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INDEX > Biological and Chemical Products

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•Chemical Products •Biological Products (therapeutic molecules, vectors)

p. 15

> Models and Technologies

p. 27

p. 7

•Molecule evaluation •Diagnostics •Testing Systems

p. 57

> Technological Platforms

p. 71

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p. 29 p. 39


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> Biological and Chemical Products

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• Chemical Products

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Thionucleoside Prodrugs and Drugs

A highly-promising family of antiviral and anticancer molecules > Introduction

The prodrug concept dictates that a pharmacological substance is administrated under an inactive form made up of two main components: the drug itself and a vector able to deliver the drug to the target cell. Once in the cell, the chemical bond between the vector and the drug is cleaved via in vivo metabolisation, thus releasing the active drug towards the target. This principle enhances the selectivity of the drug and reduces its toxicity towards non-target cells.

> Novel Synthesis Pathway

> Intellectual Property

Researchers at the Molecular Pharmacochemistry Department (Université Joseph Fourier, Grenoble-1) have recently developed a synthesis pathway giving access to a novel class of antiviral or antitumoral thionucleoside prodrugs. In the cell, these compounds compete with the natural primary substrate of DNA and RNA synthesis, therefore inhibiting cell proliferation. Such a mechanism can therefore potentially lead to many promising antiviral and anti cancer applications. To date, this novel family has been successfully tested on HIV infected human cells and tumoral cell lines.

The synthesis pathway, associated molecules and their use in pharmaceutical preparations for the treatment of viral infections and cancers are covered by a European patent application # PCT/FR2007/001784.

> Technology Status

Floralis is currently looking for partners to further develop this promising technology which demonstrates significant potential in the development of antiviral and anticancer molecules.

> Features

> Contact

• Highly flexible synthesis pathway • Original approach towards the synthesis of prodrugs

Mathieu TILQUIN

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 41 – Fax : +33 (0)4 76 00 70 38 mathieu.tilquin@floralis.fr - www.biotech-pipeline.com

> Benefits

With many anti-cancer and HIV treatments becoming less and less effective as a result of drug resistance, this technology demonstrates considerable potential as a means of creating novel antiviral or anticancer drugs.

> Key laboratory results (novel molecules originating from this process)

High efficacy demonstrated on - HIV infected human cells, with EC50 averaging 5-10 µM - human cancer cells, with CC50 averaging 10-20 µM

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A Molecular Library for Screening Biological Activities Circa 1500 new and ex isting molecules available for commercial use in screening > Introduction

The Molecular Chemistry Department of the Université Joseph Fourier, which played a key role in the development of Taxoter, the blockbuster cancer drug, has developed a highly comprehensive library of novel and already-existing molecules that is available for use in screening programmes. The role of the library is two-fold : as well as enabling organisations access to a wide range of molecules that can help them discover new activities for specific targets, the library also helps bring together industrial research teams and academic teams in order to pursue research into promising new drugs. Examples of targets that have already been tested using this library include HIV proteins, Bacteria, Enzymes.

> Specialist Services

A dedicated team of chemists expert in chemical synthesis is available to help develop new, or enhance existing structures and develop synthesis pathways.

> Molecular library procedure

> Key Features

• Circa 1500 molecules available in the library • 1120 molecules available for screening in 96 well plates (80 products per plate) • Purity averaging over 95% • Quality control ensured by NMR, UV, IR or mass spectrometry • High range of molecular diversity : Bio molecules, heterocyclic compounds (indoles, pyrroles, acridines etc., multidentates compounds, Oxygen, Nitrogen, Sulphur, polyhydroxyalted macrocycles, alkaloids, stable organic radicals, etc.)

> Contact

Mathieu TILQUIN

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 41 – Fax : +33 (0)4 76 00 70 38 mathieu.tilquin@floralis.fr - www.biotech-pipeline.com


New Selenium0 Containing Nanoparticles:

Elemental selenium, an essential micronutrient to combat ox idative stress > Introduction

Although toxic in large amounts, selenium is a key trace element that plays an important role in the functioning of antioxidant enzymes involved in the removal of free reactive oxygen species responsible for the cell damages related to oxidative stress. A team of researchers at the University of Grenoble has recently developed a novel synthesis pathway giving access to stable composite nanoparticles made of calcite and elemental selenium, allowing biological delivery to the human body of a form of selenium0. Selenium nanoparticles were recently reported to have: - less negative effects (toxicity) when compared to elemental selenium - enhanced biological activities with regards to oxidative stress and cancer Nanoparticles such as this that contain selenium could prove to be highly relevant for food supplement type applications.

> Key Features and

> Commercial Opportunity

innovative aspects

We are currently searching for industrial partners interested in licensing or co-developing this technology.

