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2010

ACTIVITY REPORT
CONTENTS

4 Note from the CEO



6 2010 Highlights

10 Cellectis In brIef

12 Our core activity

16 CellectiS In 2010

18 Our science

22 Business development

24 Corporate development

27 Human Resources - Communications



30 Subsidiaries

31 Cellectis bioresearch

34 Cellectis plant sciences

36 Ectycell

38 Cellectis therapeutics

41 Financial statements

47 APPENDICES


NOTE FROM THE CEO

2010 a year of construction


We are living in an era that is redefining the very essence of biotechnology. The core concept Growth and development
of biotechnology is based on using living organisms to transform products by means of We made several acquisitions in 2010, offering us the promise of new technological
industrial methods. This notion was revolutionized in the late 1970s with the discovery of innovations and boosting our intellectual property portfolio. In September, for example,
recombinant DNA and the production of therapeutic proteins, developments made possible we purchased all the assets of CytoPulse, a company that specializes in electroporation
by our ability to modify DNA fragments in test tubes and reintroduce the products of this systems, a technique that will enable us to introduce meganucleases, or other molecules,
engineering process into cells, thereby changing their genetic makeup. We have now reached into a wide range of different cell types. We also decided to pursue the partnerships launched
a new stage in this biotechnological revolution. Changing the genetic makeup of cells is no by CytoPulse, meaning that we are in a position to benefit from the operating licenses
longer down to chance but is performed using rational methods. A discipline once characterized granted for electroporation technology. One strand of our development strategy is based on
by genetic manipulations resulting from makeshift “tinkering” with living organisms the acquisition of technologies that complement our genome engineering technologies and
has now become a branch of engineering science. DNA programming now uses a perfect can be used for a broad range of applications, from research to therapy. In the pursuit of
knowledge of the entire genome sequence to obtain a predictable, reliable and exact result. this aim, we have also acquired non-exclusive license rights that offer us access to induced
pluripotent stem (iPS) cell technology resulting from the work of Kyoto University’s Professor
A silent revolution Shinya Yamanaka. Cellectis is the first company in the world to secure licenses for human
Predictions in the field of biotechnology are often optimistic. But the speed at which therapeutic or prophylactic applications under this portfolio and will be making these
scientists have been able to decode the DNA of the human genome, and the DNA of all technologies available to its subsidiary Ectycell so that it can become a leading global player
iving species, has constantly surpassed all predictions. Today we are at the cusp of a new in this field.
era in which genetic information will be available to everyone. It is estimated that by 2013,
the cost of decoding the human genome will be less than 1,000 euros per person, Innovation and performance
and the process will be possible in under four weeks. In just a few years, millions of people We have made considerable progress in our key business sectors this year, both in terms of
will have their genome decoded and be able to use it to design customized medical science and product development and in the area of intellectual property and sales activity.
treatments. Genome engineering is situated downstream of this wave. The technologies It goes without saying that there is still a lot to be done, and we have not yet achieved all
developed by Cellectis will make it possible to treat innate or acquired genomic defects. our goals. However, we are more convinced than ever that we possess an effective economic
Genome engineering will generate a host of new, innovative products, taking up the model and technologies with the potential to make a radical impact. Our success is under-
torch from fossil and chemical resources. These new resources from living organisms offer pinned by the people who make up our group, our resources, our culture of excellence and
vast potential for growth and sustainable development over the coming decades. our vision of the biotechnology industry, which together have made it possible for us to build
a group on a global scale.
Leader in genome engineering
Cellectis is in a strong position in this emerging industrial sector. We develop new classes
of therapeutic products with the potential to transform the way in which diseases are
treated and to cure diseases that are currently incurable. We also develop products
for research, biopharmaceutical production, agrobiotechnology, induced stem cells and,
more recently, in the area of alternative fuels. Our approach to biotechnology is poised
to bring fundamental changes to this industry in the coming decades and to offer an Dr. André Choulika, Chief Executive Officer
endless source of innovation and growth for our society.

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2010 Highlights

Cellectis and the French National Institute Cellectis receives INPI National Cellectis launches Cellectis plant New journal publication details in vivo Cellectis bioresearch and Lonza New study shows meganuclease-driven
January

January

March

April

June

July
for Agricultural Research (INRA) sign Innovation Award 2009 sciences, a subsidiary dedicated to activity of Cellectis’ meganucleases in enter development and commercial targeted integration using Cellectis
cooperation agreement Cellectis won a National Innovation plant applications muscle fibres manufacturing agreement bioresearch’s cGPS® CHO-K1 kit to be
Cellectis and INRA wished to collaborate Award from the French National Institute The main aims of this subsidiary are to Researchers at the Laval University Cellectis bioresearch and Lonza, a world highly efficient for drug discovery
in the fields of cell biology and plant for Industrial Property (INPI). Cellectis’ increase and accelerate usage of Cellectis’ Hospital Center in Quebec, Canada, leader in biotechnology manufacture Scientific research based on a unique
and animal biotechnologies. They IP Manager Michèle Paquier received proprietary technology in agricultural used meganucleases engineered by have entered into a contract for the method for generating stable cell lines
decided to pool their expertise, where the award from the President of the biology, broaden the company’s skills Cellectis to restore the expression of development and marketing of bioengi- compatible with high throughput
possible, to acquire new scientific INPI Board, Thierry Morin. The awards, base to attract new and expanded microdystrophin in human myoblasts neered cell lines. Cellectis bioresearch screening (HTS) was published in the
knowledge, to create technological organized annually by the INPI since licensing opportunities and explore the in vitro and in muscle fibers in vivo. will use its meganucleases to inactivate Journal of Biomolecular Screening.
innovations, and to share these 1991, honor small and medium-sized development of proprietary traits for (“knock-out”) the glutamine synthetase
results, knowledge, and transfer enterprises whose growth can be attri- selected applications. Cellectis plant They were therefore able to show the (GS) in CHOK1SV, Lonza’s proprietary This research showed that the techno-
technology to businesses, particularly buted to their outstanding innovation sciences is located in Minneapolis, potential of using meganucleases to host cell line. John Birch, CSO of logy developed by Cellectis bioresearch,
to small and medium-sized enterprises policies and which use a comprehensive Minnesota, USA, with laboratory space treat Duchenne muscular dystrophy, a Lonza Biopharmaceuticals, said, “Lonza based on meganuclease-driven targeted
in the agrofood, agriculture and intellectual property strategy to leverage close to the University of Minnesota hereditary disease that is characterized is delighted to work with Cellectis integration, is faster, more practical
environment sectors. business growth. “Cellectis represents a and its greenhouse facilities. Its Chief by rapid degeneration of the muscle bioresearch. This collaboration makes and more efficient than traditional
fine balance between research activities Scientific Officer, Professor Daniel Voytas, tissue, eventually leading to loss of sense and will enhance our long- methods in deriving cell-based assays
and a healthy management strategy,” currently Director of the University mobility and death. The results of this standing and successful GS technology.” for HTS studies.
said Thierry Morin.   of Minnesota Center for Genome research were published in the scientific
Engineering, is an internationally journal Gene Therapy.
renowned scientist and established
expert in plant genome engineering.

Stylized meganuclease.

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Cellectis acquires assets from Cellectis bioresearch announces Cellectis launches its new corporate Cellectis bioresearch announces Cellectis in-licenses induced pluripotent Cellectis grants Harvard Bioscience
September

September

September

October

October

December
CytoPulse Sciences Inc. availability of research kits through new website - Information sharing, interactivity establishment of subsidiary in the US stem cell technology from iPS a license to CytoPulse electroporation
CytoPulse specializes in the development, online online-store, provides enhanced and new media space Located at the Cambridge Innovation Academia Japan – First patent license instruments
manufacture and marketing of electro- accessibility to meganuclease technology Visitors to the new website are ensured Center in Cambridge, Massachusetts, in the therapeutic field Cellectis and Harvard Apparatus, a division
poration technology and equipment. Cellectis bioresearch announced the enhanced usability and information Cellectis bioresearch Inc. will be responsible Cellectis entered into two separate non- of Harvard Bioscience Inc. which develops,
Electroporation is a highly efficient way launch of its e-store, with approximately sharing, including more streamlined for the US-wide promotion of Cellectis exclusive license agreements granting manufactures and markets a broad
for molecules such as meganucleases one hundred ready-to-use products access to information about Cellectis’ bioresearch products and services. the company worldwide access to the range of tools to advance life science
to be introduced into any type of cell, available for sale online via a new func- technology and products. induced Pluripotent Stem (iPS) cell patent research and regenerative medicine
with applications ranging from research tional and intuitive website to meet the portfolio arising from the work of worldwide, signed a license agreement
and biomanufacturing to agriculture needs of both academic and industry The new Cellectis website focuses on Professor Shinya Yamanaka at the Center that grants Harvard Apparatus the
and therapeutics. “CytoPulse’s assets research. “The launch of a website with three central themes: research and for iPS Cell Research and Application worldwide exclusive right to manu-
are a great strategic acquisition for online purchasing capability was a vital technology, business development and (CiRA) at the University of Kyoto, Japan. facture and market, for research use,
Cellectis,” said Cellectis Chief Executive step in improving researchers’ access investor relations. the full line of electroporation-based
Officer André Choulika. to our meganuclease technology,” Cellectis is the first company in the world instruments acquired by Cellectis
explained Luc Selig, VP Sales and to be licensed by iPS Academia Japan to from CytoPulse in September 2010.
“As we announced in 2009, part of Marketing at Cellectis bioresearch. use this patent portfolio for applications
our development strategy is to acquire “Our product offering has expanded in human therapeutics and prophylactics. Cellectis, however, retains all rights to
technologies that complement our rapidly, and we now market over In the research tool field, this is the the use of these instruments for its own
existing meganuclease platform and can one hundred different products on first agreement with a French company, research and development programs as
be leveraged across all aspects of our three target markets.” following agreements with US and well as in clinical trials and prophylactic
business, from research to therapeutics. German companies. or therapeutic procedures, for both
We saw such an opportunity in the humans and animals.
technologies at CytoPulse Sciences
Inc. and look forward to unlocking the
value of these assets.”

