The cell & gene therapy market matures Wave of collaborations accelerate vaccine development Dealmaking in 2020 faces new challenges - Biovian
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June 2020
biopharmadealmakers.nature.com — Nurturing biopharma partnerships
The cell & gene therapy
market matures
Wave of collaborations
accelerate vaccine
development
Dealmaking in 2020
faces new challenges
Originally published as an advertising feature in the June 2020 editions of
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FEATURE
B3 Next-generation therapeutics sustain momentum
The next-generation therapeutics space has continued to progress on several
fronts in the past 12 months, but this could be set to change as the industry copes
with the COVID-19 crisis.
PROFILES
B6 Elicio Therapeutics B14 Novadip Biosciences
Cover image Gene therapy conceptual
illustration; a double stranded DNA
B8 NovaGo Therapeutics B15 Aruvant Sciences
(deoxyribonucleic acid) molecule coming B9 Biovian B16 Antapodia
out of a viral capsid. Science Photo
Library / Alamy Stock Photo. B10 Cellatoz Therapeutics Nanotherapeutics
BioPharma Dealmakers is a quarterly B11 inRegen B17 MiCAN Technologies
publication that facilitates partnering by
profiling the activities of organizations B12 Synplogen
in the biopharma field, including biotech
companies, global biopharma companies
and academic institutions.
Profiles of organizations are aligned with FEATURE
relevant editorial features that cover
different therapeutic and technological
themes in each issue. B18 Partnering for a pandemic
Note Companies that appear in this History has shown that collaborative efforts can have a crucial role in combating
issue have paid for their advertisement viral outbreaks such as the current coronavirus pandemic.
features and have final approval of
their content. If you would like to appear
in the next BioPharma Dealmakers PROFILES
please contact Claire Thompson:
c.thompson@nature.com B20 GSK Vaccines B23 TAXIS Pharmaceuticals
B21 Amicoat B24 Atriva Therapeutics
Dealmakers team
Editor Raveena Bhambra B22 Sanofi Pasteur
Editorial Assistant Georgia Francis
Profile Writers Emma Dorey,
Suzanne Elvidge, Dan Jones, Jackie Kelly,
Mary Lee Mackichan, Gaspar Taroncher-
Oldenburg, Nick Taylor
FEATURE
Feature Writers Raveena Bhambra,
Paul Verdin B25 Dealmaking in 2020: navigating a new landscape
Production Simon Fenwick,
Richard Thomas After a slow start to the year, dealmaking for the rest of 2020 is likely to be
Head of Business Development profoundly affected by the COVID-19 pandemic.
Claire Thompson
Business Development Manager
Verónica Zacatenco PROFILES
Account Executives Rebecca Djaic,
Carmen Ramirez B27 D&D PharmaTech B31 Panorama Medicine
Marketing Kimberly Petit, Jack Holloway
Publisher Richard Hughes
B28 nference B32 Henlius Biotech
B30 Noveome Biotherapeutics
Human iPSC derived glutamatergic
neurons for research and HTS
When cells need precision and consistency
www.bit.bio | info@bit.bio
FEATURE
Credit: Vitalii Gulenok / Alamy Stock Vector
Next-generation therapeutics
sustain momentum
The next-generation therapeutics space has continued to progress on several fronts in the past
12 months, but this could be set to change as the industry copes with the COVID-19 crisis.
Paul Verdin
In April 2019, the combined 2024 sales forecast for the cell, that affect cell therapies in general. It is also too soon to assess the
gene and nucleic acid therapy market was $41 billion, accord‑ impact of the COVID‑19 pandemic, which could dramatically
ing to EvaluatePharma sell‑side consensus forecasts (Biopharma affect future forecasts.
Dealmakers B15–17, June 2019). One year on, we analysed the
area again, and here we highlight the latest trends in market fore‑ Key approvals
casts, approvals, development pipeline focus, leading companies The past 12 months have kept up the recent approval momentum
and dealmaking for next‑generation therapeutics. in the field. Among the new products with the greatest expecta‑
tions is AveXis/Novartis’s Zolgensma (onasemnogene abeparv‑
Fluctuating forecasts ovec), which became the first US Food and Drug Administration
Although clinical progress has boosted the number of next‑ (FDA)‑approved gene therapy for spinal muscular atrophy (SMA)
generation therapeutic products on the market since 2019, our in May 2019. This approval also set up an interesting dynamic
analysis of the same landscape puts the overall forecast value in within the next‑generation therapeutics space, with Zolgensma
2024 at $38 billion—a 7% contraction of commercial expecta‑ launching into a market already occupied by Biogen’s Spinraza
tions (Fig. 1). (nusinersen, an antisense oligonucleotide). Both therapies target
Forecasts fluctuate of course, and volatility in forecast com‑ the underlying cause of SMA, but Zolgensma is theoretically a
mercial performance is to be expected in such a pioneering area. ‘one‑and‑done’ treatment, while Spinraza requires repeated
Looking beyond the headline value, however, reveals that forecasts administration. Zolgensma has checked Spinraza’s growth and
for DNA and RNA therapeutics (such as antisense oligonucle‑ is forecast to be the leader in an increasingly crowded SMA market
otides) and gene therapy have remained relatively stable—cell by 2024, with sales of $2.04 billion compared with $1.57 billion
therapy is where the largest declines are apparent, as forecasts for Spinraza.
have eroded by almost $3 billion (or approximately 20%) since Vyondys 53 (golodirsen), the second of Sarepta Therapeutics’
this time last year (Fig. 2). It is too soon to say whether this is the growing portfolio of exon‑skipping antisense oligonucleotides
beginning of a cooling‑off of commercial expectations for some for Duchenne muscular dystrophy (DMD), was approved by
cell therapy approaches. However, perhaps it could reflect grow‑ the FDA in December 2019. And in Europe, there was a first
ing recognition of the strong competition in some areas such as approval for bluebird bio, with a European Medicines Agency
blood cancers, as well as the access and affordability challenges (EMA) nod for Zynteglo (autologous CD34+ cells encoding the
40,000 18,000
2024 (April 2020)
35,000 Genome editing 17,000
Gene therapy 2024 (April 2019)
Sales forecast ($ million)
Sales forecast ($ million)
30,000 DNA and RNA therapeutics 16,000
Gene-modified cell therapy
25,000 Cell therapy 15,000
20,000 14,000
15,000 13,000
10,000 12,000
5,000 11,000
0 10,000
2020 2021 2022 2023 2024 Gene therapy Cell therapy DNA and RNA
therapeutics
Fig. 1 | Sales growth forecasts of cell, gene and nucleic acid Fig. 2 | Changes in sales growth forecast trends of cell, gene
therapy products from 2020 to 2024. Source: EvaluatePharma, and nucleic acid therapy products in 2024.