• An original synthesis pathway using the amino acid seleno-L-cystine and calcium hydroxide (Ca(OH)2) to produce stable calcite- selenium nanoparticles • Enhanced bioavailability • Reduced toxicity towards human cells

> Contact

> Main Applications

The main application of these novel elemental selenium containing nano-particles concerns the area of nutrition and dietary supplements related to anti oxidative stress

Mathieu TILQUIN

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 41 – Fax : +33 (0)4 76 00 70 38 mathieu.tilquin@floralis.fr - www.biotech-pipeline.com

> Intellectual Property

The Selenium containing nanoparticles, their synthesis pathway and their use as dietary supplements are protected by European patent # 08 290 234.7

Microscopic views of the selenium–calcite nano composite obtained according to our technology

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A Novel Family of Chemicals to Fight Microbial Resistance The search for novel antimicrobial agents: breaking a vicious circle > Introduction

Since the introduction of antimicrobial agents, micro-organisms have developed numerous defences rendering them resistant to these drugs. Antimicrobial resistance, in particular multi-drug resistance, is increasing at an alarming rate and severely compromises our ability to deal with infectious diseases. Over the last three decades, numerous efforts have been devoted to the research and development of generations of new antibiotic drugs. A team of researchers involved in organic synthesis at the Molecular Chemistry Department of Grenoble, key players in the development of Taxoter, the anti cancer blockbuster, has recently discovered a novel family of indole derivatives1 revealing significant potential as anti-microbial agents, particularly for their resistance-reversing effects. The development of these molecules as new drug candidates has recently been funded by the National Research Agency (L’Agence Nationale de la Recherche).

> Key Benefits

> Contact

• An original synthesis pathway allowing access to a wide range of derivatives • Interesting growth inhibition effects on sensitive bacterial strains of Staphylococcus aureus • Demonstrated resistance-reversing activity towards resistant strains of Staphylococcus aureus (NorA strain) • Low cytotoxicity on human cell lines • The know-how and expertise to work out mechanisms of action and enhance activity of ideal candidates

Mathieu TILQUIN

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 41 – Fax : +33 (0)4 76 00 70 38 mathieu.tilquin@floralis.fr – www.biotech-pipeline.com

> Intellectual Property

The family and the synthesis pathway of these indole derivatives are protected by European Patent.

> Potential Applications

• Antibacterial and Antifungal drug development

> Developmental

When subjected to resistant strains of bacteria over expressing antibiotic efflux pumps, some of the tested indole derivatives were observed to totally restore the sensitivity of the bacteria to the widely used antibiotic ciprofloxacin.

Opportunities

Floralis is currently looking for industrial partners interested in further developing this exciting technology.

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Novel CFTR channel modulators A new approach towards promising therapeutical solutions to ion channel related diseases > Introduction

In human cells, specific channel proteins encoded by different genes control the transport of chloride anions across membranes and regulate the secretion and absorption of salt and water in cells, a key mechanism of the physiological cell equilibrium. Numerous diseases are related to the malfunctioning of channel proteins. Cystic fibrosis, one of the most severe genetic diseases related to chloride channels, is due to a physical modification of the protein structure, leading to a reduced functioning of the channel protein. In other cases, the hyper-activity of channel proteins can lead to heavy fluid loss and dehydration, as observed in severe diarrhoea and cholera. A team of researchers at the Pharmacochemistry Department of Grenoble has recently developed novel, potent and selective chloride channel modulators able to either activate or inhibit the channel proteins, some of them demonstrating excellent modulating activities. These novel molecules demonstrate significant promise in the treatment of chloride channel related diseases.

> Key laboratory results

> Key features of these novel

molecules

• In vitro testing: the activation or inhibition of chloride channels were demonstrated on mouse tissues (colon) and human bronchus tissue. Our best molecules were observed active for concentrations averaging the micromolar level for activators, and the picomolar level for inhibitors.

• Water solubility facilitating their use in physiological conditions. • Excellent activities observed in vivo on mouse models (salivary glands) for both the stimulation and the inhibition of chloride channels. • Selectivity demonstrated with regards to CFTR channels.

• In vivo testing: a modulating effect on mouse and rat salivation was observed at concentrations averaging 30µM for activators, and 200pM for inhibitors. No toxicity occurred at these concentrations.

> Intellectual Property

• Selectivity: No effect on salivation was observed on knock out mouse models (animals that do not express CFTR channels), demonstrating the selectivity of our molecules with regards to CFTR channels

> Technology Status

Floralis is currently looking for industrial partner(s) to continue the in vivo proof of concept and exploit the full potential of this technology which shows particular promise to chloride channel disease applications.

This novel family of chloride channels activators, their synthesis pathway and their use in the treatment of ion channels related diseases are protected in a patent recently extended to Europe and the US. Ref # PCT/FR2004/050528

> Contact

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Mathieu TILQUIN

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 41 – Fax : +33 (0)4 76 00 70 38 mathieu.tilquin@floralis.fr - www.biotech-pipeline.com


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• Biological Products (therapeutic molecules, vectors)

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Synthelis

Effective solutions for membrane protein ex pression > Introduction Because GPCR (G Protein Coupled Receptors) form the biggest family of receptors located on the surface of human cells, they represent 50% of medicines and therapies currently available on the market (in financial terms this represents more than 30 Billion USD in annual drug sales). Current trends dictate that Cancer has now overtaken cardiovascular illnesses as a key priority in healthcare - consequently all research relating to GPCR has the potential to lead to promising new therapies or medications.

> Synthelis: a major step

forward in the production of membrane proteins

Synthelis is a business unit which provides a solution to a well known challenge in terms of biotechnological production - namely the synthesized production of membrane proteins. Around 30% of the human genome is coded for protein membranes. This family of proteins is involved in key biological processes such as cellular signaling, energy transduction or metabolic transportation. Anomalies affecting their structure or function can be directly or indirectly linked to a large number of pathologies. Consequently these molecules are the target for a large number of medicines currently planned for development. The significant difficulties associated with their production, purification and crystallization in comparison with soluble proteins demonstrates the necessity for developing new manufacturing processes. Using a cutting-edge process, Synthelis produces functional membrane proteins in soluble or proteoliposome form. These membrane proteins can be used in structural studies or functional/ electrophysiological studies, the development of vaccines or even high throughput molecule/ligand screening.