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CELLECTIS IN BRIEF

Cellectis improves life by applying its genome engineering


Worldwide pioneer in genome engineering
expertise to a broad range of applications, including human
health, bioresearch and agriculture. Established in 1999, listed on the NYSE-
Euronext Alternext market in Paris since
2007 (ALCLS)
The company designs and markets nucleases worldwide, and has formed more than 20
or “DNA scissors” such as meganucleases, academic research partnerships. 2010 operating revenues: 15,8 M €
innovative tools which enable precise
modification of the genome, as well as Since 2007, Cellectis has been listed on the Staff: 129 including 51 PhDs
other products arising from this technology. NYSE-Euronext Alternext market in Paris and
4 subsidiaries: Cellectis bioresearch,
Cellectis aims to exploit the full potential has secured over € 70 million in capital since
Cellectis therapeutics, Cellectis plant
of its technology in medicine and other its inception. While maintaining its ambitious sciences, Ectycell
areas of scientific or industrial exploration. growth targets, Cellectis has a very solid
cash balance due to increased revenue from Applications: research and biomanu-
Since its inception in 1999 by André Choulika, product sales, meganuclease production, facturing, human health, agricultural
biotechnology, stem cells
PhD, and David Sourdive, PhD, Cellectis has partnerships and license agreements.
enjoyed exclusive rights to a patent portfolio Main technologies: genome engineering,
owned by the Institut Pasteur. Professor Rodney With 10 years of work on meganucleases, protein engineering (in particular nucleases
Rothstein (Columbia University) chairs its Cellectis has acquired unmatched expertise in or DNA scissors)
Scientific Advisory Board, which comprises the field of genome engineering. The internal
IP portfolio: 83 patents granted and more
internationally renowned scientists. R&D and meganuclease platform teams have than 260 patent applications pending
broad knowledge of the field and the skills
To date, Cellectis has entered into more than required to select and integrate new tech- Locations : Paris (France); Saint Paul,
Minnesota and Cambridge, Massachussetts
50 agreements with pharmaceutical labora- nologies that would prove complementary to
(USA)
tories, seed producers and biotech companies Cellectis’ offering.
As of December 31, 2010

CELLECTIS IN BRIEF

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Our Core Activity: Genome engineering

The principle of genome engineering is simple: it involves Meganucleases are natural proteins found in many single-celled organisms. They are highly
specific “DNA scissors”. They are able to recognize their binding site by identifying a nucleic
modifying the genome of an individual or species for the acid sequence (nucleic acids are the constituents of DNA), which contains between 12 and
purposes of understanding the way it works, producing useful over 30 base pairs. This site is statistically unique in a genome. Once the DNA break has been
proteins or treating a disease. made, the cell activates its maintenance and repair system (for example, homologous recom-
bination). This system corrects the DNA molecule by using, for example, its twin copy (gene
Genetics has demonstrated the link between the physical attributes of species and their correction) or a similar fragment specifically introduced into the cell as a model (insertion or
genes, and thereby shown how particular genes are implicated in certain diseases or attri- “knock-in”). It is the same principle as the “copy and paste” function in word processing.
butes. Genome engineering enables species’ genes to be modified in order to change certain When a gene just needs to be inactivated rather than replaced, the broken DNA is bound and
attributes, to rectify an error, or to add a new trait of physiological or economic interest. loses information, therefore the targeted gene is inactivated (known as “knock-out”).
This approach is not new: cross-breeding different plants or selecting the best animals for
reproduction is based on the same principle. The aim is to improve species by giving them Cellectis manufactures meganucleases that can cut precise new sequences, and are thus tailor-
the best possible attributes – drought tolerance or pest resistance for crops, for example. made for genes of interest. The feasibility of meganuclease engineering allows the creation
of a wide range of specific tools to modify the targeted genes. It is the technological vision
The targeted approach of genome engineering is predictable, more reliable and more effective upon which Cellectis was founded 11 years ago. This was achieved when the meganuclease
than earlier techniques, and can even be applied to humans. The genomes of over 1,000 platform was able to produce custom meganuclease specific of any new gene of interest,
organisms have now been decoded. Knowledge of the sequence and location of the genes of with the same characteristics as the wild type ones (efficacy, specificity, …). This expertise in
living beings is therefore constantly improving, even though the workings of these genes are genome engineering tools production has allowed Cellectis to evolve from a tool producer to
still not fully known. Our understanding in this field allows us to manipulate genes directly. a product-delivering company.

There are three possible strategies to do this:


• Insertion is used to add a new attribute to the genome. For example in drug discovery,
Meganuclease
or in order to overcome a genetic defect like hemophilia.
Chromosome
• Correction is used to replace an existing defective sequence (which generally impacts the
gene’s functions) by a functional sequence. For example, to treat a serious genetic disease
cut
such as Duchenne muscular dystrophy.
• Inactivation is used to prevent the expression of a gene. This approach can be used to treat
persistent viral infections such as AIDS or herpes.
Gene Insertion Gene Inactivation
KNOCK IN GENE REPAIR KNOCK OUT
Our tool: Meganucleases
Compared with earlier technologies, the effective power of genome engineering lies in its
ability to insert the gene of interest in the chosen place. For many years, researchers’ methods
were akin to “playing darts blindfolded”. They would study the effect of randomly inserted
sequences, despite the fact that insertion in the wrong place can have harmful effects: one
gene can be inserted into another and inactivate it, or activate cancer mechanisms. This is Integration matrix repair matrix loss of a few
paste base pairs
where Cellectis has the competitive edge. Its expertise in meganucleases means that it is able paste
to precisely target a specific locus in the genome. Cellectis’ tools give scientists the precision
they were lacking. Homologous Homologous Non Homologous
Recombination Recombination End Joining (NHEJ)

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Our Core Activity: Applications OUR fACILITIES

DNA universality makes it Human health


Genome engineering is the basis for gene therapy. Often called “genome surgery”, this
possible for our technology type of treatment could be used to cure many genetic diseases, such as sickle cell anemia
to be applied to any kind (drepanocytosis). Research in this area has been carried out in collaboration with Cellectis at
of species (human, animal, the Memorial Sloan-Kettering Cancer Center in New York. Inserm, the CNRS, and AFM
(French Association against muscular dystrophy) are also closely involved in Cellectis’ progress
plant, bacterial, or viral) and in the therapeutic field. But genome engineering can also be used to fight viruses like herpes.
to every gene of interest. These pathogens insert their DNA into the DNA of infected cells, meaning that the
The technology conceived immune system is unable to get rid of them permanently. Cellectis’ ability to target very
precise regions of viruses’ genome in order to inactivate them might make it possible
and mastered by Cellectis to remove the genetic material of the viruses found in the infected cells. This therefore
can be used to unlock represents a potential breakthrough in the treatment of these diseases. Research teams
or restore the potential of
Agrobiotechnology
DNA, opening up a broad Meganucleases can be engineered so that they are specific to any gene of any species of
range of applications. plant. Cellectis uses its technology and expertise to provide seed producers with mega-
nucleases that can make targeted modifications in plant genomes and to develop the next
generation of high quality crop plants. Today Cellectis is developing partnership agreements
with some of the major players in the agrobiotech sector, so that genome engineering will
be accepted and widely used within this field of application. In 2010, Cellectis created Cellectis
plant sciences, a subsidiary dedicated to genome engineering applications in plants. Its aim
is to increase and accelerate usage of Cellectis’ proprietary technology in agrobiotechnology
and to develop proprietary traits for selected applications.

Research and biomanufacturing


Genome engineering is at the basis of the modern approach to fundamental research in
biology. The entire human genome sequence has been identified, as well as those of more
than a thousand species. However, biologists do not know the entire role of these genes The platform team and its robots
that have been identified. To find out the role of these genes, we can use targeted DNA
modification techniques to suppress or regulate the expression of a precise DNA sequence.
Researchers can therefore understand the role of a gene by studying the effects of its absence
or variations in its expression or its structure. In biomanufacturing, meganuclease applications
have unique competitive advantages in terms of manufacturing processes, reduction in cycle
time and improvements in protein quality. Research kits are marketed by Cellectis bioresearch
allowing meganuclease-driven targeted integration of a gene into various cell lines.
They make it easier for researchers to modify the DNA of species they are studying and
for manufacturers to screen and evaluate their products’ efficiency.

Qpix robot, meganucleases tested on targets Colored test for mutant selection FX robot, DNA production in plates

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ORGANIZATION

Four subsidiaries of Cellectis were created between 2008 and 2010. Their aim is to fully develop
the applications of our technology within their given market sectors. The parent company centralizes
the financial department of the group, the intellectual property, the legal department and other
support functions, as well as the research and development around genome engineering technologies.
The “DNA scissors” platform production will remain the strategic center of the company as a whole
as well as the driving force of the group activity.