April 2020. Source: EvaluatePharma, April 2020.
biopharmadealmakers.nature.com | June 2020 | B3
FEATURE
Duchenne muscular dystrophy
Spinal muscular atrophy
Non-Hodgkin lymphoma
Amyloidosis
Multiple myeloma
Hemophilia A
Acute myeloid leukemia
Melanoma
Sickle cell disease
Hemophilia B
Huntington disease
Thalassemia
Chronic heart failure
Limb-girdle muscular dystrophy
Hyperlipidemia
Porphyria
Parkinson disease
Epidermolysis bullosa
2024 (April 2020)
Urinary calculi/kidney stones 2024 (April 2019)
Amyotrophic lateral sclerosis
0 500 1,000 1,500 2,000 2,500 3,000 3,500 4,000 4,500
Sales forecast ($ million)
Fig. 3 | Top 20 indications in the field of cell, gene and nucleic acid therapies, based on 2024 sales forecasts. Source: EvaluatePharma,
April 2020.
βA‑T87Q‑globin gene) for patients with β‑thalassemia, as well as marketed (Zolgensma and Spinraza), and >99% of the 2024 forecast
an EMA approval for Akcea/Ionis’s Waylivra (volanesorsen), an of $3.6 billion is contributed by these marketed products.
antisense oligonucleotide therapy for familial chylomicronemia The risk inherent in these forecasts is therefore very different,
syndrome. even without factoring in uncertainty around commercial per‑
The scale and diversity of progress being made in the next‑ formance once on the market. Across the top 20 indications by
generation therapeutics space is a testament to the industry’s 2024 sales, only 6 are currently validated to the extent of regula‑
ability and effort in developing novel science into commercial tory approval and so clearly the space will continue to be highly
products. Across the industry, EvaluatePharma lists >5,300 active dynamic.
R&D programs in cell and nucleic acid medicine, an increase of
6% on the same analysis 12 months ago. Just over 2,000 of these Companies taking the lead
next‑generation therapeutic programs are in clinical development This dynamism is also reflected in the company rankings (Fig. 4).
(an increase of 8% over 12 months), with more than 200 programs This time last year Sarepta led the pack in terms of 2024 forecast
in phase 3 trials or at the regulatory filing stage. sales, and few major biopharma players featured in the top 20
by forecast revenues. Again, only 5 of the top 20 companies are
Leading indications large biopharma: Novartis, Bristol‑Myers Squibb (following the
Current clinical development pipelines in the field have a large acquisition of Celgene), Biogen, Gilead and Roche. In this year’s
focus on oncology, with 16 of the top 20 indications in cancer. The analysis, however, Novartis leapfrogs Sarepta—albeit margin‑
most studied non‑oncology indications are rare ophthalmology ally—to become the top‑ranked company in the field, with sales
conditions, Parkinson disease, osteoarthritis and peripheral vas‑ forecasts of $4.25 billion versus Sarepta’s $4.14 billion in 2024.
cular disease (Fig. 3). In preclinical research, the trend is different: Indeed, something of a niche is opening up in an otherwise
13 of the top 20 most studied indications are outside oncology. highly fragmented landscape, with Novartis and Sarepta cementing
Looking at where the value is anticipated to rise, at least in the
near term, the picture is similar to 12 months ago. The top ranked
indications by 2024 sales are those for which next‑generation Methodology box
therapeutics are more clinically and commercially mature, with This analysis used data extracted from EvaluatePharma (data
DMD, SMA and non‑Hodgkin lymphoma topping the rankings. extracted in April 2020). Company and total product sales
Interestingly, 2024 forecasts for DMD are based on substantial forecasts are Evaluate Consensus Forecasts, and represent an
sales growth from pipeline products: of the 10 next‑generation unweighted average of up to six forecasts from equity analyst
research. Sales by indication are adapted from total product
therapeutics contributing to the 2024 sales forecast of $4.4 bil‑
sales using a proprietary methodology. Historical sales, R&D
lion only two are currently marketed—Sarepta’s Vyondys 53 and pipelines and product classifications are based on company-
Exondys 51 (eteplirsen)—and 80% of this forecast figure is tied disclosed information. All analysis, modelling, mapping and
to R&D‑stage programs. For SMA, the picture is the opposite: aggregation of data uses proprietary Evaluate methodologies.
two of the three products contributing to 2024 sales are already
B4 | June 2020 | biopharmadealmakers.nature.com
FEATURE
4,500
2024 (April 2020)
4,000
2024 (April 2019)
3,500
3,000
Sales forecast ($ million)
2,500
2,000
1,500
1,000
500
0
* l st
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Fig. 4 | Top 20 companies in the field of cell, gene and nucleic acid therapies, based on 2024 sales forecasts.
*Celgene forecasts in Apr 2019. Source: EvaluatePharma, April 2020.
their leading positions and each expected to generate sales approxi‑ ophthalmic disorders), and a February 2020 worldwide devel‑
mately double those of the next highest selling company in 2024 opment and commercialization licensing deal with Sangamo
(Alnylam, in third place with $2.2 billion sales in 2024). Therapeutics for gene regulation therapies in Alzheimer disease,
The Novartis portfolio delivering these sales is highly diversi‑ Parkinson disease and other neurological disorders (including
fied, and includes the gene therapy Zolgensma for SMA (sales over $350 million upfront). In December 2019, Roche bought in to
$2 billion in 2024), the chimeric antigen receptor (CAR)‑T cell Sarepta’s SRP‑9001 through licensing of ex‑US rights in a deal
therapy Kymriah (tisagenlecleucel) for blood cancers (sales over worth $750 million upfront and potentially up to $2.85 billion.
$1 billion in 2024) and the filed lipid‑lowering RNAi candidate
inclisiran (sales over $1 billion in 2024), which was obtained Outlook
through acquisition of The Medicines Company in November On the face of it, progress in the next‑generation therapeutics
2019. For Sarepta, the near‑term focus is on DMD, with far and space continued unabated in the past 12 months—pipelines
away the biggest catalyst to 2024 being the micro‑dystrophin progressed, more innovative new products were approved by
gene therapy SRP‑9001. Despite only being in phase 2 develop‑ the regulators, deals were done and sales forecasts anticipating
ment, SRP‑9001 is forecast to be the biggest‑selling product in rapid growth in the space largely held up, barring some declines
the cell and gene therapy space in 2024, with sales of more than in cell therapy.