> The Synthelis offering

• Active proteoliposomes containing one or more different membrane proteins and preserved protein functionality • Customised soluble membrane proteins

> A flex ible approach to membrane ex pression

Membrane proteins in all of the following areas can be supplied: • Membrane proteins originating from different sources (plant, bacteria, mammals) • Membrane proteins of different types (ion channels, porins, GPCRs, virus etc) • 40 membrane proteins already successfully expressed in native and active forms

> Contact Bruno TILLIER

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 34 – Fax : +33 (0)4 76 00 70 38 bruno.tillier@floralis.fr - www.biotech-pipeline.com

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Synthelis

Effective solutions for membrane protein ex pression > Key Benefits

>We R&D Areas Addressed can support you in all of the following areas:

• The entire protein is produced using Synthelis’s patented process • Proteins are active (fully functional) • Large quantities can be produced (in Mgs) quickly (between 2-3 months) • Proteins produced demonstrate very high levels of purity

• Structural studies (crystallogenesis / NMR) • Functional studies (Enzymatic assays) • Target proteins for rational drug design • Membrane proteins for microarrays • Anti-MP antibodies production • Protein-Protein/ Ligand interaction studies • Therapeutic protein development • Vaccine Development

> Production Process

The following schematic outlines the production process leading to the production of active membrane proteins

> Contact Bruno TILLIER

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 34 – Fax : +33 (0)4 76 00 70 38 bruno.tillier@floralis.fr - www.biotech-pipeline.com

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Smartox

Synthesis of peptidic tox ins : access to an immense library of active peptides (suitable for use in the development of new drugs and therapies)

> Introduction Toxins extracted from spiders, molluscs and snakes have enabled the pharmacological characterization of a large number of ionic channels. Although pharmacological understanding of ionic channels is still limited, the discovery of active agents could play a significant role in the understanding of the physiological function of potential new targets. Within this context, Smartox is a business unit that specialises in the synthesis of bespoke peptidic toxins. These toxins demonstrate significant potential as a result of their action on Ionic channels and G-protein coupled receptors. Smartox works alongside research teams with a view to identifying and characterizing the interactions between ionic channels and toxins. Many of the resulting molecules can then form the basis of medications or therapies planned for future development.

> Range of Services

> Technical Data

• Bespoke synthesis of peptidic toxins • R&D consulting services available • Significant library of toxins available (20 toxins catalogued per month) • Customisable: toxins can be modified according to clients’ specific needs

• < 70 amino acids • Toxins originate from animals, plants, bacteria, fungietc. • Mass spectrometry (MALDI-TOF) and HPLC analysis • HPLC purification and profile • Peptide sequence and folding guaranteed

> Key Benefits

> Modification capabilities

• Synthesis carried out by microwave ensuring high levels of quality and speed of production • Expertise of Director of Science: Michel De Waard recognized as a leading expert in the study of ionic channels • Able to provide highly innovative toxins (previously uncommercialised) • Capable of producing large quantities of toxins within a short time frame (under 20 days)

> Potential Applications

> Click chemistry > N-terminal acylation > C-terminal amidation > Biotinylation > Fluorescent tag > Incorporation of non natural amino acids > Cyclic and phosphorylated peptides > C13 and N15 isotope labelled > Other modifications upon request

> Contact

Bruno TILLIER

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 34 – Fax : +33 (0)4 76 00 70 38 bruno.tillier@floralis.fr - www.biotech-pipeline.com

> Drug discovery > Drug Development > Vaccine development

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Raft (Radioselectively Addressable Functionalized Templates)

Non-viral vectorisation for the targeted delivery of therapeutic and diagnostic agents > Introduction

The technology (RAFT) is based on the use of a cyclopeptide scaffold that exposes two sides, which can be functionalised selectively. This feature opens up the possibility to link, in a structurally controlled manner, therapeutics and/or diagnostic agents to the appropriate targeting ligand. As part of this design, the platform contains multiple attachment points on each side resulting from multiple ligand-receptor interactions. Highly encouraging results have already been obtained in vivo in the diagnosis and imaging of tumours when molecules targeting tumour neo-angiogenesis together with molecules bearing imaging capabilities were conjugated to this scaffold. In addition, multivalency of the targeting ligand (RGD) was highly beneficial with regards to anti-angiogenic effect and significant reduction of tumour growth was observed. It is believed that this multivalent type of interaction further increases cellular uptake of the conjugated drug, thereby enhancing its efficacy, whilst simultaneously minimising potential side effects.

> Key Benefits

• High precision and accuracy in the targeting and delivery of and/or therapeutic agents. • Increased tumour penetration and drug uptake. • Amplified delivery of therapeutic/diagnostic agents. • Enhanced signal-to-noise ratio in diagnostics. • Higher degree of accuracy in the diagnosis, imaging, and treatment of cancers. • Increased speed of diagnosis. • Increased accuracy of imaging • Detection of metastases

> Potential Applications > > > > > >

Cancer therapy/oncology Targeted pharmaceuticals Medical imaging and diagnostics Therapeutics Radiopharmaceuticals MRI technologies

> Commercial Opportunity We are interested in identifying partners wishing to license this highly promising technology. In addition to licensing opportunities we are also interested in developing research partnerships that will enable the testing of ligands on the RAFT molecule that may result in a variety of new potential applications, be they diagnostically or therapeutically based. As the technology is based on a highly modular approach, we are seeking partners who are expert in the selective targeting of ligands or are able to provide promising contrast agents for imaging and/or diagnosis.

