SYNTHELIS Syynthelis misssion is to prroduce and provide pha
armaceuticcal industry with functiional m
membrane p
proteins to unleash thee discovery of new dru
ugs. Contact:: Bruno Tillier (CEO) E‐mail: b
bruno.tillier@
@synthelis.fr Cellphonee: +33 6 11 1
19 21 47 Direct line: +33 4 76 5
54 95 37 PRO
OJECT SUMM
MARY Syntheliss has been created 3 years ago in Grenoblee with the mission to produce an
nd provide pharmacceutical indu
ustry with functional mem
mbrane protteins to acceelerate the d
discovery of new drugs and vacccines. Memb
brane proteins are biolo
ogical moleccules which are critical tto drug disccovery and developm
ment prograams. These m
molecules represent indeeed more than 60% of th
he therapeutic targets. The man
nufacture and supply of these moleccules in theirr active form
m is still very challenging but crucial for innovvation in the pharmaceuttical sector. Syntheliss is already w
working with
h several bigg pharmaceu
utical clients,, biotech com
mpanies and
d academic teams on
n different tyypes of mem
mbrane proteeins such as G
GPCRs, ion ch
hannels, porins, viral pro
oteins, drug receptorrs, enzymes and many o
others. In leess than 3 yyears, over 5
50 membran
ne proteins have been produced at Syntheliis and the acttivity of mosst of them haas been demo
onstrated. D and engin
neers in biology and biochemistry are today w
working in 9 peoplee including several PhD
Syntheliss. The compaany has an eexclusive worrldwide licen
nse on a pateented techno
ology developed by the TIMC lab
boratory at th
he Universityy of Grenoblee. Syntheliss’s innovativve production
n process en
nables the m
manufacture of membran
ne proteins in both the quantitiees and the quality req
quired for sstructural sttudies, funcctional studiies, electrop
physiology, microarrrays, therap
peutic protein developm
ment, vaccin
ne developm
ment, antibo
ody develop
pment and ligand/reeceptor interraction studyy. As well aas focusing on membranee protein manufacture, in
n parallel, thee company iss developing innovative therapeu
utic and vaccine approaches in closee collaboratiion with thee TIMC laborratory. One anti‐tumor product and one vaccine candidaate validated in vivo are ccurrently in d
development. he proteins However, Synthelis ccell‐free lysatte is prepareed from an E. coli strain cculture. Conssequently, th
expresseed with thee system do not havee any eukaryotic post‐‐translational modification. These modificaations, especcially glycosyylation, are o
often crucial to obtain th
he functionality of the p
protein and they are essential to develop and
d register a th
herapeutic protein for usse in Human. 1 Syntheliss project is th
hus to quicklly develop neew lysates fo
or cell‐free exxpression to obtain the aactivity of a broader range of prroteins and tto access to
o the markett of the glyccosylated pro
oteins. To acchieve this plans to workk with one o
or two Ameriican research
h leaders in cell‐free technology to objectivee Synthelis p
develop such system
m as fast as po
ossible and p
provide soluttions to the p
pharmaceuticcal industry tto produce d better biolo
ogics. new and
The ultim
mate objective of our p
project is strrongly to accelerate thee developmeent of news drugs and vacciness for the beneefit of the paatients. 
A
About the c
company an
nd the projeect Syntheliss is a compaany specializzing in the p
production, purification p
aand characteerization of membrane proteins (MPs) using a patenteed cell‐free based techn
nology. The biological m
molecules pro
oduced by developmentt programs, for drugs an
nd vaccines, within the Syntheliss are critical to drug disccovery and d
biotech aand pharmacceutical industries. The sup
pply and maanufacture o
of this type of moleculles, which rrepresent more m
than 60
0% of the therapeu
utic targets, has proven to be highly problematic, due to ttechnical ob
bstacles linkeed to their manufaccture (cytoto
oxicity, aggrregation and
d misfoldingg). Synthelis’’s patented cell‐free prrocess can produce membrane proteins in b
both the quaantity and the quality req
quired by ind
dustry, leadin
ng the way of cost‐efficieency. to huge potential gaiins in terms o
Today, SSynthelis provvides a rangee of services to deliver fu
unctional membrane protteins in solub
ble form or in a pro
oteoliposomee format. Th
hese protein
ns can then be used fo
or vaccine d
developmentt, antibody developm
ment, proteiin vectorization, screenin
ng & display technologies, in‐vitro diaagnostic and
d structural biology. Synthelis haas an exclusivve worldwidee license on a patent ow
wned by the U
University off Grenoble. 2 Syntheliss approach iss based on the use of a ccell‐free systtem tuned‐up
p to producee functional membrane proteins embedded iinto the lipid
d bilayer of lip
posomes. Cell‐freee expression is gaining this last deccade more and more interest and validation tto express membraane protein as shown in multiple publications from diffferent acadeemic groupss. Cell‐free ogy presents the advantaage of an open system; tthis feature aallows the in
ntroduction o
of different technolo
componeents, co‐facttors, chapero
ones, redox rreagents as w
well as liposo
omes, which are present during the protein ssynthesis. Taking advantage of f this featuree Synthelis haas developed
d a strong know‐how to screen and define the d to the pro
otein duringg its synthessis in view to t obtain a functional right conditions to be provided
pharmaceutical clients, b
biotech comp
panies and moleculee. Synthelis is already working with several big p
academic teams on different types of mem
mbrane proteeins such as GPCRs, ion channels, porins, viral ptors, enzymes and manyy others. In less than 3 years, y