$2.5 billion. But it should be noted this activity predates the COVID‑19
The remainder of the top 20 company ranking is comprised of pandemic that has swept across the world. It seems unavoidable
numerous smaller and focused players, with several of their peers that the industry will feel a negative impact from this unparal‑
serving as take‑out targets for major biopharma in the recent leled crisis; for example, in delays to clinical trial progress and
past—for example, AveXis, Spark and The Medicines Company. potential delays in regulatory approval for new products—and
next‑generation therapeutics will not be immune to this.
Dealmaking trends It is less clear how industry and societal thinking may evolve
Major pharmaceutical companies have predominantly entered the based on the impact of the pandemic; for example, in terms of
space through acquisition. Novartis has been particularly active in allocation of R&D and healthcare spending, and prioritization of
building its leading position through acquisition—its $8.7 billion research into infectious diseases over rare genetic and oncology
purchase of AveXis in 2018 was followed up in November 2019 settings. According to EvaluatePharma data,
A DV E RT I S E M E N T F E AT U R E
Elicio Therapeutics Inc.
www.elicio.com
Orchestrating the immune system
for precision immunity
Elicio’s lymph node-targeting Amphiphile technology delivers potent T cell
activation and boosts the effects of engineered cell therapies.
Immune cells are naturally gifted in recognizing
1 Albumin binder 2 Linker 3 Therapeutic payload options
antigens and fighting off infection and disease. But,
✓ Lymph node targeting ✓ Improves solubility
just like talented people, they need nurturing and Small
✓ APC presentation a
the right training to fulfil their true potential. For molecules
immune cells this means a spell in lymph nodes— O
the training camps of the immune system—where b Peptides
O
they receive specialized instruction in the art of O
c Nucleic acids
immune surveillance and attack. O
Today’s immunotherapies do not make use of
this powerful immunological form of education. d Proteins
The promise and effectiveness of immunotherapies
are widely recognized: chimeric antigen receptor T Fig. 1 | A modular conjugation approach for delivery of immune therapeutics to the lymph node. The
(CAR-T) cell therapies directed against the CD19 technology enables a lipophilic tail to bind to a linker domain, which is then able to attach to various types of
tumor antigen have been particularly effective immunomodulatory payload molecules.
against hematological malignancies, and check-
point inhibitors (CPIs) have emerged as a major at the Massachusetts Institute of Technology. Irvine then interact with effector immune cells as part of
focus for treating solid tumors. brought together materials scientists, immunolo- their training to become potent antigen-targeting
Yet the full potential of these therapeutic gists and oncologists to work at the interface of cells (Fig. 2).
approaches has not yet been unleashed. CAR-T materials science and immunology in an effort to
cell therapies can struggle to achieve clinically ben- solve the problem of how to target payloads to the Portfolio of candidates
eficial T cell expansion and persistence, often lack lymph nodes. Elicio has a range of candidates based on AMP
the ability to effectively infiltrate the tumor micro- Lymph nodes are one of the key secondary lym- technology in its proprietary pipeline: cancer vac-
environment and over time lose their tumor-killing phoid tissues where immune cells congregate and cines that combine antigenic peptides and adjuvant
functions. At the same time, CPI therapies have where adaptive immune responses are initiated. It is with an AMP molecule; AMP-linked activators of
demonstrated the ability of the immune response here that the complex cellular interactions required CAR-T cells for hematological and solid tumors;
to kill solid tumors, but their efficacy has been lim- for an effective immune response are finely orches- AMP cytokines; and AMP adjuvants.
ited because in these therapies few spontaneously trated, and is why the lymphatic system is said to Elicio’s most advanced cancer vaccine program
arising T cells infiltrate tumors that have a low rate be the brain or command centre of the immune is focused on patients with tumors carrying muta-
of neoantigen mutation. The key to overcoming system. The learning environment of the lymph tions in KRAS, which make up roughly 25% of all
these limitations, Elicio Therapeutics believes, is to node endows immune cells with skills that are human solid tumors and are even more prevalent
make use of the specialized immunological training harder to learn elsewhere, such as how to achieve in specific cancers—up to 90% of pancreatic can-
environment of the lymph nodes, to prime T cells T cell expansion and persistence; how to effectively cers, 50% of colorectal cancers and 30% of non-
to become more effective at their job. hone in on and penetrate solid tumors; and how to small-cell lung cancers. KRAS is widely recognized
promote immune memory and antigen spreading. as promising in immunotherapy, and has been
Transporting immunomodulatory Getting molecules of interest into lymph nodes, singled out by the National Cancer Institute as
payloads and making sure they stay there long enough one of the only true public neoantigens, meaning
Elicio is tackling this challenge with next-gener- to do useful work, faces some key hurdles. One that it is not only highly prevalent and clinically
ation immunotherapies based on its proprietary of the most fundamental is that the smaller the relevant, but also a target that the immune system
Amphiphile (AMP) technology, which can effec- molecule, the less likely it is to accumulate in the is especially well suited to recognizing as a tumor-
tively ferry immunomodulatory payloads—from lymph nodes—an issue that affects small mol- differentiating marker. And the biology of KRAS
small molecules and peptides to DNA and pro- ecules, peptides, proteins and other biopolymers. is compelling as mutations in this gene need to
teins—to the lymph nodes, where immune cells The AMP strategy is to piggyback on a very large be maintained in all the tumor cells in most of
learn how to recognize these immunomodulators molecule, one that naturally accumulates in lymph the tumor types in which it is implicated. So if
and react appropriately to them. Elicio is applying nodes: albumin. all tumor cells carrying KRAS mutations can be
the AMP platform to developing new cancer vac- The core of the AMP technology is a lipophilic tail eradicated in a tumor, there is potential for a long,
cines, creating more potent responses from CAR-T that mimics fatty acids that albumin naturally binds durable response.
cells and delivering cytokines, immunomodulators to, connected to a linker domain to which various Elicio’s ELI-002 comprises AMPs carrying com-
and adjuvants to lymph nodes. The unique, broadly types of immunomodulatory payload molecules mon KRAS-mutated peptides, along with a powerful
applicable lymph node-targeting AMP technology can be attached (Fig. 1). When injected into tissue, immune-activating adjuvant, to elicit an immune
has the potential to address many unmet medical cargo-loaded AMPs bind to locally present albumin, response that engages both innate immunity
needs and bring enormous benefits to patients. are transported through the lymphatic vessels and (dendritic cells) and adaptive immunity (T cells)
The AMP technology grew out of the multi-disci- finally accumulate in lymph nodes. Here, the immu- to increase tumor targeting. ELI-002 targets the
plinary lab of Darrell Irvine, a biological engineer at nomodulatory payload ferried to the lymph nodes is seven position 12 and 13 KRAS mutations that are
the Koch Institute for Integrative Cancer Research taken up by antigen-presenting cells (APCs), which seen in more than 99% of KRAS-driven cancers,
B6 | June 2020 | biopharmadealmakers.nature.com 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 T
A DV E RT I S E M E N T F E AT U R E
Subcutaneous
Elicio is using its AMP technology platform to
injection site AMP AMP compounds bearing
compound bring out the best in CAR-T cell therapies. The
(a) peptide antigens
or (b) CAR ligands are approach is to attach CAR-T activators to AMPs,
injected into recipients which, once carried to lymph nodes by albumin,
1 Binding to insert themselves into the surface of APCs through
and upon binding to
albumin at
albumin, are transported their fatty acid tails. These APCs then present the
injection site
into the lymph nodes activator molecules to CAR-T cells in the lymph
Albumin
nodes, priming them to mount a potent response
to tumor cells carrying the antigen they have been
engineered to recognize (Fig. 2).