> Contact

Nicole GIRAUD

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 42 – Fax :+33 (0)4 76 00 70 38 nicole.giraud@floralis.fr - www.biotech-pipeline.com

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Promising Aculeatin Derivatives

New weapons against malaria > Introduction

Aculeatins belong to a novel family of molecules recently isolated from the plant Amonum aculeatum commonly used in Papua New Guinea as a traditional medicine to treat fever and malaria. Researchers at the Molecular Pharmacochemistry department, University Joseph Fourier, have developed a unique synthesis pathway giving access to a wide range of aculeatin derivatives. This highly flexible diversity-oriented approach enables the synthesis of numerous and complex derivatives, some of which already demonstrate enhanced antiplasmodium activities and reduced cell toxicity. This new method of synthesis can result in opportunities regarding both the molecular optimization of aculeatins, as well as an understanding of their mode of action.

> Key features • Novel aculeatin derivatives with low toxicity towards human cell lines • Acute anti plasmodium and anti toxoplasmosis activities evidenced in vitro

> Benefits

The technology has the potential to produce a wide range of derivatives, enabling a clear understanding of structure-activity relationships (SAR). By establishing a critical mass where sufficient numbers of molecules are available, followed by an in-depth analysis of the structure-activity relationship, the identification ol lead compounds is made possible.

> Key Laboratory Results

> Intellectual Property Covered by French Patent # 07/06929 (October 3, 2007)

> Technology Status

Floralis is currently looking for partners to further develop this exciting technology which demonstrates significant potential in the development of highly promising molecules with malaria inhibiting properties.

> Contact Mathieu TILQUIN

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 41 – Fax : +33 (0)4 76 00 70 38 mathieu.tilquin@floralis.fr - www.biotech-pipeline.com

• High efficiency in terms of parasite inhibitiion (in vitro assays) - IC50 on Plasmodium falciparum as low as 8090nM - IC50 on Toxoplasma gondii under 180nM • Ability to cure plasmodium infected erythrocytes within one hour of exposure (ex vivo assays)

• Low toxicity levels in human blood cells (IC50 reaching 9-11µM)

The Plasmodium falciparum parasite causes Malaria, one of the world’s most common infectious disease killing over one million people each year, mainly in subtropical climates.

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Onéox : Development of new bioactive compounds Medicinal Chemistry of Polyphenols: their potential use as bioactive compounds > Introduction

A team from the Department of Medicinal Chemistry is expert in the extraction of natural active substances as well as in the development and synthesis of analogues. These new synthesized compounds can prove to be highly advantageous to companies interested in identifying new molecules of therapeutic and cosmetic value. The department has patented a number of inventions related to the use of polyphenol derivatives in pharmacy and cosmetology which in turn have led to the commercialization of active polyphenols in cosmetology. These factors may differentiate the department from other laboratories and can potentially lead to reduced lead times necessary for synthesizing or extracting new molecules.

> Therapeutic Molecules

Two principal services are available from the department, namely the extraction of molecules from natural sources as well as the synthesis of natural products and their analogs.

> Services Natural Molecules: overview of services on offer • Preparation of extracts from natural sources New synthesised organic molecules: overview of services on offer • Synthesis of natural polyphenols derivatives and flavonoids o Short synthesis methods o Scale-up (in terms of quantities produced) • Characterization o Structural analysis o Stability studies o Toxicity profile • Optimization of bioactive derivatives o Pharmaco-modulation o Structure - activity relationships

> Key Benefits

The following are examples of the types of new molecules that are either already available or can be extracted/synthesised through research programmes • New source of antioxydants • Prevention of cardio-vascular illnesses • Anticancer agents targeting the mitotic spindle • Inhibitors for proteins causing multiple resistance to chemotherapy treatment • Inhibitors and activators of CFTR channels • Anti-inflammatoires • Antibacterials • Anti-parasite molecules • Antivirals

> Fields of Use

• Pharmaceutical industries (oncology, parasitology, inflammation, cardiovascular illnesses, elderly) • Cosmetics • Drug Development • Agribusiness (food manufacturing and nutraceutical products)

Consulting activity • Evaluation of project viability • Proposals relating to innovative projects

> Contact

Onéox Onéox

Véronique SENDRA

6 Allée de Bethléem – F-38610 Gières Tél. +33 (0)4 76 00 78 30 – Fax : +33 (0)4 76 00 70 38 veronique.sendra@floralis.fr - www.biotech-pipeline.com

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Jardin Alpin du LautaretTM High Altitude Plant Collection > Introduction Established in 1899, the Jardin Alpin du Lautaret™ is a high altitude plant collection located in the French Alps with a fully-equipped laboratory that is of special interest to companies looking to develop innovative drugs or products. A wide range of plants emanating from a variety of national and international sources are grown and maintained at the centre. The harsh nature of their natural habitat can provide potential answers to many scientific questions and enable the identification of new molecules.