over 5
50 membran
ne proteins proteins, drug recep
nts and the aactivity of mo
ost of them has been deemonstrated. However, have beeen delivered to our clien
Syntheliss cell‐free lyssate is prepared from an E. coli strain culture. Consequ
uently, the p
proteins exprressed with the system do not havee any eukaryyotic post‐translational modificaation. These modification
ns, especiallyy glycosylatio
on, are often
n crucial to o
obtain the fu
unctionality of the protein and they are esseential to devvelop and register a therrapeutic prottein for use in Human. hus to quicklly develop neew lysates fo
or cell‐free exxpression to obtain the aactivity of a Syntheliss project is th
broader range of proteins and to access tto the markket of the glycosylated proteins. Different US orthwestern University (Chicago) orr Matthew academic laboratories like Mickkael Jewett’’s lab at No
a
working on ssuch projects. They would be ideal DeLisa’s team at Corrnell Universsity (Ithaca) are already w
with a French private com
mpany and partnerss for Syntheliis if they havve an interestt to work in connection w
agree to
o grant the exploitation o
of the resultss of a collabo
orative projeect to Syntheelis. Americaan partners with an internationaal recognition will also ggive to Synth
helis a much higher cred
dibility than today as a uropean com
mpany and will w thus trem
mendously heelp Synthelis in developing a businesss in North small Eu
America. 3 
The innovative and creative aspects of the project Today most of the therapeutic proteins are produced in cell based systems with around 30% in E. coli strain and almost 60% in mammalian cells (CHO and HEK). These systems have some advantages and are used for decades now at an industrial scale. They have however a lot of drawbacks and many proteins cannot be efficiently produced by this way, especially cytotoxic proteins as well as membrane proteins and this, when the part of the biologics are constantly growing in the drug market. For these reasons a lot of drug development programs are blocked or stopped because the production system commonly used is not able to deliver the therapeutic protein either in enough quantity or with the appropriated properties or both. In broad outline, the bacterial systems gives usually rise to good expression yield at low cost but do not make any posttranslational glycosylation when the mammalian systems provide the opposite and are very costly. We really believe that cell‐free system is one of the most promising approaches to produce therapeutic proteins in terms of quantity and quality. We have already demonstrated at Synthelis that cell‐free system is able to produce membrane proteins in sufficient amount to develop a protein therapy or a new vaccine. However we want to optimize the cell‐free technology to obtain posttranslational modifications. These modifications, particularly glycosylation, are crucial for the stability and the efficacy of a therapeutic protein. Several academic groups have already paved the way to develop innovative cell‐free system able to provide posttranslational modifications. Our project is to gather and select American leaders to develop such system with us as fast as possible and provide solutions to the pharmaceutical industry to produce new and better biologics. 
Social impact, feasibility and economic viability of the project Our project is to rally a few major US researchers and their team involved in synthetic biology and cell‐
free expression to work in close and efficient collaboration with Synthelis to develop one or two new cell‐free systems able to produce proteins with posttranslational modifications to get the protein active. The social impact for our future partners will be first to raise their profile in their field through the different communications and publications expected from the project. In addition they will be part of the inventors in case some patent applications are filled in during the project. The project could also give them the opportunity to pursue their work with Synthelis as external scientific consultant or to get a position as CSO or CTO in a future US subsidiary of Synthelis. The ultimate objective of our project is strongly to accelerate the development of news drugs and vaccines for the benefit of the patients. If we are able to produce a broader range of therapeutic targets and antigens in their active form with this project, much more new therapies, vaccines and drugs could be developed to cure cancers, infectious or genetic diseases, metabolic, neurologic as well as neurodegenerative disorders and many others pathologies. In terms of feasibility we mentioned above that a few academic groups have already reported some results on cell‐free system able to provide posttranslational modifications. 4 We want to start our project from this preliminary work and really adapt cell free production system to deliver proteins with the desired post‐translational modifications for their use in drug screening or as biologic. Taking account the knowledge and the previous works on the cell‐free technlogy, we except to get the first workable results in one year. Even if the chemical molecules are still dominating the drug market, the part of the biologics is more and more important representing around 20 % of the market and posting a double‐digit annual growth rate. Most of these biologics are glycosylated. The therapeutic targets used in the drug discovery process also require often the appropriate glycosylation to be active. The achievement of this project will thus strongly interest the pharmaceutical industry and drastically accelerate Synthelis development in Europe as well as in the US. 5