2 Lymph node 3 Migration of Elicio’s proof-of-concept studies have shown how
trafficking T cells to tumor effective AMP CAR-T activators are. In a standard
on albumin CAR-T cell approach, at best 20% of a patient’s
T cells are converted to recognize the tumor anti-
gen that the CAR-T cells have been engineered to
MHC a detect. When combined with AMP CAR-T activa-
b In the lymph node, APCs take tors, however, this jumps to as much as 70% or
Tumor cell
TCR up or surface-present AMP more in animal models. In addition, a number of
compounds to stimulate current CAR-T therapies that have shown potent
(a) TCR-T or (b) CAR-T cells anticancer activity have been hampered in practice
to induce T cell activation,
proliferation, and by toxicity caused by the high doses required for
tumor-homing Enhanced trafficking systemic delivery. The AMP technology can rescue
CAR these CAR-T therapies by targeting lower doses to
of T cells into solid
tumors results in the lymph nodes so they become highly effective
antitumor activity tumor-destroying cells, while limiting exposure to
TCR-T cell Active CAR-T cell Inactive CAR-T cell
other sites in the body.
Fig. 2 | Targeting the lymph nodes with Elicio’s amphiphile technology. Loaded with its immunomodulatory Compared with CAR-T cell therapy alone, Elicio’s
payload, the amphiphiles (AMPs) are injected into tissue where they bind to locally present albumin. From AMP–CAR-T combination leads to a tenfold
there they travel through the lymphatic vessels to gather in the lymph nodes. Antigen-presenting cells increase in the infiltration of solid tumors, a ten-
(APCs) in the lymph nodes then internalize or surface-present the AMP payloads to enable potent fold greater cytokine response, enhanced cytolytic
activating interactions with TCR-T or CAR-T cells, which empower them to seek out and destroy tumor function and the induction of ‘antigen spreading’,
cells. CAR, chimeric antigen receptor; TCR, T cell receptor; MHC, major histocompatibility complex. in which the native immune response is triggered
to recognize tumor-specific antigens other than
and contains seven AMP peptides containing these control arm to ELI-002 at the time of relapse, the one targeted by the CAR-T cell. In models in
mutations plus an AMP carrying a CpG Toll-like so that RECIST radiographic data on metastatic which CAR-T cell therapy by itself provides no
receptor 9 agonist. disease can be assessed. The trial is planned to detectable therapeutic effect, the AMP–CAR-T
Preclinical in vivo models have demonstrated begin in 2020. combination leads to durable cure in a large pro-
that ELI-002 is precisely targeted to lymph nodes, Elicio has recently begun a collaboration with James portion of animals.
where it creates a powerful T cell response that is Yang’s laboratory at the National Cancer Institute, Beyond developing AMP cancer vaccines and
more than 100 times greater than that achieved which has pioneered T cell therapies for solid tumors, CAR-T cell activator, Elicio is developing ELI-004,
with conventional therapies. These lymph node- to characterize T cell responses to ELI-002 in mice an AMP-adjuvant with applications in a variety of
primed T cells, which become prolific producers genetically engineered to carry human leukocyte indications and therapies, including as the adju-
of cytokines that are important for an effective antigen (HLA) genes important for the immune vant component of ELI-002. Finally, Elicio has
antitumor response, are highly effective killers of response. This study will not only inform how patient earlier-stage programs using AMP technology to
KRAS-specific targets, and are able to specifically responses are monitored in the clinical study of ELI- deliver cytokines, immunomodulators and other
recognize all seven mutational variants of KRAS. 002, but will also help use trial data to identify novel adjuvants to the lymph nodes for stimulating a
Similar AMP vaccine approaches developed by T cell receptors for future T cell therapies. potent immune response.
Elicio and tested in other models have produced Elicio’s other major application of AMPs is to Immunotherapies have proved their worth, but
complete cures and resistance to otherwise lethal unleash the full potential of CAR-T cell therapies. for many specific therapies their full effectiveness
doses of tumor re-challenge. CAR-T cell therapies have demonstrated remark- has remained untapped, or they have been beset
In colorectal cancer care, patients with KRAS able therapeutic results and have been shown to by problems linked to toxicity. AMP technology
mutations are excluded from treatment with mono- completely eliminate tumors in some forms of addresses both issues. Elicio’s strategy is to con-
clonal antibodies against epidermal growth factor cancer, especially hematological malignancies, in tinue developing AMP applications to expand the
receptor, so that a therapeutic candidate for this some patients. Yet they have failed to show similar range of diseases to which it can be applied, and to
subgroup holds potential to address a large group benefits in most other cancer settings, with solid focus on building a proprietary pipeline around this
currently in need of an effective therapy. tumors posing a particular challenge—largely due core platform. At the same time, Elicio is keen to
Elicio is poised to begin a prospective, multi- to the fact that current CAR-T cells lack the ability partner with companies developing complementary
center phase 1/2 clinical trial of ELI-002 in patients to properly expand their numbers, to efficiently technology, specifically in the cell therapy space, to
with locally advanced pancreatic ductal adenocar- infiltrate solid tumors and to effectively kill cancer usher in a new era of immunotherapies.
cinoma, colorectal cancer and other tumors after cells. A major reason for these limitations is that
standard therapy. In the clinical trial of ELI-002, CAR-T cells, as currently used, do not engage the
patients will be screened to identify those with lymph nodes at all. As a result, they are not acti- Robert Connelly, CEO
CONTACT
tumors containing KRAS mutation and with mini- vated at these key immune-orchestrating sites, and Elicio Therapeutics Inc.
mal residual disease assessed by the presence of miss out on the education and training that lymph Cambridge, MA, USA
circulating tumor DNA—a group of patients that nodes provide to ensure that T cells become the Tel: +1-339-206-0793
almost universally relapse. The trial is designed best cancer-destroying cells they can be and remain Email: robert.connelly@elicio.com
to allow crossover of patients assigned to the functional and expanded over time.