Cellectis and its subsidiaries

CELLECTIS IN 2010 Cellectis


Technologies development, protein production platform,
intellectual property, support functions.

Cellectis bioresearch Cellectis therapeutics Cellectis plant sciences Ectycell


Founded in 2008, Cellectis Cellectis therapeutics, Established in March 2010, Ectycell was established in
bioresearch develops and launched in 2008 under Cellectis plant sciences September 2009 to research
markets research and the name Cellectis genome is a subsidiary dedicated and commercialize industrial
production kits that make surgery, is dedicated to the to the applications of uses of stem cells.
genome engineering development of innovative meganucleases to plants.
accessible to biological therapeutic approaches using Its main mission is to increase The initial goals are to
researchers and companies meganucleases to treat and accelerate usage of develop tools for generating
worldwide. genetic diseases, cancers and induced pluripotent stem cells
persistent viral infections. Cellectis’ proprietary from adult cells, robust,
It offers turnkey solutions, Cellectis genome surgery technology in agricultural reproducible differentiation
enabling biologists to design seeks to treat patients biology, broaden the of stem cells, and cell libraries
their daily work tools with suffering from serious diseases company’s platform to for testing drug candidates.
control and precision, resistant to conventional attract new and expanded
such as cell lines with the treatment. Its prospective licensing opportunities
features of a healthy therapy targets the very and explore the development
or diseased organ or tissue. DNA sequence responsible of proprietary traits for
for the disease that may be selected applications.
of congenital origin
(genetic desease) or acquired
(viral infection or cancer).

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OUR Science Research and Development

This achievement resulted from a proper In 2010 we used dozens of meganucleases The core activity of Cellectis In the labs at Cellectis, upstream research
industrialization of our processes, which in immortalized cells, plants, animal models is split into two areas. One team of
illustrates the overall maturity and adapta- and stem cells. This broad applicability is
internal R&D team is to researchers focuses on the engineering of
bility of the organization. This enhanced a key feature of the potential of Cellectis engineer meganucleases that proteins – meganucleases in particular –
production capacity means that Cellectis technology. The amount of data gathered are specific to a chosen DNA in order to improve their activity and speci-
can position itself as a supplier of tools by different teams, both at Cellectis and ficity, and to increase the sequence space
for a very broad spectrum of applications elsewhere, is indicative of the robustness
target, i.e. to create “custom” that can be targeted by these “tailor-made”
and products. of this technology. Many of these results will meganucleases for each gene meganucleases. The other team focuses
be published throughout 2011. of interest. on the activity of meganucleases in cells,
But the progress that has been made in and particularly on improving the efficiency
our manufacturing processes should not Finally, our research has enabled us to assess The teams at Cellectis can identify the of gene targeting and its recombination.
Dr. Frédéric Pâques, Chief Scientific Officer overshadow the advances made in the the challenges that lie ahead, particularly areas responsible for the “DNA scissor” This team is also working on new appli-
application of our products. One of the in 2011 and and it is the therapeutic sector function within the meganuclease structure, cations for meganucleases.
2010 was a particularly most significant achievements is the use of which holds some of the biggest challenges as well as the areas that correspond to
our products in genome surgery, which is for us. Among them, the ability to get our the recognition of specific DNA sites. Our In 2010, the R&D group made important
productive year in terms of now happening on an unprecedented scale, molecules in sufficient numbers into the progress, including the identification of
researchers are therefore able to modify
the research and advancement with over 15 collaborations with academic target cells will be a major priority for our the recognition and DNA fixation area so new protein structures with the capability
research labs all over the world (HSR-TIGET research. Another key priority is ensuring to be engineered more quickly and
of our core technology. One as to generate new variants that target new
in Milan, VIB in Leuven, Children Hospital the safety of this approach, which is directly sites in a genome. As a result of this research, offering new properties. This led to new
of our main achievements in Boston, …) producing both in vitro and linked to the specificity of the meganucleases. Cellectis now has a large bank of proteins meganucleases with optimized usage.
was the consolidation of in vivo data. This represents a greater The specificity criteria are the most strictly with over 40,000 motifs that can be
number of meganucleases used as well as applied in therapeutic applications,
our production platform in combined to obtain chimeric proteins
a broader variety of application methods, and safety most stringently assessed. capable of binding to different sequence A very complete publication, which
order to produce a record particularly the cell types that can be combinations of the DNA. describes the different tools used in
number of meganucleases successfully targeted. Both aspects are Safety and vectorization (or the method genome engineering and compares their
directly linked to the increase in our used to insert a meganuclease into a target properties, was published in Current Gene
(271 in 2010). Therapy by the Cellectis research team at
manufacturing capacity, which is meeting cell) are therefore the two key words
the growing needs of our customers, for 2011, as we spend the year focusing the end of 2010.
our partners and our in-house research wholeheartedly on the applications of
Meganucleases and other Tools for
and development activities. genome engineering – across research Targeted Genome Engineering: Perspectives
tools, agriculture or medicine. and Challenges for Gene Therapy
Silva G, Poirot L, Galetto R, Smith J,
Dr. Frédéric Pâques Montoya G, Duchateau P, Pâques F.
Curr Gene Ther. 2010, Dec 24

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Production Platform Computational biology

The scientists identify the protein modules By carrying out its research work, the At Cellectis, the mission of the Computational design involves using
whose DNA targets match with fragments Platform team is able to expand the software based on energy level calculations
from the targeted genome site. Then they database, enhancing Cellectis’ knowledge
computational biology team in a protein, and completely relies on the
combine the modules to create a new and scientific expertise. 2010 was marked is to produce engineered availability of structural data (i.e. tridimen-
meganuclease with recognition specificity by a reduction and stabilization in meganucleases using a rational sional structures of meganucleases bound
for the required gene target. The activity manufacturing times within the Platform. to their DNA target). Cellectis established in
of each newly created meganuclease is This resulted in a significant increase in
approach. 2009-2010 a dedicated computational
then tested in a series of functional trials our production output, with 271 mega- New meganucleases are today essentially biology group, in parallel with the set up
developed by Cellectis. nucleases manufactured in 2010 compared produced by a so-called semi-rational of a major structural biology program.
with 99 in 2009. approach: collections of meganuclease The program is held at the CNIO (Madrid)
All the creation and analysis work is carried variants are built by randomly modifying in collaboration with Dr Guillermo Montoya.
out by the production Platform team, who specific areas of the protein, and these Exclusive access to a significant amount of Dr. George Silva, head of the computational biology
create from start to finish all the enzymes structural data has been a key factor in the
When a project requires a An article describing the work of Cellectis collections are tested by the platform to department
used and sold by Cellectis. The Platform on meganucleases and the techniques identify the mutants with the expected computational biology group gaining a better
different site in the genome to team creates high quality meganucleases used to create and produce new proteins properties. Striving for a rational approach understanding of the mechanisms governing
be modified, Cellectis’ teams compliant with the precise specifications of that can cut new targets was published in
aims at determining, with more precision, meganuclease/DNA interactions, and
each Cellectis partner or customer, internal November in the journal Protein Engineering optimizing the molecular modeling process
create a new meganuclease Design and Selections. This article also
which variants are more likely to be
and external. The Platform team can functional in order to generate and test a and gradually replacing the experimental
from the Omegabase, validate and secure orders by supplying each
describes the broad range of applications
smaller number of these variants. high-throughput screening method.
of meganucleases: development of cell
a bank of meganucleases customer with a solution that best meets its lines enabling protein expression, modified
needs. Using its array of robots, the Platform
with modified characteristics, plants and animals, therapeutics applications The Cellectis computational biology program
team is able to measure the activity of a like gene therapy, or creation of a new aims to improve Platform performance in An article was published in the scientific
property of Cellectis. vast number of meganucleases. It is actually class of antiviral drugs. terms of delivery, cost, capacity, sequencing journal Nucleic Acids Research, resulting
able to run up to 1 million tests per week. area and product quality. There has been from a collaboration between Cellectis and
The I-CreI meganuclease and its Dr. Guillermo Montoya’s laboratory at the
regular progress in the last few years and
engineered derivatives: applications from CNIO of Madrid. It describes the structure of
These data are then processed, analyzed with the use of innovative new techniques
cell modification to gene therapy a meganuclease bound to its DNA target.
and used to design meganucleases that are recently implemented at Cellectis, we can
Arnould S, Delenda C, Grizot S,
appropriate for each project. The Platform Desseaux C, Pâques F, Silva GH, Smith J. better address the core performance Molecular basis of engineered mega-
team enables the research departments to Protein Eng Des Sel. 2010, Nov 3 improvement aim of computational biology. nuclease targeting of the endogenous
assess their theories in standard production Print: 2011 Jan. 24(1-2) pp27-31 human RAG1 locus.
conditions while following strict procedures Muñoz IG, Prieto J, Subramanian S,
that guarantee full sample traceability and Coloma J, Redondo P, Villate M, Merino N,
quality. This work is supported by a bio- Marenchino M, D’Abramo M, Gervasio FL,
informatics team that supplies essential data Grizot S, Daboussi F, Smith J, Chion-Sotinel I,
to the research teams, enabling them to Pâques F, Duchateau P, Alibés A, Stricher F,
Serrano L, Blanco FJ, Montoya G.
predict the correct structures for developing
Nucleic Acids Res. 2010, Sep 16
effective meganucleases in the shortest
Print: 2011; 39;729-743
possible time.

