Every day matters

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This paid-for advertorial by Twist Bioscience appeared in the Therapeutic Antibodies Guide – DDW Volume 25 – Issue 1, Winter 2023/2024

Improving gene synthesis speed can reduce workflow times, saving you invaluable time, says Twist Bioscience.

Time can mean more than money when you’re studying a deadly pathogen. The importance of speed and efficiency crystalises 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 labour and resource intensive. 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 characterised 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 the1,2,3,4 drug known as Evusheld.

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 infection5. 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 harboured 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 characterisation 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 synthesise 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 11 in their paper for a detailed timeline).

This process resulted in nearly 400 expressed antibody variants and multiple promising leads, at least two of which would eventually receive emergency use authorisation (under the trade name Evusheld)6. For over a year, Evusheld provided prophylactic protection for immunocompromised people, a group that was often unable to benefit from vaccines.

SARS-CoV-2 has since evolved into variants that are not well neutralised by Evusheld thus reducing the therapeutic value of these antibodies in their current iteration7. 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 five 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 neutralisation of authentic SARS-CoV-2 virus, and partnering with downstream manufacturing partners like Twist for expedited – yet accurate – gene synthesis1.

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 recognising the value of expedited gene synthesis, Twist has built a manufacturing facility, designed to enable large-scale, accurate gene synthesis at speeds never before seen (now offered as Express Genes).

Through Twist’s Express Genes8 offering, you can order genes of any length between 300bp to 5000bp with standard complexity. Prioritisation and other optimisations make it routine to manufacture Express Genes in five to seven 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 quickly and you can get back to advancing your studies. Whether you’re combatting a global pathogen, building novel proteins, or engineering biosynthetic pathways, time is of the essence, and Twist will help you seize the day.

Advanced antibody discovery: The Twist gold standard

Twist Biopharma Solutions has recently developed an advanced suite of antibody discovery and development tools to enable rapid and productive research. Twist’s combined offering includes its unparalleled synthesis platform that is used to create phage-display libraries containing billions of variants; the use of the advanced DiversimATM mouse for hybridoma-based screening; and Beacon-based single-B cell sequencing for high- throughput, multiplexed B-cell screening from multiple different species, including mouse, rabbit, and alpaca. Each technology can be used individually. But when combined, they enable researchers to maximise their shots on goal through massively parallel antibody screening.

References:

  1. https://www.nature.com/articles/s41591-020-0998-x
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8543371/
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10175065/#jiad014-B14
  4. https://www.covid19treatmentguidelines.nih.gov/therapies/antivirals-including-antibody-products/anti-sars-cov-2-monoclonal-antibodies/#:~:text=Four%20anti%2DSARS%2DCoV%2D,mild%20to%20moderate%20COVID%2D19.
  5. https://www.astrazeneca.com/content/dam/az/Investor_Relations/annual-report-2022/pdf/AstraZeneca_AR_2022.pdf
  6. https://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#
  7. https://www.covid19treatmentguidelines.nih.gov/therapies/antivirals-including-antibody-products/anti-sars-cov-2-monoclonal-antibodies/#:~:text=Four%20anti%2DSARS%2DCoV%2D,mild%20to%20moderate%20COVID%2D19.
  8. https://www.twistbioscience.com/products/genes?tab=clonal

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