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 T biopharmadealmakers.nature.com | June 2020 | B7A DV E RT I S E M E N T F E AT U R E
NovaGo Therapeutics AG
www.novagotherapeutics.com
Novel regenerative treatments for
CNS disorders and cerebral stroke
Biotech start-up company NovaGo is developing human antibodies that stimulate nerve repair and
regeneration following a stroke. The company’s lead candidate anti-Nogo-A antibody (NG004)
is ready for phase 1 trials, and it is looking for partners to develop it through the clinic.
Stroke is the leading cause of adult disability in Stroke
the developed world, affecting approximately lesion
33 million patients worldwide and costing more than
€40 billion per year in direct and indirect costs in the
EU alone. Following a stroke, rapid re-establishment
of blood flow can reduce tissue and neuron injury,
Oligodendrocyte Nogo-A Sprouting
but there is no pharmacotherapy available that can
of nerve
regenerate damaged regions of the brain; the main- fibers
stay of stroke treatment is rehabilitation therapy, NG004 Nogo66
Δ20
which typically results in only modest improvements LINGO1, NgR1
or recovery of function, leaving more than half of and p75
stroke patients severely and permanently disabled.
As the global incidence of stroke is increasing at the S1PR2 Nerve fiber growth
same time as death from stroke is declining, stroke Actin destabilization and
is now a disease of chronically disabled survivors, Neuron growth cone collapse
many of whom lose their independence and are
forced to live in nursing homes. Fig. 1 | NovaGo’s anti-Nogo-A therapy for stroke. The recombinant human monoclonal antibody NG004
NovaGo Therapeutics, a biotech start-up induces neurite outgrowth by blocking the binding of Nogo-A to the Nogo-A receptor complex, preventing
company that develops human antibodies that its activation (centre box). This allows neurons to make new connections, thereby promoting the
stimulate nerve repair and regeneration, is set to neurological regenerative healing process, which in turn leads to a higher degree of functional recovery
address this large unmet medical need. The com- (right). Regeneration is observed near the injured site and in contralateral areas of the brain. This illustration
pany’s co-founder and president, Martin E. Schwab, is a prediction of how NG004 could work in humans based on data obtained from current animal models.
previously discovered that neurite growth inhibi-
tors prevent repair and regeneration in the central After a cerebral stroke, animals given the antibody Clinical studies partners
nervous system (CNS). Although needed for proper for 2 weeks followed by 4 weeks of rehabilitation NovaGo’s founding and management team has a
CNS development and maintenance, they obstruct exercises recover 70–85% of function compared proven track record in research and drug devel-
the regenerative process following stroke or injury, with only 40% for control animals receiving rehab opment, and maintains international networks
limiting recovery of function. Schwab identified alone. “Our anti-Nogo-A therapy boosts the sprout- across academia and industry, including close col-
Nogo-A as a key inhibitor of axonal growth. Since ing of new nerve fibers, and the newly formed laborations with the University of Zurich and the
then he has founded NovaGo Therapeutics to pur- circuits are stabilized by intensive training,” said University Hospital in Zurich, Switzerland, where
sue the development of regenerative therapies for Vianna. “Our results have overthrown the dogma the company has its headquarters. NovaGo has
CNS disorders. A strategic partnership with bio- in medicine that injuries of the brain and spinal cord started a series B investment round and is look-
pharmaceutical company Neurimmune enabled the will not heal and cannot be repaired.” ing for suitable investors willing to participate as
discovery of specifically targeted human-derived Furthermore, the time window for administering partners to support clinical studies of anti-Nogo-
antibodies that block Nogo-A. the anti-Nogo-A therapy extends from days to weeks A through proof of concept to phase 2. “We are
By inhibiting Nogo-A, NovaGo’s lead anti-Nogo-A or even months after a stroke, enabling treatment looking for investors who have an understanding
antibody (NG004) induces neurite outgrowth—not of chronic strokes, months after the acute infarct. of stroke and are willing to partner with us on this
only near the injured site but also in contralateral Phase 1 trials are scheduled to start by the middle journey,” said Vianna. “Our first-in-class regenera-
or other areas of the brain. The neuronal sprout- of 2021. A trial in patients with spinal cord injury is tive therapy for stroke has a unique mechanism
ing, together with rehabilitation exercise, enables already ongoing and has shown that anti-Nogo-A of action that leads to a large degree of functional
significantly more recovery of function than rehab therapies are safe and tolerable. However, high recovery that could be life changing for sufferers of
alone (Fig. 1). “Unlike a neuroprotectant, our recom- patient heterogeneity in stroke research presents this debilitating and disabling condition.”
binant human monoclonal antibody allows neurons a challenge, as recovery for each patient will depend
to make new connections,” explained Eduardo on the type, size and location of the resulting lesion,
Vianna, CEO. “This promotes the central nervous their age, concurrent disorders and so on. Therefore,
system’s regenerative healing process and neuro- end points will include recovery of motor functions
logical recovery and should allow stroke patients and quality of life assessment using stroke-specific Eduardo Vianna
CONTACT
to recover much more function.” scales. “Clinically, any improvement in nerve fiber NovaGo Therapeutics AG
Preclinical studies in rodent and non-human regeneration and neural circuit repair is expected Schlieren, Switzerland
primate models demonstrate that anti-Nogo-A to have a strong impact on patients’ outcomes and Tel: +41 43 300 52 63
therapy is highly effective in enhancing nerve fiber could dramatically enhance their quality of life,” Email: info@novagotherapeutics.com
repair and the formation of new fiber connections. said Vianna.
B8 | June 2020 | biopharmadealmakers.nature.com 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 TA DV E RT I S E M E N T F E AT U R E
Biovian
www.biovian.com
Biovian: a true one-stop-shop CDMO with
gene therapy capacity and a Nordic ethos
Covering the whole production chain from the supply end to the value end, Nordic Biovian delivers a
comprehensive and reliable manufacturing service, enabling the development of medical therapies.
Biovian is clearing bottlenecks in gene therapy pro-
duction with its complete one-stop-shop service.
Guided by its Nordic ethos, the contract develop-
ment and manufacturing organization (CDMO)
has built a reputation for delivering high-quality
work on time and on budget to a global client base.
Having done so, Biovian is continuing to expand its
operation, adding scale and capabilities to support
the development of breakthrough therapies.
‘One-stop shop’ is a term frequently used in the
CDMO space, yet it is often poorly defined. Biovian
views the concept along two axes, the supply chain
and the value chain. To be a true one-stop shop, a
CDMO needs to offer the full breadth of services
along both the supply chain and the value chain.