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Business Development

The Business Development strategy In 2010, Cellectis entered Harvard Apparatus granted license Agreement with Lonza for modification
comprises five main areas, which will From a Business Development perspective, agreement of bioengineered cell line
help Cellectis advance its leadership 2010 initiated a shift in focus from
into a license agreement with This agreement granted Harvard Apparatus Cellectis bioresearch will use its mega-
in genome engineering. outlicensing of intellectual property Boehringer Ingelheim to obtain, the worldwide exclusive right to manufacture nucleases to inactivate (“knock-out”) the
towards generating income from products
developed using such intellectual property.
breed and utilize animal models and market, for research use, the full line of glutamine synthetase (GS) gene in CHOK1SV,
These are: electroporation-based instruments that Lonza’s proprietary host cell line. Lonza is
Whereas the main source of revenue for pharmaceutical research Cellectis acquired from CytoPulse. world leader in therapeutic proteins produc-
remained licenses to homologous recom-
• To give priority to meganucleases for
bination patents, the incorporation and
throughout Europe, as well as tion. Its ability to control production of the
therapeutic applications in order to treat expansion of Cellectis plant sciences, with Bayer HealthCare to use Cellectis retains all rights to use these instru- highest quality cell lines makes the company
rare genetic diseases and viral infections, the expansion of the stem cell activities ments for its own research and development a perfect partner for the application of
and to develop new products to fight cancer in Ectycell thanks to the Shinya Yamanaka
its homologous recombination programs as well as in clinical trials and pro- Cellectis technology and its meganucleases.
Dr. Dirk Pollet, Chief Business Officer or to improve allogeneic transplantation iPS license, and the acquisition of patents. BASF plant sciences phylactic or therapeutic procedures, for both
the CytoPulse electroporation technology
(transplant between two genetically
will form the cornerstones of products
has also broadened its collabo- humans and animals. Under the agreement, “We are delighted to be work-
The aim of the Business different persons).
based on Cellectis genome engineering ration with Cellectis to utilize Cellectis will receive a payment of $1.3 M
ing with Cellectis bioresearch.
from Harvard Apparatus. Cellectis will also
Development team is • To pro-actively transfer its technology to
technologies. This trend will continue
its custom meganucleases. continue to receive annual licensing fees This collaboration makes sense
through 2011 where Cellectis expects
to commercialize Cellectis’ major academic and industrial laboratories significant income from licensing of from some of its customers. and will enhance our long-
intellectual property and for research purposes. its intellectual property portfolio, but also Acquisition of assets from CytoPulse Inc.
expects to sign an increasing number Electroporation is a very efficient way of License to use Evrogen fluorescent standing and successful GS
to acquire other companies’ • To enter into business agreements in its of partnerships to develop innovative inserting molecules such as meganucleases proteins technology.”
IP that would support the four main fields of application: healthcare, products in multiple fields. into any type of cell and has applications This non-exclusive agreement with Evrogen
John Birch, CSO of Lonza Biopharmaceuticals
development of new biotechnology, agricultural biotechnology, ranging from research and biomanufacturing (Moscow, Russia) has allowed Cellectis
Dr. Dirk Pollet, Chief Business Officer to agriculture and therapeutics.
and stem cells. bioresearch to incorporate these proteins
technologies or products. into its own products and thus expand its
License agreement with Midwest
Cellectis’ innovative intellectual Through this transaction, Cellectis acquired Oilseeds for plant transformation
• To strengthen privileged partnerships range of genome engineering tools.
three other technologies based on elec- This agreement enables Cellectis plant
property has a broad range established with some of the major players
sciences to use Midwest Oilseeds’ Aerosol
in agricultural biotechnology. troporation and developed by CytoPulse: The integration matrix is one of the key com-
of applications such as Dermavax for transdermal DNA vaccination, ponents of the Cellectis bioresearch kits. It
Beam Injector (ABI) technology for the
health, agriculture or research Oncovet for veterinary vaccination appli- targeted modification of plant genomes.
• And to sustain Cellectis’ competitive is this matrix that allows the user to express
regarding stem cells and advantage by continuing to enhance its cations, and Hybrimmune to manufacture a gene of interest. By extending the choice
hybridomas for monoclonal antibodies The Midwest Oilseeds ABI technology
patent portfolio and by increasing its of promoters and tags in these matrices,
alternative energies. The technological lead and expertise in order production. The transaction was finalized Cellectis bioresearch can offer its customers
enables functional meganucleases to be
Business Development team is on September 2, 2010, for $2.2 M. delivered directly into plant cells, thus avoid-
to bring value to the portfolio. a full range of methods to achieve single-
ing the need for DNA vectors. This approach
also in charge of the business phase developments, thus saving valuable
will allow Cellectis plant sciences to modify
time during experiments.
contracts with our partners. plant genomes without integrating DNA in
the plant.

22 l Cellectis l Activity Report 2010 l l Cellectis l Activity Report 2010 l 23


Corporate Development

The aim is to organize a collection of cells Cellectis has also entered into a collabora- Meganucleases offer new Focus on oil substitute
that represent the physiology, pathology tion with CiRA to combine Cellectis’ genome Our meganuclease technology would be
and diversity of a population so that we can engineering technologies with CiRA’s iPS cell
possibilities for establishing well suited to help optimize these traits and
understand this diversity in vitro. The initial technology to improve the natural character- a viable alternative to oil. enable an industrialization of the processes.
purpose is to utilize stem cells to improve istics of iPS cells for use as cellular tools. Microalgae are actually As a natural source, algae alone are currently
understanding of diseases and their mecha- thought to be able to meet the demand
nisms. If we can collect cell samples from
thought to be a very promising
“We are starting 2011 with for fuel effectively without competing with
donors who have these diseases, and have source of alternative to another need, such as food supply. Algae
the essential keys for success.
access to their medical files, it will then be oil derivative: fuel, chemical also use the process of photosynthesis and
possible to study the disease via the induced It is now up to us to ensure therefore need light, water and CO2, making
Pluripotent Stem (iPS) cells generated from
molecules or materials.
that our projects reach their them an environmentally friendly fuel.
the patient’s cells. This is partly due to their
Dr. David Sourdive, EVP Corporate Development full potential.” Dr. Alberto Amato, project leader, genome engineering
strong ability to produce It was for these reasons that, in 2010, on algae
The CellMill platform project was therefore Cellectis set up a research team to focus on
The aim of the Corporate set up primarily to industrialize iPS cells and Dr. David Sourdive oils and their growth and micro-algae, and diatoms in particular, as a
Development team for 2010 make them both robust and safe. 2010 effective yield rate. possible substitute for oil. Diatoms already
enabled us to ensure that all our projects play an important role in the environment
was to set into action the materialized by giving them the necessary because they produce one-fifth of all oxygen
opportunities available to us resources. The CellMill project received produced on earth every year. Diatoms
in the field of stem cells by a funding commitment from the regional are unicellular algae found in most humid
authorities, the Caisse des dépôts et environments and offer huge diversity, with
establishing a cell platform consignations (Bank for Official Deposits) 100,000 species already identified.
for population leading to and OSEO, a public enterprise whose
two different applications: aim is to fund and support innovation and A preliminary program was therefore set
company growth. up at Cellectis in order to provide proof of
research tools and cell therapy principle as soon as possible, particularly
Different kinds of diatoms

(transplants). In addition, two non-exclusive license agree- regarding the potential of meganuclease
ments have given Cellectis worldwide access efficiency in these algae.
to the induced Pluripotent Stem (iPS) cell
patent portfolio arising from the work of
Professor Shinya Yamanaka at the Center for
iPS Cell Research and Application (CiRA) at
the University of Kyoto (Japan). Cellectis is
the first company in the world to be licensed
by iPS Academia Japan under this iPS cell
patent portfolio for human therapeutics and
prophylactics.