> Key Features/Benefits

•A garden and high altitude laboratory based at 2100m The Jardin du Lautaret is the only high altitude plant collection in existence in France and one of very few that exist on a global scale. The harsh climatic environment in which these plants exist can result in the development of data that is of special interest to cosmetic and pharmaceutical companies. • Over 2300 alpine and other mountain plant species Biodiversity : access to a huge variety of plants around the world •Seeds exchanged with 50 countries Access to rare and new plants, a fact that may prove beneficial for both ecological and commercial reasons • Plants adapted to life in extreme conditions (cold, intense light, wind, etc.) Access to promising molecules that have demonstrated a proven resistance to extreme climatic conditions. Additionally the centre offers an extremely wide variety of medicinal and edible plants • Laboratory equipped with a wide range of modern equipment (centrifuge, spectrophotometer, freeze dryer, etc.) This enables certain projects to be carried out at the research centre that would otherwise be impossible to implement • Artist’s Studio The centre is also equipped with an artist’s studio that can be used by botanists, or used for commercial purposes (illustrators have shown interest in using the site)

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> Plants and Molecules

ex hibiting special properties

The centre carries out a wide range of research projects ranging from those based at molecular & cellular levels, to tissue-based studies and ecology-based projects. The centre is also able to work on the physiological and biochemical mechanisms of plant systems which can lead to the characterisation of molecules of interest exhibiting stress tolerance to all of the following factors: • high light radiation (including UV) • low temperatures • water stress/snow • Poor soil quality

> Contact

Nicole GIRAUD

6 Allée de Bethléem – F-38610 Gières Tel.+33 (0)4 76 00 78 42 – Fax : +33 (0)4 76 00 70 38 nicole.giraud@floralis.fr - www.biotech-pipeline.com


Jardin Alpin du LautaretTM High Altitude Plant Collection

> Ex amples of plants of note

> Research Opportunities

Arnica montana: possesses vulnerary, astringent and sudorific properties. Aconitum napellus: possesses analgesic, hypotensive respiratory and cardiac paralysis properties

Research contracts can be put in place enabling organisations to carry out scientific studies at this high altitude research centre. In addition, certain plants from the centre can be provided for use in studies off-site. The centre also offers a range of consultancy services for organisations wishing to implement New Product Development activities (using new vegetal material)

> Potential Applications

The high altitude plant collection is of special interest to companies working in the following fields: • Pharmaceutical development • Cosmetology • Medical research • Phytotherapy • Nutraceutics

> Contact Nicole GIRAUD

6 Allée de Bethléem – F-38610 Gières Tel.+33 (0)4 76 00 78 42 – Fax : +33 (0)4 76 00 70 38 nicole.giraud@floralis.fr - www.biotech-pipeline.com

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BacVac A bacterial vaccine with the potential to target glioblastoma, cancer and other infectious diseases > Background

Vaccines that target antigen specific cellular immune response could cure cancer and many infectious diseases. Despite many advances in this field, technologies for vectorisation of proteic antigens remains to be optimised for the development of vaccines.

> Introduction

Method of injecting antigens through the SSTT of P. aeruginosa and cellular immune response

Certain gram negative bacteria possess a complex protein secretion apparatus known as the type three secretion system (TTSS) which delivers effector protein into the cytoplasm of dendritic cells in order to modulate host cellular functions.

This bacterial vaccine enables the stimulation of cellular immunity against a specific antigen. The antigen is injected in the cytoplasm of the dendritic cell via the type III secretion system of P. aeruginosa. The injected antigens are driven to the endogenous pathway and the peptides produced are delivered to the CMH1. They are then specifically recognized by T CD8 lymphocytes+ thus enabling the activation of a cellular response against this antigen. The vaccine must be administered by subcutaneous (or intradermic) injection to ensure the proper targeting of dentritic cells.

Using the BAC-VAC technology, we have identified and optimized a potential drug targeted towards glioblastoma, based on an antigen tested on mice. In the test, tumoral cells were injected into two mice populations, one of which had been injected with the potential drug. The survival rate after 50 days shows the real therapeutic potential of this antigen.

> Contact Bruno TILLIER

6 Allée de Bethléem – f-38610 Gières Tél. +33 (0)4 76 00 78 34 – Fax : +33 (0)4 76 00 70 38 bruno.tillier@floralis.fr – www.biotech-pipeline.com

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BacVac

A bacterial vaccine with the potential to target glioblastoma, cancer and other infectious diseases > Key Benefits

As a result of its highly immunogenic character, P aeruginosa will stimulate an immune response without need for adjuvants. The vaccinal strain has been chosen for its reduced virulence. This bacterial vaccine can combine several epitopes of one or more genes of interest and induce a cellular immune response. The vector can be injected subcutaneously ensuring it is recognized directly by the dendritic cells. It is then destroyed thereby avoiding its dissemination in the host and the environment in general.

> IP Status

Protected by Patent n°W02005049644 Polack B., Toussaint B., Quénée L. (2005) Tool for the transfer and production of proteins using Pseudomonas type III se-cretion system.

> Developmental Opportinities

We are currently looking for industrial partners interested in further developing these exciting new technologies.

The production of P aeruginosa is both easy to produce and cost-effective as the quantities required for it to function effectively are minimal.

> Potential Applications

> Contact

• Oncology • Virally infectious diseases • Parasitic diseases • Veterinary medicine

Bruno TILLIER

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 34 – Fax : +33 (0)4 76 00 70 38 bruno.tillier@floralis.fr – www.biotech-pipeline.com

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> Models and Technologies

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â&#x20AC;˘ Molecule Evaluation

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Onéox : Analysis of the effects of bioactive compounds

Determination of the effects of your products on the proox idant and antiox idant balance > Introduction

Our innovative scientific models and methodologies, focusing on oxidative stress, are the result of a combination of our technical expertise and the cutting-edge technology we have at our disposal in our Grenoble laboratories.

