reshapingthe production of dna-based therapies

A D V E R T I S E M E N T F E A T U R E

A D V E R T I S E R R E TA I N S S O L E R E S P O N S I B I L I T Y F O R C O N T E N TB10 | June 2021 | www.nature.com/biopharmdeal

Touchlightwww.touchlight.com

Reshaping the production of DNA-based therapiesTouchlight’s DNA synthesis platform is ready to meet the growing demands of the genetic medicine industry.

The success of mRNA COVID-19 vaccines dem-onstrates that nucleic acid-based therapies are aneffective and safe strategy for preventing SARS-CoV-2 infection. Although DNA or mRNA vaccinesare easier to make than traditional vaccines, whichrequire the production of live or attenuated virusesor viral proteins, generating massive quantities ofthe sequence of interest can be challenging.

Typically, DNA is produced in bacteria grownin large stainless steel fermenters, followed bycomplex purification methods. “The process isexpensive, takes a long time and the resulting DNAcontains unwanted bacterial sequences such asantibiotic resistance genes,” said Helen Horton,Chief Research Officer at Touchlight and memberof the UK government Vaccines Taskforce.

Touchlight, a privately owned UK-based companyfounded in 2007, has developed a rapid, scalable,easy to transfer, cell-free method to make uniqueDNA vectors, known as Doggybone DNA (dbDNA)(Fig. 1). Touchlight’s dbDNA can be manufacturedto good manufacturing practice (GMP) at multi-gram scale in a 5-day process. “Our linear, double-stranded DNA constructs can be produced muchmore rapidly than traditional plasmid DNA withsimple, inexpensive benchtop equipment, whichwould allow developing nations to produce theirown vaccines,” Horton explained.

Touchlight has established a contract develop-ment and manufacturing organization (CDMO)that is currently deploying the dbDNA technologyacross a multitude of modalities within geneticmedicine, including in viral vector manufacturing,genome editing and the production of nucleic acidmedicines (mRNA and DNA).

The company is also investing in its own portfolioof products linked to its production process to driveproof-of-concept and validation of the technology inkey genetic medicine markets. “There is a growingnumber of proof-of-concept studies in animals fora whole range of DNA-based therapies,” Hortonsaid, “and we are ideally placed to enable the rapiddevelopment of products into the clinic as we caneasily up-scale production”.

The COVID-19 pandemic has highlighted the urgentneed for technologies such as dbDNA to solve issueswith vaccine supply chains as well as to respond tonew variants. “The possibility of producing gramquantities of DNA from emerging virus variants withindays demonstrates how our platform can improvepreparedness for the next pandemic,” she added.

Realizing the potential of DNA vaccinesHistorically, DNA vaccines have not provided robustantibody responses in humans, partly owing to dif-ficulties in delivering them to the nucleus of antigen-presenting cells. However, they offer a number

of advantages over mRNA vaccines, includingthe stimulation of both a strong cellular immuneresponse by T cells as well the production of anti-bodies by B cells, and stability at room temperature,making them much easier to deploy in countrieswhere the cold chain is difficult to maintain.

Although no DNA vaccines have yet been licensedfor humans, they are used in the veterinary arenato protect diverse species, including salmon, pigs,dogs and horses, against disease. Touchlight hasrecently partnered with Stonehaven Incubate todevelop new vaccine solutions for aquaculture, andis exploring the use of DNA vaccine candidates forvarious animal health indications.

Several DNA vaccines are undergoing clinical tri-als for the treatment of cancer and for preventingSARS-CoV-2 infection. Zydus Cadila’s plasmid DNA-based COVID-19 vaccine (ZyCoV-D) delivered via aneedle-free injection system is now in phase 3 trialsin India and could become the first DNA vaccine tobe approved for humans.

“We are just starting to witness the potential ofDNA in the vaccine field,” Horton said. Touchlight’sinnovation team is working on developing new typesof dbDNA that can target specific cells to enhanceDNA immunogenicity, avoid the need for deliverydevices and elicit an effective, long-lasting response.

Cancer Research UK has partnered with Touchlightto progress its DNA vaccine candidate for solidtumors (TGL-100) through phase 1/2 clinical tri-als in patients with head and neck squamous cellcarcinoma. “The vaccine consists of dbDNA thatencodes two cancer antigens found in more than95% of head and neck cancers that are not humanpapillomavirus-driven, as well as at high rates innon-small cell lung cancer and other solid tumors,”Horton explained.

Touchlight is also developing a novel DNA vac-cine against SARS-CoV-2 that directs an immuneresponse not just against the virus’s spike protein,as current vaccines do, but also against other partsof the virus. This could stimulate a more robustresponse and confer broader protection against newvariants. In addition, the company is exploring theuse of different routes of administration. “Currentvaccines are all delivered intramuscularly, which isknown to elicit a systemic immune response; we arelooking at simultaneous intradermal and intranasaladministration to induce a strong mucosal immuneresponse,” Horton said.

dbDNA-based vaccines can be used to delivermore than one antigen, and, unlike viral vector-based vaccines, there is no risk of developinganti-vector immunity. Thus, they can be used toboost previously administered vaccines and usedrepeatedly, which is critical for therapeutic cancervaccines that need to be administered every fewweeks and seasonal influenza vaccines.

Touchlight is already collaborating with mostmajor mRNA vaccine companies, and its latestfundraising round will enable it to triple its manu-facturing capacity and produce up to 1�kg of GMPDNA per month from early 2022. “Our goal is tomeet the growing demand for starting material inthe manufacture of mRNA vaccines, whilst drivingnew or improved forms of potentially life-savinggenetic medicines,” Horton concluded.

Bulk formulation,fill and QC release.

Circular DNA templatecontaining target sequence.

TemplateDNAdenatured

Rolling circleamplification

Cleave andcovalentlyclose

Φ 29 DNAPolymeraseinitiatesrolling circleamplification

Protelomerasecleavage-joiningreactionproducesdbDNA

Firstpurification

Secondpurification

Backbonedigested

Backboneremoved

Restriction enzymesand exonucleasesdigest and degradenon-target sequence

Fig. 1 | Touchlight’s DNA synthesis platform. Manufacturing DNA vectors known as Doggybone DNA(dbDNA) in a rapid, scalable, easy to transfer and cell-free method.

Helen Horton, Chief Research OfficerTouchlightLondon, UKTel: +44 20 8481 9227Email: helen.horton@touchlight.com

CON

TACT