24 l Cellectis l Activity Report 2010 l l Cellectis l Activity Report 2010 l 25


Intellectual Property Human Resources – Communications

We have since developed a strong propri- With a headcount that has The policy at Cellectis involves enabling our The new Cellectis website focuses on three
etary portfolio, with patents across three Evolution of Cellectis’ IP portfolio staff to evolve as the company does so. central themes:
broad categories – general principles,
grown from 5 in 2000 to 129 Reflective of their passion and determination
Number of patents granted to Cellectis, per year
meganucleases and their specific appli- and geographic area at the end of 2010, the key to see Cellectis become a major player in • Research and technology
cations, and manufacturing processes of word in our company is clearly biotechnology, some of the previous project • Business development
modified meganucleases. Our strategy leaders are now at the head of a department • Investor relations
involves expanding the intellectual property
100
“development,” in terms and some laboratory technicians have taken
portfolio to further protect our products, 80 of our employees and their up engineering assistant functions. In addition to these focus areas, the website
their applications, and the corresponding talents, as well as our core offers new features and fresh content including:
body of technological knowledge. 60 Moreover, Cellectis provides support for
technology. those individuals who would like to further • Several specific RSS feeds, so that
40
The Intellectual Property Team
At the end of 2010, Cellectis owned the their education in engineering. subscribers can monitor the Company’s
rights to 83 patents worldwide, including 35 business in real time, choosing only the
20
in the United States and Canada. This means These dynamics help us attract new talent subjects that interest them.
One of Cellectis’ foremost that 25 new patents were obtained over the 0 to Cellectis, unify current staff and establish
assets is its intellectual property course of the year. Cellectis currently has a genuine company identity in the midst • Information sharing via social networks

2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
more than 260 patent applications pending. of continuous growth and development. (particularly Facebook and Twitter).
portfolio. The Institut Pasteur In 2010, Cellectis bought all the assets of US/CA Europe Asia Australia Cellectis is proud of its team spirit and intends
patent families covering the use CytoPulse Inc., a company that specializes to expand all its energy to maintain it. • Downloadable documents that explain
of homologous recombination in electroporation systems, and through this Cellectis’ technology.
operation obtained 16 new patents to add Team building is also achieved through
and meganuclease-type to its intellectual property portfolio. Thanks seminars and other regular in-house events • Illustrative videos and regular features on
endonucleases for inducing to these new patents, Cellectis will receive a that are organized by the Communications various aspects of Cellectis’ technology
DNA recombination formed regular income (>$600,000 in 2009), derived Department. The department is also respon- to help improve the public’s understanding
from the granting of exploitation licenses sible for promoting Cellectis’ technology of our scientific progress.
the platform upon which for CytoPulse’s HybrimuneTM electrofusion and expertise. One of the main tools set up
Cellectis was initially founded. technology. by the Communications Department in
2010 was the new corporate website with
The company strives to optimize and uphold several key features: information sharing,
the intellectual property it licensed from the interactivity and a dedicated media area.
Institut Pasteur. Cellectis also endeavors to
promote its intellectual property by defend- In light of its expansion, Cellectis chose to
ing its own rights, while respecting the rights provide visitors to the website with clearer
of others. and more accessible insight into its work,
products and achievements. Visitors to the
new website are ensured enhanced usability
and information sharing, including more
streamlined access to information about
Cellectis’ technologies and products.

26 l Cellectis l Activity Report 2010 l l Cellectis l Activity Report 2010 l 27


Shareholder relations

“Cellectis is a dynamic Event: first R&D Day


On November 30, 2010, Cellectis held its
company in which team Cellectis’ staff
first Research & Development Day, to which
spirit and strong motivation Breakdown by categories
it invited investors, analysts and the media.
are the driving forces that This event, intended to be the first in a series,
was a chance for Cellectis to forge stronger
lead us further every day ties with the investment community, get to
in pursuing innovative 25% know these individuals better, and exchange
and fascinating matters.” ideas. The guests gained a more in-depth
Christelle Rochon, Researcher in Cellular and Molecular
4% understanding of the business activities
Biology at Ectycell of Cellectis and its subsidiaries with a tour of
Ectycell Team the premises, in particular the laboratories,
“Cellectis is a hub of during which they met the teams that have
71% made Cellectis the company it is today and
“My position in the IT group innovation in which represent the values it upholds.
is central to the business communication among
Following a tour of its proprietary technology
and involves working closely teams and between
facility that creates, produces and tests
with all the staff at Cellectis. departments flows actively. Scientific Departments (SD) meganucleases, members of the Cellectis
Business Development
I’m glad I can help them Working with teams Administration Letters to shareholders management and scientific teams detailed
the activities within its core business areas:
progress their research.” that are highly skilled and It is very important for Cellectis to forge
meganuclease engineering technology,
Sandra Lapèze, Network and System Technician open is a very rewarding Breakdown by subsidiaries
Total: 129 (including 4 in the USA and 2 in the UK)
closer links with its shareholders and this
research tools, genome engineering in plants,
is why the Letter to Shareholders project
personal and professional was initiated in 2010. This is a quarterly
and therapeutic programs. Laboratories tour
“I chose to work at Cellectis experience for me.” letter addressed solely to shareholders that
Dr Serge Braun, from the French Muscular The Cellectis Communications team also
because it is a well-known, Justin Eyquem, Trainee Engineering preparing summarizes and comments on all the latest
manages everything that relates to the
Dystrophy Association (AFM), gave an
growing biotech in France his thesis at Cellectis therapeutics news. It offers a way for Cellectis CEO André
update on his organization’s collaboration publication of yearly and half-yearly financial
Choulika to maintain direct and regular
that is developing innovative contact and thus build a lasting and trust-
with Cellectis in therapeutics. To conclude results, and organizes the general assemblies
the event, the potential applications of which are chaired by Christian Policard,
technologies with the objective based relationship between Cellectis and its
Chairman of the Board of Directors, and
induced pluripotent stem cell (iPS) techno-
of becoming the leader shareholders. Each Letter to Shareholders
logies, for which Cellectis recently signed a attended by all the Cellectis shareholders.
also has a “3 Questions” interview with one
in genome engineering.” of the key people at Cellectis on a topic of
license agreement with iPS Academia Japan,
were also described. All the information about the general
Julien Pontin, Senior Lab technician particular relevance to the company at the
assemblies is available in the Investors area
Cellectis 71% SD time of issue. There is also a ‘Focus’ on one
Cellectis bioresearch 71% SD The presentations are available at on the Cellectis website www.cellectis.com.
of our constantly-evolving activities.
Cellectis therapeutics* 100% SD www.cellectis.com/investors.
Cellectis plant sciences 100% SD
Ectycell 100% SD

*ex genome surgery

28 l Cellectis l Activity Report 2010 l l Cellectis l Activity Report 2010 l 29


Cellectis bioresearch

2010 Highlights
2010 was for Cellectis bioresearch a year of consolidation in terms of research and develop-
ment, such that we are now able to market over 150 products. We are particularly pleased
with this growth, given that we only launched our first kit in December 2008 following the
creation of Cellectis bioresearch in June of that year. We are able to supply a large number
of new products, illustrating a very diverse offering. In 2010, we have adapted our products to
a variety of cell lines, evidence of the efficiency by which we bring new products to market.
We also adopted a new marketing strategy to increase our visibility and rapidly come to
competition with the main global players in research. This involved both traditional advertising
in the press and on the web, as well as attendance at some 20 trade shows, but also more
original marketing methods: an interactive web platform aimed at the scientific community
engaged in using new genomics-related techniques1 and a competition to provide financing
for a post-doctoral position involving a project including genome customization. From a
business perspective, the results were very encouraging since we more than doubled our
operating revenues. We also integrated the market share of CytoPulse, an American company

SUBSIDIARIES whose assets we acquired. This included a complete range of electroporation instruments
already commercialized, as well as the related intellectual property. Cellectis bioresearch’s 2010
operating revenues met the targets and expectations set. In the current economic climate,
this is something we can be very proud of. Our success is due to our talented team,
which now includes 20 employees, two-thirds in R&D and one-third in sales and marketing. Marc Le Bozec, Chief Financial Officer of Cellectis and
Chief Executive Officer of Cellectis bioresearch

Challenges for 2011


During the coming year, we will focus on three main areas to achieve our goal of providing
our customers with thousands of products. The first area is technology. Whereas we currently
supply mainly targeted integration tools, our aim is to supply both targeted modification and
inactivation solutions also. The second area is to expand our product line in other species, such
as plants like Arabidopsis thaliana, a widely-used plant model, or other key animal models,
such as nematode C. elegans. In 2011 these key models are to undergo NHEJ (Non Homo-
logous End Joining) meganuclease or TALEN (Transcription Activator-Like Effector Nuclease)
testing, once this new technology is fully implemented on our platform. The third area of focus
will be to expand our field of applications to the ADMET (Absorption, Distribution, Metabo-
lism, Excretion and Toxicity) test to supply a cell line for cancer research, closer to the patient’s
physiological reality. More generally, we aim to maintain our growth and to achieve short-term
profitability while we deploy a field sales force in Europe and the United States. It was with
this in mind that the American subsidiary Cellectis bioresearch Inc. was set up in October
2010. Our aim for 2011 is to set up teams in the United States and Europe, to put us on an
equal footing with our competitors. The next two years will be decisive as they will determine 1
www.genome-engineering.com
the type of profitability we can expect to achieve.

Marc Le Bozec, CEO of Cellectis bioresearch

30 l Cellectis l Activity Report 2010 l l Cellectis l Activity Report 2010 l 31


Cellectis bioresearch supplies researchers in the life sciences with
easy and ready-to-use tools for creating cells and organisms that
have the desired performance.
Cellectis bioresearch develops and markets genome customization products that can be used
cGPS
cGPS®® cGPS®®
to create stable and isogenic cell lines, with characteristics and performances adapted to three Custom
Custom
main markets: drug development, gene function studies and protein production.
Integration of a natural Meganuclease Meganuclease
recognition site engineering
cGPS and cGPS Custom kits
® ®

These kits are an easy and efficient way of using Cellectis’ meganuclease technologies.
With the kits, a gene can be integrated into an extremely precise site in the genome.

“The challenge is to replace At the end of 2010, Cellectis bioresearch was supplying over 150 products via its online
traditional cell engineering shop and international distribution network (India and Canada). The company Cellectis
methods based on random bioresearch Inc. was recently set up in Cambridge, Massachusetts (United States) to
promote the company’s products and cell line engineering services throughout America.
modification with targeted Wild type
DNA Repair
Engineered
DNA Repair
Meganuclease Meganuclease
integration.” The genome customization kits contain reagents and protocols that enable precise and
Marc Le Bozec targeted modification of DNA sequences in the genome of interest, of whether a cell line,
a primary cell, a stem cell or an entire organism.