Biovian meets that definition (Fig. 1). On the
supply chain, Biovian’s services span from master
cell banking to qualified person release of the final
labelled drug product.
Similarly, on the value chain Biovian’s services run Fig. 1 | Biovian offers clients a true one-stop-shop good manufacturing practice (GMP) contract
from preclinical supply up to commercial supply or development and manufacturing organization (CDMO) service, with modularity available from gene
manufacturing, enabling it to continue supporting to finished vial.
clients as they take molecules through development
and onto the market. At each stage, Biovian adheres education system, Biovian’s staff share its focus on Specifically, Biovian moved into the production
to good manufacturing practice (GMP) and works quality, honesty and reliability, values that are rein- of the plasmids that form the building blocks of
out of fully inspected, fully certified facilities. forced through the nature of interactions between viral vectors, making it a true one-stop shop for
The breadth of Biovian’s offering along both the the company and its employees. gene therapies.
supply and value chains differentiates it from some By taking a straightforward, human-centric Biovian is continuing to add to its capabilities.
other CDMOs, which present themselves as one- approach to internal and external relationships, In 2021, the CDMO will open an aseptic filling
stop shops but have gaps in their offerings that force Biovian has built a culture that prioritizes customer line for recombinant proteins and plasmid DNA,
clients to enlist other service providers for some satisfaction and employee fulfillment equally. The adding to its existing biosafety level 1 and 2 viral
work. Biovian is a true one-stop-shop CDMO. result is a CDMO that is institutionally driven to vector fill-and-finish capabilities. The new fully
deliver on its promises. automated filling line, which supports batches of
How Nordic values guide Biovian up to 10,000 vials, features a restricted-access
The clear definition of one-stop shop is in keeping Investing to serve changing client needs barrier system to ensure aseptic quality without
with Biovian’s straightforward, transparent approach Biovian’s strong relationships with employees and sacrificing process flexibility.
to all communications and interactions with clients. clients alike help it stay abreast of changes in the The investments in viral vectors and fill-and-
As a Finnish CDMO, Biovian’s approach is informed type of services biopharma companies need. Such finish capacity are in line with the approach that
by the culture and world-leading education system insights helped Biovian to foresee the ongoing surge has established Biovian as a premium CDMO. In
of the Nordic region. Words such as quality, hon- in demand for gene therapy manufacturing services a competitive market, Biovian has differentiated
esty and reliability that are inextricably linked to the and invest accordingly. Having done so, Biovian itself by pairing leading-edge production capabili-
Nordic region are embedded deep in Biovian’s ethos. is easing two critical bottlenecks in gene therapy ties with its Nordic ethos, enabling it to deliver the
That ethos can be boiled down to a simple state- production today: viral vectors and plasmids. materials clients need, when they need them, at
ment: “We do what we say we will do.” Those eight In 2020, Biovian opened an expanded GMP viral the agreed quality.
words capture the essence of Biovian’s approach vector manufacturing plant, more than doubling
to clients, an approach that has enabled it to build its capacity to make adeno-associated viruses,
a global customer base since it began operating in adenoviruses and other viral vectors vital to the
2003. If Biovian says it will provide a deliverable by delivery of gene therapies. Through the expansion, Antti Nieminen, Director,
CONTACT
a particular date for a particular price, clients can be Biovian added a 200 l bioreactor, equipping it to Business Development and Projects
confident it will do everything in its power to do so. continue to serve clients as they take gene therapies Biovian
Biovian’s ability to live up to those expectations into late-phase clinical trials and onto the market. Turku, Finland
rests on its employees, who have the expertise and Reflecting Biovian’s definition of one-stop shop, Tel: +358 40 502 13 32
scientific skills needed for challenging projects. that expansion along the supply chain was accom- Email: antti.nieminen@biovian.com
As importantly, having come through the Finnish panied by an expansion along the value chain.
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 T biopharmadealmakers.nature.com | June 2020 | B9A DV E RT I S E M E N T F E AT U R E
Cellatoz Therapeutics, Inc.
cellatozrx.com/en
A new era of cell therapies for intractable diseases
Biotech company Cellatoz Therapeutics is developing innovative cell therapies by applying its proprietary cells, known
as A-to-Z cells to multiple therapeutic areas. The company is now looking for partners to develop the therapies further.
Cellatoz Therapeutics is leveraging lessons learnt Cell types Functions Indications
from the first wave of cell therapies to overcome
barriers to the treatment of intractable diseases. 16
ENK
Equipped with proprietary cells, Cellatoz is ushering
in a new era for cell therapies defined by cell-specific CD16 ADCC and
markers and the regeneration of damaged cells or immune
balancing Lung cancer
tissues. Now, having generated evidence that its
approach has potential, Cellatoz is seeking a partner NK cell
and funding to bring its cell therapies to patients.
NRPC Prostate cancer
Early attempts to use stem cells to treat disease
failed to live up to expectations, with the harvesting Ovarian cancer
Peripheral PNI caused by
and activation of primary cells and mesenchymal nerve
stem cells (MSCs) yielding therapies with marginal CMT disease
regeneration and other
efficacy. The setbacks pointed to a new way forward diseases
for the field, leading Cellatoz to set out in 2017 to
create reliable, novel, stem cell therapies. MSSC Osteoarthritis
Cellatoz’s approach is based on proprietary cells, Skeletal tissue
known as A-to-Z cells, with applications in multiple regeneration
therapeutic areas. Rather than simply harvesting (bone, cartilage,
tendon, etc.)
and activating primary cells and MSCs, Cellatoz is
working with different starting materials and dif-
ferentiating them to create therapies capable of Fig. 1 | Applications of the proprietary A-to-Z cells at Cellatoz. The illustration shows the individual
treating intractable diseases. functions of each of the cell types and the diseases that they directly target. 16ENK, CD16-highly expressing
NK cell; ADCC, antibody-dependent cellular cytotoxicity; CMT, Charcot–Marie–Tooth; MSSC,
How A-to-Z cells treat disease musculoskeletal stem cell; NRPC, neuronal regeneration-promoting cell; PNI, peripheral nerve injury.