> A wide range of models are > Evaluation of available including

•Mitochondria •Cell culture •Animals developing stress induced by age, diet or environment •Clinical studies carried out in association with the Center of Clinical Investigation (Grenoble University Hospital)

• Bioactive compounds • Dietary supplements • Novel food • Nutraceuticals

> Biological parameters studied

• Endogenous and exogenous antioxidant defence o Endogenous : enzymes, glutathione, SH groups, plasma total antioxidant capacity o Exogenous : micronutrient status (vitamins, carotenoids, selenium, Zinc, etc.) • Oxidative damage to o Lipids (TBAR’s) o Proteins (SH groups) o DNA (comet assay on total blood, cell or tissues) • Measure of mitochondria activity

> Contact Véronique SENDRA

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 30 – Fax : +33 (0)4 76 00 70 38 veronique.sendra@floralis.fr - www.biotech-pipeline.com

Onéox Onéox

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Prevention of Cardiovascular illness Evaluation of a cardio protective molecules > Introduction The «Organ to Organism» platform offers research tools and services for the physiological analysis of the human body

> Key benefits

In vivo services

> Congenitive heart failure

• Unique physiopathological models (animals) > Ventricular fibrillation > Congestive heart failure > Resistance to Iscemia > Resistance to Reperfusin > Insulin resistance • Surgical know-how • Molecule and tissue investigations • Imaging

models

> Pharmacological or nutritional protocols (preventative or curative) > Echocardiographical analysis of contractile dysfunction > Invasive evaluation of hemodynamic function (Vein and artery systems, pressure measurements)

Ex-vivo services

> Applications

> Isolated heart model

• Pharmaceutical industry • Food supplements • Functional ingredients • Agribusiness

• Widespread ischemia • Isolated ischemia

Evaluation of molecule activity > Miocardial pain during ischemia/reperfusion pump rate/flow > Miocardial integrity (enzymatic measurements, histology degree of cardiac arrest)

> Contact

> Isolated aortal rings

Marie-Gabrielle JOUAN

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 00 61 – Fax : +33 (0)4 76 00 70 38 marie-gabrielle.jouan@floralis.fr www.biotech-pipeline.com

• Measurement of vascular integrity • Measurement of vascular contractility • Identification of molecule effect

Ad

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Stress et neuro digestive interactions > Introduction

The Institute of Neuroscience of the University Joseph Fourier, Grenoble, expert in the field of brain/digestive system interaction is able to carry out research as part of your new molecule and therapeutic R&D programmes.

> Evaluation of key

parameters such as:

• Para-ceullular intestinal permeability • Inflammation • Pain • Digestive motivity

> Evaluation of active

> Benefits

• Stress, pain and inflammation models • Primary cultures for enteric nervous systems • Vagal neurostimulation • Sympatho-vagal balance studies • Measurement of sympathic activity

> Applications > Pharmaceutical industries > Food supplements > Functional ingredients

molecules and new therapy development

> In vitro: Cellular biology, molecular and biochemical

biology

> In vivo: animal based experimentation models > Clinic al research

> Contact Nicole GIRAUD

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 41 – Fax : +33 (0)4 76 00 70 38 mathieu.tilquin@floralis.fr - www.biotech-pipeline.com

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Potential therapeutic targets in renal cell carcinoma Novel Drug Testing Approaches > Introduction

Protein-kinases are attractive targets for anti-neoplastic therapy in a wide spectrum of tumors. The research team is specialized in studying renal cell carcinoma (RCC) which accounts for 2-3% of all malignant diseases in adults in Europe. A major challenge in designing new kinase inhibitors is to determine which kinases to inhibit to maximize the efficacy and therapeutic index. Thus, defining the essential «kinome» in individual cancers represents a new approach to identifying new clinical biomarkers and to designing efficient multitargeted kinase inhibitors. In this context, the characterization of the kinome events unique to CRC could be of critical significance for future innovative therapies. Based on Grenoble team know-how in the protein kinase field, together with a facilitated access to functional genomic and chemogenomic platforms, researchers should provide you with new avenues to uncover novel therapeutic targets, thus accelerating oncology drug development.

1) Characterization of your new drug with a complete new approach • We can evaluate your drug activity and/ or toxicity on various cancer cell lines and analyze their cellular effects on cell cultures or cocultures. • In follow-up studies/ from these results, kinases that have been modified by this drug can be researched in follow up studies.

Key Benefits The possibility of finding specific kinase signatures in a rapid and reliable manner is a powerful approach. Proof of concept will look at whether the effects of the RNAi observed in vitro would translate in vivo into altered tumour development. This approach will help to distinguish those kinases that are the drivers of tumor progression from those that are passengers in the process.

2) Kinase loss-of-function RNAi screen • We can identify kinase requirements for renal carcinoma cells grown on cell lines using a commercial panel of RNAi directed to all human kinases or lentivirus transduction method

> Contact Nicole GIRAUD

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 42 – Fax : +33 (0)4 76 00 70 38 nicole.giraud@floralis.fr - www.biotech-pipeline.com

33


Potential therapeutic targets in renal cell carcinoma Drug Testing Approaches > Fields of application

3) Definition of the identified hits as potential clinical biomarkers and/or new drug targets

> Drug discovery > Drug development > Oncology > Diagnosis

3.1 Clinical biomarkers To categorize renal tumours at diagnosis into distinct molecular subtypes, we will determine whether the identified survival kinases could represent pathwayspecific biomarkers that are clinically useful in the diagnosis and prognosis of this disease. Key benefits The developmental challenge is that discovery of a biomarker and clinical testing of a drug active on it, are often interdependent and should ideally move forward in parallel. 3.2 Drug targets We will determine whether the targets identified in the RNAi screens may represent bona-fide cancer targets in themselves and will focus on the identification of small molecule inhibitors of kinases characterized as essential for renal cancer cell survival.