Targeted integration involves a “copy and paste” process that is performed by a


meganuclease, an integration matrix and the homologous recombination process. A study showed that Cellectis bioresearch’s technology based on meganuclease-driven
targeted integration is faster, more reliable and more efficient than traditional methods in Meganuclease-Driven Targeted Integration
Cellectis bioresearch’s targeted integration kits are easy and ready-to-use, and include deriving cell-based assays for High Throughput Screening (HTS) studies, which allow rapid in CHO-K1 Cells for the Fast Generation of
HTS-Compatible Cell-Based Assays
a complete protocol. Each kit contains all the components that are needed for targeted screening of a vast number Cabaniols J, Ouvry C, Lamamy V, Fery I,
integration: a wild-type or engineered meganuclease, an integration matrix, and, in of new molecules. Meganuclease-driven targeted integration using Cellectis Craplet M.L, Moulharat N, Guenin S.P,
Bedut S, Nosjean O, Ferry G, Devavry S,
cGPS® kits a cell line. bioresearch’s cGPS®CHO-K1 kit is therefore highly efficient for drug development. Jacqmarcq C, Lebuhotel C, Mathis L,
Delenda C, Boutin J.A, Duchâteau P,
Cogé F, and Pâques F
The ‘research kits’ line now includes five new cell types, and the product offering includes The results of this scientific study focusing on a unique method for generating stable cell J. Biomol. Screen. Sept 2010 - vol 15 no 8
a pIM Store, a collection of around 100 integration matrices that can be used with different lines compatible with high throughput screening were published online July 12, 2010 by the p. 956-967
kits. In 2010, Cellectis bioresearch launched its first customized service to deliver stable Journal of Biomolecular Screening.
clones by cGPS targeted integration. 2010 also saw a major R&D partnership with Lonza, a
world leader in biotechnology manufacturing with the aim of modifying Lonza’s proprietary
cell line CHOK1SV used to produce biotechnological drugs.

32 l Cellectis l Activity Report 2010 l l Cellectis l Activity Report 2010 l 33


Cellectis plant sciences

Between now and the year 2050, the world’s population will The near-term goal of Cellectis plant sciences is to move away from model plants (Arabi-
dopsis and tobacco) and to apply its technology to commercial plant species. The Cellectis
grow from approximately 6 billion to more than 9 billion people. plant sciences team already has expertise in transforming corn, rice and soybean, and these
This increase in population size, coupled with a changing skills will be essential in deploying the next phase of the company.
climate and increasingly limited resources for agriculture, will
It has to be taken into account that the regulatory process required to release genetically
place enormous strains on our planet’s collective ability to provide modified plants into the environment is very expensive. As Cellectis plant sciences scientific
the food, fuel and fiber necessary to sustain humankind. team implements its genome engineering strategies, they ensure that only minimal
changes are made to the plant’s genome. It is hoped that plant genomes modified with
One bright spot on this otherwise troublesome scenario is the promise of new technologies. this kind of precision will be better accepted in the marketplace.
Genome engineering, in particular, will provide new crop plants with traits that can meet
the demands placed on agriculture in the coming decades. Pr. Daniel Voytas, Chief Scientific Officer of
Professor Voytas has been with Cellectis plant sciences as Chief Scientific Officer since Cellectis plant sciences
Created in March 2010, Cellectis plant sciences is a subsidiary dedicated to applying the company was set up. He is a professor in the Department of Genetics, Cell Biology
sequence-specific nucleases for plants to develop new species with traits of value. The and Development, and Director of the Center for Genome Engineering at the University “This is a very exciting time in
company’s main goals are to increase and accelerate use of Cellectis’ proprietary techno- of Minnesota in Minneapolis. Specializing in molecular biology and genetics, Pr. Voytas’ plant biology, and our recent
logy in agricultural biotechnology, to broaden the company’s expertise to attract new and research focuses on plant genome modification using nucleases that can recognize
expanded licensing opportunities, and to explore the development of proprietary traits.
advances in genome engineering
specific DNA sequences.
mark a new era. It is stimulating
Cellectis plant sciences is directed by a world-class scientific team. The company’s scientists He is an elected Fellow of the American Association for the Advancement of Science. to be involved in a company
were the first to implement genome engineering in plants. Among the team members is He is an Associate Editor for the journal Genetics and Editor-in-Chief for the journal
the subsidiary Chief Scientific Officer, Daniel Voytas, who is internationally renowned for
that can have such a direct
Mobile DNA. He is the co-founder of the Zinc Finger Consortium, a group of scientists
his work on plant genome engineering. Dr. Voytas is also a professor at the University of dedicated to promoting applications of zinc finger proteins for genome modification. impact on human lives and the
Minnesota where he heads the Center for Genome Engineering. Dr. Feng Zhang serves He has authored or co-authored dozens of scientific papers in the field of genome well-being of the planet.”
as the subsidiary Director of Research, and he has extensive experience in maize, rice and engineering in plant species. Pr. Daniel Voytas
Arabidopsis genome modification. In addition, the company is staffed by two PhD-level
scientists and two research associates.

In its first year of operation, Cellectis plant sciences demonstrated efficient modification
of plant genes by engineered meganucleases. Luc Mathis, Programs and Business Deve-
lopment Director, highlighted that within months of its inception, Cellectis plant sciences
obtained proof-of-concept data. These results demonstrate that meganucleases have similar
capacities in plant cells as previously shown in human cells. From this strong data, Cellectis
plant sciences is now focusing on its commercial aims: to deliver products, services and
licenses for the agriculture industry as well as to build a portfolio of agricultural traits in its
field of expertise – targeted mutagenesis in selected plant species.

34 l Cellectis l Activity Report 2010 l l Cellectis l Activity Report 2010 l 35


Ectycell

Ectycell was established in September 2009 to apply the Ectycell was founded on the fact that developing early-stage high throughput screening
assays that better predict a molecule’s effect on the organism as a whole or on a geneti-
benefits of Cellectis’ core technologies to developments cally diverse population could significantly reduce the high attrition rate currently observed
within the field of stem cells, especially induced pluripotent during drug development. Advances under development at Ectycell may also open new
stem (iPS) cells. opportunities in therapeutics, including regenerative medicine.

This subsidiary will utilize these technologies to transform stem cells into true develop- What is an induced Pluripotent Stem cell?
ment and manufacturing tools that will be novel, robust, reproducible and usable in high An induced pluripotent Stem cell (or iPS cell) is an adult cell that has been reprogrammed
throughput experiments. to behave like an embryonic Stem cell (or ES cell).

Ectycell has a number of research initiatives underway that take advantage of the benefits When an ovum is fertilized, the egg divides, and within a short space of time cells are
of meganucleases for genomic engineering. These programs include: formed that have the potential to develop into all the tissues of the body. These cells are
called embryonic stem cells and are known as pluripotent cells. Pluripotency is the ability
• Development of ‘Clean iPS Cells’ by generating iPS cells from adult cells using targeted to generate all different cell types. How to make an iPS

integration and excision of reprogramming factors, which will circumvent the necessity to 4 genes
use random viral integration methods for iPS cell production. As they mature, ES cells gradually lose their differentiation potential and develop a
functional specialization. For example, a lymphocyte will tackle infections, whereas a
• Development of novel and reproducible methods for cellular differentiation from iPS cells pancreatic cell will be capable of producing insulin – for the rest of its life.
using targeted genome engineering technologies.
Until recently, it was believed to be impossible for a cell to return to a state of immaturity
“Ectycell is responsible for • Development of robust methodologies and processes for large scale production of iPS and recover its differentiation potential. In 2006, the team of Professor Shinya Yamanaka
and differentiated cells at Kyoto University demonstrated that it is possible to reprogram a mature adult cell to give
spreading Cellectis’ genome it back the properties of an embryonic stem cell. In order for this adult cell to return to a
Adult cell

engineering technologies onto • Creation of iPS based cell libraries that will be ideally suited to high throughput drug state of immaturity and be able to differentiate into all cell types, you just need it to express
the stem cell field in order to screening applications. four genes (not normally expressed in adult cells). These cells are termed induced pluripo-
tent stem cells, or iPS cells.
transform these cells into true
In October, Cellectis in-licensed induced Pluripotent Stem Cell Technology from iPS Academia Pluripotent stem cells
manufacturing tools that Japan. The two separate non-exclusive agreements grant Cellectis worldwide access
are robust, reproducible and to the induced Pluripotent Stem (iPS) cells patent portfolio arising from the work of
Professor Shinya Yamanaka at the Center for iPS Cell Research and Application (CiRA)
usable in high throughput
of the University of Kyoto, Japan.
experiments.”
David Sourdive, CEO of Ectycell Professor Yamanaka and his colleagues pioneered this groundbreaking work and Cellectis
precisely required cell types like ...
is the first company worldwide to be licensed by iPS Academia Japan under this iPS cell
patent portfolio for human therapeutics and prophylactics.