Cellatoz has discussed three applications of its
A-to-Z cells to date (Fig. 1). In one program, Cellatoz disease and other health conditions caused by dam- The progress of the programs has led Cellatoz to
is using pluripotent stem cells to create musculo- age to the peripheral nervous system. CLZ-2002 seek support for the next steps. With the MSSC
skeletal stem cells (MSSCs) capable of differentiat- remyelinated sciatic nerves in an animal model CLZ-1001 targeting osteoarthritis, a major indica-
ing into bone, tendon, muscle and cartilage. As the of CMT, driving Cellatoz to start testing the cell tion, Cellatoz is seeking a partner to support clinical
cells themselves, as well as the methodology and therapy in another animal model1. development of that drug candidate.
media used to make them, are proprietary, Cellatoz Cellatoz is also developing autologous CD16- Cellatoz is taking a different approach to CLZ-
is in the process of establishing a thicket of patents. highly expressing natural killer cells (16ENKs). Using 2002 and CLZ-3001. As CLZ-2002 targets a rare
The protection is more comprehensive than is usual a proprietary high-yield method, Cellatoz manufac- disease, CMT, Cellatoz is talking to patient advocacy
as ordinarily companies use non-proprietary cells. tures homogenized NK cells that express CD16 on groups and plans to take that cell therapy forward
There is evidence that Cellatoz’s proprietary their surface. Cellatoz thinks the presence of CD16 itself using the proceeds of a series B round that it
approach to cell therapy could translate into bet- will lead to antibody-dependent cellular cytotoxic- is in the process of raising. Cellatoz also plans to
ter outcomes. Nonclinical studies showed that ity, suggesting that 16ENKs will work synergistically test CLZ-3001 in patients in Korea, its home market,
a MSSC therapy, CLZ-1001, proliferates and dif- with immuno-oncology drugs. and Japan itself before expanding globally.
ferentiates at the injection site to regenerate bone Work is underway to validate that hypothesis by Through the clinical trials, Cellatoz stands to
tissue, thereby enabling recovery from severe inju- testing Cellatoz’s lead 16ENK, CLZ-3001, in ovarian validate the hypothesis that its A-to-Z cells could
ries. Buoyed by the data, Cellatoz plans to develop cancer and other tumor types. As an autologous perform better than the first generation of cell thera-
CLZ-1001 as a treatment for osteoarthritis of the cell therapy, CLZ-3001 is suitable for repeat dosing, pies based on primary cells and undifferentiated
knee, either as a new drug or in combination with enabling Cellatoz the potential to treat cancer by MSCs. In doing so, Cellatoz will lead to the era of cell
a medical device. rebalancing the immune system, rather than by just therapy 2.0, unlocking the therapeutic potential of
Cellatoz is advancing MSSCs in parallel to work on activating certain cells. human cells to tackle major unmet medical needs.
allogeneic neuronal regeneration-promoting cells 1. Park, S. et al. Int. J. Mol. Sci. 19, E2393 (2018).
(NRPCs). These Schwann-like cells are differenti- Taking the pipeline forward
ated from tonsil-derived MSCs. By differentiating Having raised a $10 million series A financing
the cells, Cellatoz has improved on the efficacy round in 2019, Cellatoz has advanced its lead pro- Jaeseung Lim, Chief Executive Officer
CONTACT
of MSCs that are merely harvested and isolated. grams into nonclinical studies with a view to filing & Chief Scientific Officer/Co-founder
NRPCs secrete neurotropic factors to induce axon investigational new drugs (INDs) in the first half Cellatoz Therapeutics, Inc.
sprouting and remyelination of damaged nerves. of 2021. The work is taking place at a state-of-the- Gyeonggi-do, Republic of Korea
In light of those characteristics, Cellatoz is art research laboratory and good manufacturing Tel: + 82 31 622 4300
applying NRPCs, in the form of CLZ-2002, to the practice (GMP) production plant that Cellatoz Email: jlim@cellatozrx.com
treatment of Charcot–Marie–Tooth (CMT) type 1A constructed to house its 35-person team.
B10 | June 2020 | biopharmadealmakers.nature.com 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 TA DV E RT I S E M E N T F E AT U R E
inRegen
www.inregen.com
A personalized approach to halting kidney disease
inRegen’s personalized progenitor cell therapy injects autologous kidney cells (REACT) into patients’ damaged kidneys, where
cells migrate and restore kidney function. The cell-based treatment is showing signs of promise in ongoing phase 2 trials.
inRegen has developed a treatment for chronic INJECTION MIGRATION
kidney disease (CKD), now in phase 2 trials, that
leverages a patient’s own kidney cells to repair dam- INTEGRATION
age and improve kidney function. The approach is an
auto-transplant of progenitor cells obtained via kid- New cells
ney biopsy and then reintroduced back into the kid- integrate
ney where they migrate to damaged kidney tissue, REPAIR and/or
averting disease progression. According to inRegen Formulation is REGENERATION
CEO Tim Bertram, “Our personalized, autologous injected in the New
Live cells
cell therapy doesn’t require immunosuppression, is cortex of the glomeruli
migrate to
given as a simple injection, yet has unique potential diseased kidney
injured Cytokines
to restore renal function lost to progressive CKD, structures generate
transforming treatment and outcomes by delaying healthy new
or preventing end-stage kidney disease.” Progenitor cell
therapy structures in
Kidney disease affects ~850 million people world- the nephron
wide. In the USA alone, 37 million people, half of
them diabetic, suffer from CKD and are at risk of New
progressing to kidney failure. Arnold Silva, Director tubules
of Clinical Research, Boise Kidney and Hypertension
Institute, and an investigator in inRegen’s clinical
trials, notes, “The full impact of CKD has been under-
appreciated, with little in the way of new treatments
in the last two decades. Current therapies typically Fig. 1 | Renal progenitor REACT patient-derived cell therapy. Autologous kidney progenitor cells are
address the effects of reduced renal function, such injected into the kidney, where they rapidly migrate to diseased areas and integrate into nephronic
as anemia, acid/base imbalance and hypertension, structures (glomeruli and tubules), re-establishing kidney repair potential and restoring function.
or underlying systemic disease, like diabetes and
autoimmune disorders. inRegen’s cell-based therapy reintroduced into the kidney via injection on an treatment group. The studies are nearing comple-
treats the kidney itself, and may finally offer a means outpatient basis, without the need for immuno- tion, with phase 3 trials slated to begin within the
to stop or even reverse CKD progression.” suppression. The infused progenitor cells migrate year. In addition, a phase 1 trial in adult patients with
rapidly to diseased areas, replacing damaged cells in CKD due to congenital anomalies of the kidney and
Identifying kidney regeneration cells tubules and glomeruli and regenerating new neph- urinary tract (CAKUT) is currently enrolling in the
Although kidneys are normally capable of recover- ron structures (Fig. 1). The cells also localize in the USA and will be expanding to Mexico, where lack
ing from acute injury, there is no current scientific interstitium, reducing fibrosis and inflammation, of surgical correction of CAKUT in childhood leads
support for the existence of a kidney stem cell. while modulating epithelial transdifferentiation. to a higher incidence of CKD in adulthood.