> Contact

Key features Expertise of the researcher’s team in the development of new CK2 inhibitors and in the use of multidisciplinary tools

Nicole GIRAUD

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 42 – Fax : +33 (0)4 76 00 70 38 nicole.giraud@floralis.fr - www.biotech-pipeline.com

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In Ovo Screening Molecule Identification A highly innovative technology that determines the efficiency of molecules and rapidly evaluates their innocuity

> Introduction

Services Available

The ability to evaluate potential molecules of interest quickly and efficiently obtained from high throughput screening is an essential element of modern R&D programmes. However up until now, once a potential molecule of interest has been discovered, it is essential to carry out tests on animals - a process which is fraught with legal, technical and ethical issues as well as being time consuming.

► Embryonic toxicological analyses can be carried out at different time points ► Macroscopic analyses to detect potential malformations and mortality induced by treatments ► Biomarker Research, histological and molecular analyses (In situ hybridization, immunohistochemistry, cells culture genotoxicityetc.). ► Comparative analyses, correlation between phenotypic results and molecular pathway networks, databank analyses

This innovative in ovo screening technology enables healthcare professionals to avoid the pitfalls associated with animal testing by using a process that is both fast and efficient. In ovo screening, covering embryonic toxicology, angiogenesis, and tumor growth is a radical new means of speeding up the process of evaluating new molecules of interest; before carrying out pre-clinical testing on animals.

Angiogenic tests (CAM assay): Proposed tests • Deposit of molecules of interest on chorioallantoic membrane - either directly oretc. - after their insertion in a gel/sponge

Furthermore, the efficiency of this process ensures that the screening process is optimised; with all low-value molecules being eliminated from the study at a very early stage.

• Single or repeat applications can be made

> Three different

Services Available

services are available, either independently or in combination

► In vivo CAM Assay ► Daily observations (up to seven consecutive days) to assess the efficacy of the treatment ► Angiogenesis quantification

Toxicological tests available/Embryonic Distribution

> Contact

The process can be applied in two distinct ways: a) by means of injection into the embryo outlining bio distribution and b) by targeting specific organs to gain a clearer understanding of the chosen molecule’s effect

Florence ALESANDRINI

6 Allée de Bethléem – F-38610 Gières Tél. +33 (0)4 76 00 78 35 – Fax : +33 (0)4 76 00 70 38 florence.alesandrini@floralis.fr www.biotech-pipeline.com

• Injection of molecules of interest into: - embryo (100μl) - developing organs (25nl). • Targeted injection into organs: - muscles, heart, liver, blood vessels, skin, kidneys, pigmentary, digestive system, brain, genital organs, bones, etc.

35


In Ovo Screening Molecule Identification Human tumor growth: proposed tests • In ovo transplantation of tumoral cells (on chorioallantoic membrane): - from mass-cultured cells (up to 7 days) - or inserted into a gel • Injection* of molecules of interest into tumors or deposited on the surface. Services Available ► Tests in parallel to assess the sensitivity of the treatment on tumor cell lines ► Macroscopic analyses on growth and/or on the vascularization of tumors ► Histological and molecular analyses (In situ hybridization, cell cultures, immuno-histochemistry, biomarkers, genotoxicityetc.). ► Comparative analyses, correlation between phenotypic results and molecular regulation pathways, databank analyses

> Key Benefits • Highly sensitive model - Low concentrations of molecules/samples in a small volume of injection required (from ml to nl) - Ability to detect multiple biomarkers simultaneously - Possibility to carry out several tests simultaneously • Study relevant to the whole organism - Model enables the implementation of physiological and metabolic/molecular process studies relating to pathways as well as studies of complex molecular pathways - It covers standard model tests for cellular differentiation, tumour growth and angiogenesis • Amniotic vertebrea Model - Similar results to those you would expect to find in human physiology - Also features strong/very strong similarity with mammals for development, metabolism, molecular regulation, pathways

• Ethical model - Complies with demands made by the REACH directive - Exempt from legislation regarding animal testing • Short, highly accurate and reproducible tests - Increases efficiency of process/more experiments can be carried out within the same time frame. • Analysis of high throughput screening - Enables user to test molecules that have just been discovered to give a rapid indication of toxicity/innocuity - Potential to optimise molecules already in development - Reduction of risk in R&D programs = cost effective • Breakdown of molecules suitable for testing : Bio medicines, chemical molecules, nanostructures, siRNA, peptids - Highly versatile model

> Potential Applications ► Drug discovery ► Drug development ► Toxicology ► Oncology ► Cosmetologyetc.

> Commercial Opportunity Floralis is currently looking for industrial partners who may benefit from this exciting new technology as part of their R&D programs.