... Nerve cells ... Blood cells ... Cardiac cells

36 l Cellectis l Activity Report 2010 l l Cellectis l Activity Report 2010 l 37


Cellectis therapeutics

Cellectis therapeutics, launched in 2008 under the name Cellectis 2010 was a turning point for Cellectis therapeutics, which
genome surgery, focuses on the development of innovative obtained very promising results, particularly in terms of proof of
therapeutic approaches that use meganucleases to treat genetic concept on the antiviral activity of meganucleases*.
diseases (such as muscular dystrophies and hemophilias…), cancers During the year, we also made significant progress in our cell
and persistent viral infections (herpes keratitis, AIDS). therapy programs.
This subsidiary has a team of 19, including 10 PhDs, and endeavors to find innovative Indeed, our team has been able to identify good targets for the so-called “Safe Harbor”
treatments to treat patients with serious conditions that are resistant to conventional approach. This approach consists in defining a site in a genome that allows the insertion of
therapy. Cellectis therapeutics’ aim is to fulfill unmet medical needs. The treatment a new gene, which might be expressed without interfering with the cell functions.
Dr. Carole Desseaux, Director of operations at
paradigm involves targeting the DNA sequence that causes the disease, which may be Cellectis therapeutics
innate (genetic disease) or acquired (viral infection, cancers). We also implemented an effective non-viral vectorization approach using the electro-
poration system obtained from the takeover of CytoPulse’s assets. In addition, we
The genome surgery approach aims to fight the cause of a particular disease and cure obtained very good preliminary results in homologous recombination in primary cells,
“Meganucleases can
the patient, rather than merely treat symptoms. Since its inception, Cellectis therapeutics which prepare the ground for our cell therapy development.
has worked together with its partners – academic research groups and clinicians all over resolve the issue of random
the world (including Children Hospital Boston, Institut de la Vision, Genomic Vision, CNRS, In gene therapy, the results obtained by our Canadian partners on Duchenne muscular integration. The precision
INSERM, and many others) – to transform its research into effective medical treatments. dystrophy* offers a good example of the energy put in our therapeutic research on
of the Cellectis technology
meganucleases by our academic partners.
Current clinical trials means that the new
“2010 was a year of intensive After Cellectis’ buyout of the assets of CytoPulse in September 2010, the company decided In conclusion, our work in 2010 enabled us to obtain proofs of concept and confirm gene can be delivered at
learning for both the Cellectis to pursue the partnership program that had been set up by CytoPulse for the use of electro- our scientific and regulatory strategy. We start 2011 with the aim of obtaining proofs of
a predetermined and safe
porators for vaccination. CytoPulse’s electroporation technology is particularly effective for principle for these results on key pathologies such as hemophilia*.
therapeutics teams and the location. We have high
integrating molecules such as meganucleases into any kind of cell.
partners and organizations in Dr. Carole Desseaux hopes that one day this
the medical biotechnology field Cellectis supplies the Dermavax intradermal electroporation equipment to laboratories research will lead to
carrying out clinical trials requiring this kind of equipment. Dermavax is a system that
with whom we collaborated. effective and life-enhancing
applies an electric field to facilitate the integration of small fragments of DNA into cells,
Alongside the first proofs of thereby potentializing the effect of DNA vaccines by stimulating the immune response. therapies for hemophilia
concept, we often pioneered patients.”
Although Dermavax was originally developed for cancer vaccine treatments, it is also
technology use, production and Dr. Thierry VandenDriessche and Dr. Marinee
being tested today as a prophylactic approach on HIV infections. Three clinical trials are
validation.” being conducted at the Karolinska Institute and at the Cancer Center in Stockholm,
Chuah, VIB Vesalius Research Center at the
Catholic University of Leuven (Belgium)
Sylvain Arnould, PhD, preclinical project leader in the laboratories headed by Professors Britta Wahren and Eric Sandström, as well as at
at Cellectis therapeutics
Uppsala University by Professor Totterman and Doctor Yachnin.

* more information next page

38 l Cellectis l Activity Report 2010 l l Cellectis l Activity Report 2010 l 39


Herpes virus
Scientists from Cellectis therapeutics, the French National Center for Medical Research
(CNRS), and Institut de la Vision (Paris) have used Cellectis’ proprietary meganucleases to
successfully prevent infection of cultured cells by a herpes virus (HSV-1). The research was
published in the journal Molecular Therapy. These are the first proof of concept datas to
show that meganucleases can prevent viral infection. The article describes how scientists
used specific meganucleases engineered by Cellectis to prevent the infection of human
cultured cells by HSV-1.

Subsequent analysis of the treated cells by sequencing showed that the viral DNA had
successfully been clipped by the meganuclease, and therefore lost its capacity to replicate
and spread.
Publications

Herpes virus
Duchenne muscular dystrophy
Meganuclease-mediated Inhibition of Researchers at the Laval University Hospital Center in Quebec (Canada) used mega-
HSV1 Infection in Cultured Cells nucleases engineered by Cellectis to restore the expression of microdystrophin in human
Grosse S, Huot N, Mahiet C, Arnould S,
Barradeau S, Clerre DL, Chion-Sotinel I, myoblasts in vitro and in human cells in vivo. They were therefore able to show the
Jacqmarcq C, Chapellier B, Ergani A, potential of using meganucleases to treat Duchenne muscular dystrophy. These new
Desseaux C, Cédrone F, Conseiller E,
Pâques F, Labetoulle M, Smith J.
findings were published in the scientific journal Gene Therapy.
Molecular Therapy. 2011 Jan 11.
Gene therapy for treating hemophilia
Duchenne muscular dystrophy
Meganucleases can restore the reading The life sciences research institute VIB and Cellectis are collaborating on research into new
frame of a mutated dystrophin approaches to treat hemophilia. They are using meganucleases to replace faulty blood
Chapdelaine P, Pichavant C, Rousseau J,
Pâques F and Tremblay J.P
clotting factor genes with functional copies. Hemophilia is a group of hereditary, recessive,
Gene Therapy (2010) 17, 846–858; X-linked genetic disorders that impair the body’s ability to control blood clotting or
coagulation. Hemophilia patients suffer to various degrees from uncontrolled internal or
external bleeding if a blood vessel is broken. In areas such as the brain or inside joints,
this bleeding can be fatal or permanently debilitating. Financial Statements

40 l Cellectis l Activity Report 2010 l l Cellectis l Activity Report 2010 l 41


Financial statements

Assets Equity and Liabilities

Figures in thousands of euros December 31 2010 December 31 2009 Figures in thousands of euros December 31 2010 December 31 2009
Note:
Net intangible assets 3 976 903 Share capital 584 582
Since 2010, the company has endeavored to
improve the quality of its financial reporting by Net tangible assets 3 913 2 893 Share premium and reserves 45 170 52 404
publishing complete accounts in line with IFRS
standards. Non-current financial assets 231 231 Net income/loss (8 063) (7 768)

This process is an ongoing one, requiring further Deferred tax assets 8 169 5 133 Equity 37 691 45 218
restatements, particularly those concerning
revenue recognition, leasing contracts, deferred Total non-current assets 16 289 9 160 Retirement benefit obligation 120 42
tax assets and the capitalization of certain
development expenses. The figures presented
Inventories 153 118 Borrowings 809 491
here therefore include all the restatements
Trade receivables 2 491 1 768 Other financial liabilities 588 795
required by IFRS standards, but at the time of
publishing this report, the consolidated accounts
Research tax credit and subsidies 6 588 1 570 Provisions 50 71
were still being reviewed by the statutory auditors.
Other current assets 2 486 2 465 Total non current liabilities 1 567 1 399

Cash and cash equivalents 24 048 45 080 Borrowings 560 748

Total current assets 35 766 51 001 Other financial liabilities 257 107

TOTAL ASSETS 52 055 60 161 Trade accounts payable 8 464 6 548

Deferred income 3 516 6 141


Intangible assets at December 31, 2010 included € 2.4 M of development expenses and Total current liabilities 12 797 13 544
€ 1.5 million for patents licensed. Research and development expenses concerning kits and
TOTAL EQUITY AND LIABILITIES 52 055 60 161
plant activities are included under assets for the first time in 2010, which differs from
fiscal year 2009. This is a result of the growth of both activities which now generate recur-
rent revenues. The total of patent assets significantly increased as a result of the acquisition of Tangible assets mainly consisted of laboratory equipment.
CytoPulse, Inc. assets. The tax credit associated with losses carried forward by Cellectis and its subsidiaries was
capitalized, given the prospects for recoverability.

The (current and non-current) “Borrowings” item mainly corresponded to the restatement of
leasing contracts for laboratory equipment.

The other financial liabilities consisted of refundable advances granted to the group for
various research programs. In summary, the company financial debt is negligible while equity
capital reached € 38 M at the end of 2010.

