Every Day Matters

Time can mean more than money when you’re studying a deadly pathogen. The importance of speed and efficiency crystalizes when you see a virus like SARS-CoV-2 spreading across the globe, sending thousands of people to the hospital every week. Such was the environment in early 2020 when Seth Zost, Pavlo Gilchuck, and several other researchers from Vanderbilt University Medical Center set out to develop a  therapeutic antibody against the now infamous  virus¹.
 
Traditionally, therapeutic antibody discovery is a labor and resource-intensive process. Pools that are millions of antibodies deep—typically sourced from patients, inoculated animals, or synthetic libraries—must be screened and pared down to just the tens or hundreds of candidates with the most potential. From this enriched selection, promising candidates are identified only after each antibody is characterized both in vitro and in vivo. When all is said and done, this process may take months or years to complete.
 
However, Zost, Gilchuck, and their colleagues managed to home in on promising candidates in just 78 days, identifying antibodies that would later be used in the drug known as Evusheld ^1-4. Between December 2021 and January 2023, more than a million doses of Evusheld were purchased by countries around the world, ultimately as a means to protect immunocompromised people from SARS-CoV-2 infection ⁵. Achieving this remarkable feat hinged on the team’s ability to move fast and overcome common workflow bottlenecks, something they achieved through partnerships with industry leaders like Twist.

78 Days of Antibody Discovery

Like many researchers before them, Zost, Gilchuck, and their colleagues began the search for therapeutic antibodies in the plasma fraction of convalescent patients. ELISA testing had shown that each patient—previously infected by SARS-CoV-2—now harbored antibodies that bound to various domains on the virus’ spike protein (S protein). Memory B cells were then isolated and cultured, followed by a dual workflow involving single-cell sequencing and, separately, B cell characterization using Berkeley Lights Beacon optofluidics. These two workflows helped to identify hundreds of antibody variants—including their heavy and light-chain elements—that showed specific activity against the S protein.
 
As is standard, antibody candidates identified using single-cell sequencing needed to be expressed in mammalian CHO cells (to create a stable source of each antibody for subsequent characterization). To do so, the team needed to synthesize each antibody and their many variants. For this, the team turned to Twist who provided expedited gene synthesis, enabling the synthesis, cloning, transfection, and expression of candidate antibodies in just 22 days (see Figure 1 in their paper ¹ for a detailed timeline).
 
Overall, this process resulted in nearly 400 expressed antibody variants and multiple promising leads, at least two of which would eventually receive emergency use authorization (under the trade name Evusheld) ⁶. For more than a year, Evusheld provided prophylactic protection for immunocompromised people, a population that was often unable to directly benefit from vaccines.
 

 
SARS-CoV-2 has since evolved into variants that are not well neutralized by Evusheld, thus reducing the therapeutic value of these antibodies in their current iteration ⁴. Nonetheless, the speed at which they were discovered helped these antibodies to quickly reach the market, benefiting many thousands of people at a critical time in the pandemic. Had the process been slower, the window in which Evusheld was therapeutically valuable—and thus the number of people it was able to help—would likely have been much smaller.

Gene synthesis in just 5 days

The speedy discovery of therapeutic antibodies demonstrated by Zost, Gilchuck, and their colleagues was, in part, thanks to several workflow advances that included functional screening at the single-B-cell level, high-throughput (hundreds to thousands) screening of mAbs for neutralization of authentic SARS-CoV-2 virus, and partnering with downstream manufacturing partners like Twist for expedited—yet accurate—gene synthesis ¹.
 
Accordingly, these innovations are increasingly adopted for biologics development. But, speedy gene synthesis is valuable well beyond antibody development. Waiting for genes to be synthesized represents an often overlooked drag on project timelines. Reducing this drag can create a cumulative effect of improved efficiency and productivity.
 
In recognizing the value of expedited gene synthesis, Twist has built a new manufacturing facility which has been carefully designed to enable large-scale, accurate gene synthesis at speeds never before seen (now offered as Express Genes).
 
Through Twist’s Express Genes offering, you can order genes of any length between 300bp to 5000bp with standard complexity. Prioritization and other optimizations make it routine to manufacture Express Genes in just 5-7 business days.* And, the speed is not at the expense of quality—every manufactured gene is NGS-verified to ensure sequence perfect production of the desired sequence. Overnight shipping ensures the genes, delivered in both Twist Catalog or Custom Vectors, will arrive at the bench quickly, and you can get back to advancing your studies. Whether you’re combating a global pathogen, building novel proteins, or engineering biosynthetic pathways, time is of the essence, and Twist is here to help you seize the day.
 
Click here to learn about Twist Express Genes >

References

1. Zost, Seth J., et al. “Rapid Isolation and Profiling of a Diverse Panel of Human Monoclonal Antibodies Targeting the SARS-CoV-2 Spike Protein.” Nature Medicine, vol. 26, no. 9, 10 July 2020, pp. 1422–1427, https://doi.org/10.1038/s41591-020-0998-x.
2. Dong, Jinhui, et al. “Genetic and Structural Basis for SARS-CoV-2 Variant Neutralization by a Two-Antibody Cocktail.” Nature Microbiology, vol. 6, no. 10, 1 Oct. 2021, pp. 1233–1244, www.nature.com/articles/s41564-021-00972-2, https://doi.org/10.1038/s41564-021-00972-2.
3. Forte-Soto, Pablo, et al. “Safety, Tolerability and Pharmacokinetics of Half-Life Extended Severe Acute Respiratory Syndrome Coronavirus 2 Neutralizing Monoclonal Antibodies AZD7442 (Tixagevimab-Cilgavimab) in Healthy Adults.” The Journal of Infectious Diseases, vol. 227, no. 10, 23 Jan. 2023, pp. 1153–1163, https://doi.org/10.1093/infdis/jiad014.
4. “Anti-SARS-CoV-2 Monoclonal Antibodies.” COVID-19 Treatment Guidelines, www.covid19treatmentguidelines.nih.gov/therapies/antivirals-including-antibody-products/anti-sars-cov-2-monoclonal-antibodies/
5. “What science can do AstraZeneca Annual Report and Form 20-F Information 2022” AstraZeneca, 2022 https://www.astrazeneca.com/content/dam/az/Investor_Relations/annual-report-2022/pdf/AstraZeneca_AR_2022.pdf
6. “Evusheld (Formerly AZD7442) Long-Acting Antibody Combination Authorised for Emergency Use in the US for Pre-Exposure Prophylaxis (Prevention) of COVID-19.” Www.astrazeneca.com, 8 Dec. 2021, www.astrazeneca.com/media-centre/press-releases/2021/evusheld-long-acting-antibody-combination-authorised-for-emergency-use-in-the-us-for-pre-exposure-prophylaxis-prevention-of-covid-19.html.

Terms and Conditions: *Advertised turnaround time for Express Clonal Genes is 5-7 business days and is based on extensive production experience. Your production time may vary from sequence-to-sequence. International orders may require additional shipping time.