies offers a solu- tion and can respond to specific shifts in demand. However, having a midscale option available to scale up further if needed is a critical consideration to cope with larger swings in demand. Many new mAb formats also require linker proteins; for example, many [bsAb] fragments require linkers between the different domains. Additionally, the variability in downstream processing for these new formats means that flexibil- ity is key. At Lonza's Portsmouth, NH, site, the company is develop- ing a new mid-scale facility with 6 kL stainless steel (SS) reactors, combined with a "plug-and-play" approach to downstream manufac- turing that leverages both single-use and stainless-steel technologies. The goal is to provide a smooth path from clinical to commercial, with the right scale and technology, at the right time. CONCLUSION To sh i f t ma nu fac t u r i ng of t he n e x t g e n e r a t i o n o f b i o l o g i c s dr ugs into higher gear, pharma a n d b i o t e c h c o m p a n i e s w i l l ne e d access to broad, d ive r se, and flexible platforms and assets that they can tailor to the spe- cific needs of molecules they are developing. Because the biolog- ic s pip el i ne is b ecom i ng more complex and diverse, the indus- try can no longer rely on the one- si ze-f its-a ll approach per fec ted for sca led-up m Ab produc t ion. Many biotech innovators— espe- cially smaller or virtual firms— can benefit from partnering with external organizations, such as CDMOs, that have flexible man- u fac t u r i ng a sset s, rat her t ha n i nvest i ng heav i ly to bu i ld i n- house resources. It is worth noting that these problems and questions will not be solved by any one company or scientist; it will require innova- tion that pushes the envelope. For example, in 2018 Lonza opened a new innovation center in Haifa, Israel, aimed at translating new ideas at the convergence of bioen- gineering and digital technologies into commercial manufacturing. Working with start-ups and uni- versities, sometimes from outside a company's field of expertise and with potentially unfamiliar risks, opens up new possibilities for the future of manufacturing. T he u lt i mate goa l is to f i nd ways to develop new, i n nova- tive, and life-saving therapies and get them to patients quickly and effectively, wherever they are in the world. REFERENCES 1. L. Fan, C.C. Frye, and A.J. Racher, Pharmaceutical Bioprocessing 1, 487– 502 (2013). 2. F.M. Wurm, Nature Biotechnology 22, 1393–1398 (2004). 3. D.H. Nam, C. Rodriguez, and A.G. Remacle, et al., Proc Natl Acad Sci USA 113, 14970–14975 (2016). 4. FDA, "FDA Approves New Treatment to Prevent Bleeding in Certain Patients with Hemophilia A," Press Release, Nov. 16, 2017. 5. S. Mariathasan and M.W. Tan, Trends Mol Med 23, 135–149 (2017). 6. A. Beck, et al., Nature Reviews Drug Discovery 16, 315–337 (2017). 7. Visiongain, "Next Generation Antibody Therapies Market Forecast 2016–2026," Press Release, May 11, 2016. 8. O. Obrezanova, et al., mAbs 7, 352–363 (2015). 9. J. Zurdo, Pharmaceutical Bioprocessing 1, 29–50 (2013). BP

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