Undeterred by the decade-old challenge, with inRegen scientists hypothesize that kidney pro- Kidney progenitor cells are highly sensitive to
venture backing, inRegen scientists pursued a genitor cells are programmed to heal damage, but handling and prone to apoptosis. inRegen has
functional approach, systematically testing multiple in CKD become trapped by scars and effete from developed proprietary methods to enable isolation,
kidney cell types in hundreds of combinations chronic inflammation, preventing normal function. growth, formulation, and shipping of its cell-based
to deconvolute the activity in healthy kidneys This view is supported by the observation that these therapy and holds extensive intellectual property
responsible for regeneration in vivo. Their efforts progenitor cells produce high levels of anti-inflam- (200-plus patents and patent applications) for
ultimately succeeded in identifying a combination matory cytokines. By isolating and re-infusing these composition, therapeutic use and methods of
of cells able to form kidney tubules and Bowman’s expert repair cells, inRegen’s therapy may replenish manufacturing. For patients in the on-going clini-
capsule in vitro. The cell mix included kidney pro- natural reserves, allowing them to re-establish and cal trials, GMP manufacturing of autologous cell
genitors with distinct phenotypic markers, including maintain a healthy baseline function in the kidney. treatments is being conducted in partnership with
SIX2, OSR1, PAX2 and RET1. In preclinical studies, Twin City Bio. inRegen plans to scale up clinical and
this combination of cells was able to induce new Promising clinical trials commercial efforts to address the global scope of
nephron formation, reduce disease and stabilize or A first-in-human study with inRegen’s progenitor the unmet need in CKD.
improve multiple kidney functions, demonstrating cell-based treatment, conducted at the Karolinska 1. Kelley, R. et al. Cell Transplant. 22, 1023–1039 (2013).
long-term improvement in three different rodent Institute (Sweden), demonstrated that it was well
models of severe CKD and a 70% nephrectomized tolerated. The therapy was granted US Food and
canine model1. Drug Administration fast-track status, and phase 2 Tim Bertram, CEO
CONTACT
In the REACT (Renal Autologus Cell Therapy) trials in patients with diabetes with moderate to inRegen
clinical trials, patients undergo a kidney biopsy, severe CKD were approved. Interim results of the Grand Cayman, Cayman Islands
and cells are isolated from the tissue under good randomized, controlled phase 2 trial showed earlier Tel: +1-336-448-2845/2880
manufacturing practice (GMP) conditions. The disease progression to dialysis in the control (stan- Email: tim.bertram@inregen.com
selected autologous, healthy progenitor cells are dard-of-care) group compared with the REACT
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 T biopharmadealmakers.nature.com | June 2020 | B11A DV E RT I S E M E N T F E AT U R E
Synplogen Co., Ltd.
www.synplogen.com
Using one-step DNA assembly
to create designer DNA
Japanese company Synplogen uses technology based on over a decade of academic research
to design and manufacture long and complex sequences of synthetic DNA. The company
is also engaged in novel drug discovery and R&D of gene and cell therapies.
As the synthetic biology market continues to grow, 47 7 9 37
there is increasing demand for longer length, error- 26 35 24 34 50 DNA fragments
2
36 38
25
33
41
46
40 20
+
1
23
18
free DNA of over 5,000 bp in length, sometimes 9
45
10
11
48 29
27
39
17
50
21
Plasmid vector
22
44
12
15
much longer. These sequences of bespoke DNA 19
8
31
28
43
13
14
32
16
30
5
49
3 4
42
are crucial for unlocking the power of synthetic
biology for use in a wide range of sectors such as One step
medical, industrial biotech, materials engineering,
and the chemical, agricultural and energy sectors. 1 5 10 15 20 25 30 35 40 45 50
However, creating these designer strands accu-
rately, efficiently and cost-effectively can be chal-
lenging. Factors such as the length, complexity or Plasmid DNA assembled 50 DNA fragments
B. subtilis with designed orientation and order
repetitiveness of the sequence, or unusually high
concentrations of certain types of nucleotides, often Plasmid extraction
make certain desirable DNA sequences difficult
or impossible to synthesize with currently com-
Synthesized long DNA (~100 kb)
mercialized methods. Synplogen’s mission is to
develop and commercialize technologies for the
design and synthesis of these complex and high- By adjusting the size of material DNA fragments strictly,
value stretches of DNA, which are traditionally gene assembly of more than 50 fragments is feasible:
challenging to manufacture. • Feasible to construct • Very precise DNA • Construction is • Automation
~100 kb DNA with compared with other finished in a single friendly
The origins of the technology designed sequence methods step
In 2003, Kenji Tsuge and his colleagues at the
Mitsubishi Kagaku Institute of Life Sciences cre- Fig. 1 | Synplogen’s OGAB technology. Ordered gene assembly in Bacillus subtilis (OGAB) uses B. subtilis to
ated a technology for the one-step assembly of assemble DNA fragments into a specific orientation and order to create long-chain DNA.
DNA fragments into a strand of DNA with a specific
order and orientation. The proprietary technology, Creating longer length DNA using OGAB exponentially harder to achieve as the length of the
known as ordered gene assembly in Bacillus subtilis Long chain DNA is constructed in vitro, using strands linear DNA increases. On the other hand, yeast-
(OGAB), grew out of a project to create hybrid bac- of genetic material of around 1,000 bp in length. based technologies can struggle with GC-rich DNA,
terial genomes, as well as novel genomic DNA not These strands or ‘blocks’ of DNA then have to be especially at 70% or greater. To overcome these
found in existing organisms (Fig. 1). OGAB became linked together using cell-based processes. Many issues, Synplogen chose the well-characterized
the basis for Kobe City-based startup Synplogen, companies and researchers use Escherichia coli or organism B. subtilis, known for its industrial use in
founded in February 2017 by Tsuge and Akihiko budding yeasts for this process, but each of these the production of natto (fermented soya beans), to
Kondo, now both company directors. In May 2019, techniques has its own challenges. On one hand, use as the basis for the OGAB technology.
Synplogen licensed another key companion tech- in the case of E. coli, as it can only take up circular Synplogen’s OGAB-based platform can assemble
nology from Kobe University for the combinatorial DNA, an additional step is required to circularize linear DNA strands of up to 100 kb with very high
use of the OGAB method (combi-OGAB), which the genetic material in vitro. However, the effi- precision. 50 or more DNA fragments, referred
was developed by Tsuge during his time there. ciency of in vitro circularization is low and becomes to as OGAB blocks, can be used with a success
B12 | June 2020 | biopharmadealmakers.nature.com 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 TYou can also read