42 l Cellectis l Activity Report 2010 l l Cellectis l Activity Report 2010 l 43


Profit & Loss Cash Flow Statement
2010 2009 2010 2009
Figures in thousands of euros 12 months 12 months Figures in thousands of euros 12 months 12 months

Sales 8 166 7 613 Net income/loss of the year (8 063) (7 768)


Other revenues (Research tax credit & subsidies) 1
7 609 2 527 Depreciation & amortization 1 186 793
Total operating revenues 15 775 10 140 Capital gain on assets disposal (61)
Cost of Sales (licensing-in) (1 445) (1 449) Deferred Taxes (3 036) (1 749)
Gross Margin Profit 14 330 8 691 Share based payments 435 1 045
Research and Development (12 311) (7 971) Other non cash items 144 (30)
Marketing and Administration (13 457) (10 601) Cash Flow from operating activities before Working Capital change (9 334) (7 770)
Other income 0 78 (Increase) / Decrease in accounts receivable (758) (893)
Other expenses (27) (Increase) / Decrease of Research Tax Credit & Subsidies (5 018) 1 321
Current operating income/loss (11 465) (9 803) (Decrease) / Increase of trade accounts payable 1 916 71
Financial income 485 463 Net change in other assets and liabilities (2 672) 3 952
Financial expenses (153) (173) Change in working capital (6 532) (4 451)
Other financial income & expenses 34 (4) NET CASH PROVIDED (USED) BY OPERATING ACTIVITIES (15 866) (3 319)
Net operating income/loss 366 286 Acquisition of intangible assets (3 528) (1 017)
Income tax 3 036 1 749 Acquisition of tangible assets (1 477) (448)
NET INCOME (8 063) (7 768) Acquisition of financial assets
Net income form sale of tangible assets 729 719
1
Including research tax credit 6 148 1 255 NET CASH PROVIDED (USED) BY INVESTING ACTIVITIES (4 276) (746)
New borrowings 0 0
Revenues from licenses and research kit sales increased by more than 7% in 2010. This Repayment of long-term borrowings (983) (1 079)
increase is significant considering certain agreements with major groups that have been placed Proceeds from issuance of common stock 93 22 296
on hold or in the midst of reorganization, particularly during the launch period of new NET CASH PROVIDED (USED) BY FINANCING ACTIVITIES (890) 21 217
research kits. The next fiscal year is expected to show further progress, particularly in kit sales
and related services.
CHANGE IN CASH AND CASH EQUIVALENTS (21 032) 17 152

The R&D tax credit increased significantly in 2010 (€ 6.1 M compared with € 1.3 M in 2009), Opening cash and cash equivalents 45 080 27 928
mainly due to the increase in R&D expenditure (+54%) and the reduction in grants received Closing cash and cash equivalents 24 048 45 080
in 2010. A background study was conducted by Cellectis with the help of consultants in order INCREASE (DECREASE) IN CASH AND CASH EQUIVALENTS (21 032) 17 152
to estimate the R&D tax credit.
The increase in the R&D tax credit in 2010 resulted in a considerable increase in this receivable
The increase in operating expenses in 2010 is due to the implementation of a major growth
at December 31. Intangible investments in 2010 consisted of € 1.9 M capitalized development
strategy outlined in 2009, the consolidation of upstream research teams for Cellectis, and
expenses, along with patent acquisitions. Approximately one third of the year’s cash burn
application platform development for each of the subsidiaries. Research and development
was affected by a temporary unfavorable variation in working capital requirements. In 2011,
expenses increased by approximately 50%, which remains consistent with the staff increase
the change in cash (and cash equivalents) is expected to be near the level of net income.
(+50% from the end of 2009 to the end of 2010).

44 l Cellectis l Activity Report 2010 l l Cellectis l Activity Report 2010 l 45


Share Price and Capital Structure

Cellectis’ share price saw a downturn during the 2010 financial year. In fact, the first
Share Price Evolution trading day of 2010 finished at a price of € 10.95 per share and the last day (December
31st) finished at a price of € 7.40 per share, thus showing a net fall of 32.4%. Several
Share Price in € Share Volume in thousands of shares
12
factors explain this downturn: the continued exit of venture capitalists as historical
100
11 shareholders, low daily trade volumes and market volatility linked to significant macro-
80
10 economic uncertainty.
60
9
40
8 The capital structure has continued to evolve by the exit of venture capital shareholders
7 20 and changes resulting from the capital increase at the end of 2009. The free float
6 0 has now reached more than 60% but the “hard core” holding, centered around the two
Apr Jul Oct
2010
2009

founders, the Institut Pasteur, the business angel present in the capital since 2000
€ 100 million market capitalization. About 10,000 share and the industrial companies that entered in 2008 (Regeneron) and 2009 (Monsanto),
average volume.

NYSE-Euronext ACLS.PA
remains unchanged.
Appendices
Shareholders Breakdown as of December 31, 2010

1. Free float 62% 2

2. Corporate Partners 4% 3

3. Founders & Management 15%

4. Business Angel 10%


1 4
5. Venture Capitals 5%

6. Institut Pasteur 4%
5
6

46 l Cellectis l Activity Report 2010 l l Cellectis l Activity Report 2010 l 47


Governance

Executive Committee Board of Directors Scientific Advisory Board


The Executive Committee is composed of the senior-level management of Cellectis, which The Board of Directors determines the The Scientific Advisory Board, set up in
establishes consolidated objectives, monitors the strategic projects and decides on priorities. company strategy and oversees Cellectis 2002, is composed of eight active members,
Its members implement the company’s strategy and direct its day-to-day operations. The activities. Members of the Board of appointed for one year and meets twice a
Committee includes André Choulika and David Sourdive, the company’s co-founders. Directors serve for a term of three years; year. Its mission is to outline Cellectis’ broad
the Chairman convenes meetings scientific orientations. It presents Cellectis’
André Choulika, PhD, Chief Executive Officer when it is deemed necessary or desirable. management team with methods and
strategies to achieve the company’s techno-
André Choulika, PhD, founder of Cellectis SA, has served as Chief Executive Officer since On December 31, 2010: logical goals. It evaluates the work achieved
the company’s inception. Dr. Choulika is a pioneer in the analysis and use of meganucleases during the year and the results obtained.
to modify complex genomes. He has made many of the critical observations in the field Christian Policard, PhD
On December 31, 2010:
Executive Commitee, from left to right: and is an author of the most significant patents on the use of meganucleases in vivo. Chairman, co-founder of Biotech
David Sourdive, André Choulika, Frédéric Pâques, Dr. Choulika received a PhD in Molecular Virology form University of Paris VI / Institut Developpement Conseils
Dirk Pollet, Sylvie Delassus, Marc Le Bozec Prof. François Jacob, Honorary Chairman, PhD
Pasteur. Dr. Choulika has made post-doctoral studies at the Harvard Medical School within
Collège de France, Paris, France
the department of Molecular Medicine of Boston’s Children’s Hospital. Martin Bitsch, MD
Independent director, Consultant Prof. Rodney J. Rothstein, PhD, Chairman
David Sourdive, PhD, Executive Vice President, Corporate Development Columbia University, New York, USA
André Choulika, PhD
Prof. Frederick W. Alt, PhD
David Sourdive, PhD, co-founded Cellectis SA with Dr Choulika, and has served as Director, Chief Executive Officer, Cellectis
Howard Hughes Medical Institute,
Director since 2000. Prior to inception of the company, Dr Sourdive was the head of
Chevy Chase, USA; Harvard
Biotechnology Laboratory at the Centre d’Etudes du Bouchet (French Ministry of Defense). Alain Godard
Medical School, Boston, USA
At the same time, Dr Sourdive was heading a research group in Immunology at the Pasteur Independent director, Former Head of
Institute. Dr. Sourdive attended Ecole Polytechnique and received a PhD in Molecular Aventis Cropscience board of directors, Prof. Bernard Dujon, PhD
Virology form University of Paris VII/ Institut Pasteur. Dr Sourdive then applied Consultant Université Pierre et Marie Curie (Paris VI) -
recombination tracking technologies to anti-viral immune memory, at the Emory University Institut Pasteur, Paris, France
Vaccine Center in Atlanta. Roger J. Hajjar, MD
Prof. Alain Fischer, MD, PhD
Director, Kaminvest Holding Representative
Hôpital Necker - Enfants Malades, Paris,
France
Frédéric Pâques, PhD, Chief Scientific Officer Richard C. Mulligan, PhD
Independent director, Mallinckrodt Profes- Prof. James E. Haber, PhD
Marc Le Bozec, Chief Financial Officer sor of Genetics at Harvard Medical School Brandeis University, Waltham, USA
and Director of the Harvard Gene Therapy
Prof. Denis Pompon, PhD
Dirk Pollet, PhD, Chief Business Officer Initiative
Center of Molecular Genetics,
Gif-sur-Yvette, France
Sylvie Delassus, PhD, Senior Vice President, Corporate Communication David Sourdive, PhD
Director, Executive Vice President, Prof. José-Alain Sahel, MD, PhD
Corporate Development, Cellectis Hôpital des Quinze-Vingts, Paris, France

Prof. Luis Serrano, PhD


Pascale Altier
Center for Genomic Regulation,
Observer, Institut Pasteur Representative
Barcelona, Spain

48 l Cellectis l Activity Report 2010 l l Cellectis l Activity Report 2010 l 49


®
Cellectis

Contact:
Cellectis
102 avenue Gaston Roussel
93230 Romainville
France
Tel: +33 (0)1 41 83 99 00
investors@cellectis.com
www.cellectis.com

Photos:
Ramon Martinez
Franck Beloncle
Cellectis
Tim Rummelhoff
Eric Merle
INRA Christophe Maitre
Cédric Porchez
iStockphoto

Graphic Design:
Valentina Herrmann

Printing:
GraphiCentre

Printed on FSC certified recycled


paper using vegetable based inks.

Disclaimer
This publication and the information contained
herein do not constitute an offer to sell or subscribe,
or a solicitation of an offer to buy or subscribe,
for shares in Cellectis in any country. This
publication contains forward-looking statements
that relate to the Company’s objectives based
on the current expectations and assumptions of
the Company’s management only and involve
unforeseeable risk and uncertainties that could
cause the Company to fail to achieve the objectives
expressed by the forward-looking statements bove.
MADE BY CELLECTIS

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