> Contact

Florence ALESANDRINI

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 35 – Fax : +33 (0)4 76 00 70 38 florence.alesandrini@floralis.fr www.floralis.fr

* Different doses can be injected either singly or in repetion at different stages of development

36


ID Cell: Evaluation of antimicrobial treatments A highly efficient molecule testing service that ex ploits one of the largest bacterial strain libraries in France

> Introduction

ID Cell enables healthcare professionals to evaluate the antimicrobrial activity of specific molecules on a large panel of bacterial strains. One of the key benefits of ID Cell is the vast array of bacterial strains that are available for research purposes. Over 300 bacterial strains are available, including more than 50 reference strains. A large panel of grampositive and gram-negative species are represented, as well as mycobacteria and other intracellular pathogens. The critical mass of this library can therefore help to ensure that the full potential of a molecule’s activity is fully exploited

> Features / Benefits

> One of the largest bacterial strain libraries available in France • Ensures that molecules can be matched to specific bacterial strains increasing the overall accuracy of research results > Services are provided by Grenoble University Hospital (Laboratoire de Bactériologie Département des Agents Infectieux, Pôle de Biologie), and Institut Jean Roget (Laboratoire d’Adaptation et Pathogénie des Microorganismes, CNRS, UMR 5163). • The team is renowned for its work in antibiotic susceptibility testing and molecular evaluation. • Team’s expertise can be incorporated into postresearch analysis > L3 laboratory environment enables the testing of biosafety level 3 pathogens • Wide range of bacterial strains available optimises the research process and increases accuracy of results.

> Applications

• Discovery of new antimicrobial molecules or treatments • Determination of potential resistance mechanisms • Evaluation of frequency for antimicrobial resistance selection • Identification of bacterial contaminations • Analyses with regards to long-term efficiency

> Commercial Opportunities Please contact us to find out more about the wide range of molecular screening services that are available from ID Cell.

> Contact Bruno TILLIER

> Services Available

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 34 – Fax : +33 (0)4 76 00 70 38 bruno.tillier@floralis.fr - www.biotech-pipeline.com

• Test can be performed using a broad panel of bacteria types, including human pathogens • Evaluations carried out using customized in vitro models (axenic media and cell systems) • Identification of resistant bacteria and genetic mechanisms involved in drug resistance ID-cell evaluates the activity of your antimicrobial agents, physical and chemical compounds, their mode of action and the resistance mechanisms of microorganisms to these drugs.

37


ID Cell : evaluation of drug activity A highly efficient molecule testing service that ex ploits one of the largest cancer cell line libraries in France

> Introduction

ID Cell enables healthcare professionals to evaluate the action of specific molecules on a large panel of cancer-cell lines. One of the key benefits of ID Cell is the vast array of cancer cell lines that are available for research purposes. Over 30 cell lines are available. The critical mass of this cell line library can therefore help to ensure that the full potential of a molecule’s activity is fully exploited

> Features / Benefits

• One of the largest cancer cell-line libraries available in France o Ensures that molecules can be matched to specific cancer cell lines increasing the overall accuracy of research results

> Commercial Opportunities Please contact us to find out more about the wide range of molecular screening services that are available from ID Cell.

• Services are provided by Grenoble UH, CytologyHistology, Biology & Cell Pathology Department o The team is renowned for its work in molecular evaluation. The team’s expertise can be incorporated into post-research analysis

> Service Available • MTT colorimetric assay enables the measurement of cellular proliferation and therefore cell viability • Flow-cytometric approach and fluorescent dyes • Cytotoxicity tests for cytotoxic molecules screening • Histological analyses and histomorphometry

> Contact

6 Allée de Bethléem – F-38610 Gières Tél. +33 (0)4 76 00 78 30 – Fax : +33 (0)4 76 00 70 38 veonique.sendra@floralis.fr - www.biotech-pipeline.com

> Applications • • • • •

Véronique SENDRA

Morphological analysis and quantification Determination of the apoptosis induction pathway Quantification of the expression of genes Identification and detection of tumorous tissues Determination of drug action on the cell cycle

As well as evaluating drug action on cancer cell lines, ID Cell can also identify any subsequent cellular effects and analyse different tissue types: leukaemic, colon & lung cancer cell lines etc

38


â&#x20AC;˘ Diagnostics

39


40


ScreenVac In vivo high throughput screening of antigenic target > Introduction

Certain gram negative bacteria possess a complex protein secretion apparatus known as the type three secretion system (TTSS) which delivers effector protein into the cytoplasm of eukaryotic cells in order to modulate host cellular functions.

> Key Benefits

> IP Status

Traditional methods of vaccine development necessitate the production of large quantities of antigens, can be expensive and require the use of adjuvants which can increase levels of immunogenicity.

Protected by Patent n°W02005049644 Polack B., Toussaint B., Quénée L. (2005) Tool for the transfer and production of proteins using Pseudomonas type III se-cretion system.

A highly simple production process combined with the fact that adjuvants are not needed ensures that Screenvac can radically increase the speed at which antigens can be discovered.

> Potential Applications

The inventors intend to use their technology to develop a service platform for in vivo antigen screening. The technology is of specific interest to healthcare professionals working in the following fields

> Contact Bruno TILLIER

> Vaccines > Antigen screening and optimization > Cancer and other infectious diseases > Human and animal healthcare

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 34 – Fax : +33 (0)4 76 00 70 38 bruno.tillier@floralis.fr - www.biotech-pipeline.com

41


Prevention of cardiovascular illness Omega 3, Omega 6, fatty acids > Introduction

Several epidemiological studies have demonstrated the potential of the Omega 3 fatty acid in the prevention of cardiovascular illness, a major cause of mortality in industrialised countries. These studies are evidence of the important of reducing the gap between fatty acids n-6/ fatty acids n-3 in diets. Fatty acids n-3 need to be included in our diets by means of oily fish. The increased consumption of fish and of over fishing is leading to diminishing fish stocks meaning that this can no longer be counted on as an answer to the phenomenon, one where long food chains and an ever-growing population further complicate this problem.

> Know-how

• New procedures aimed at targeting the synthesis of omega-3 through animal cells. Methods offering new and significant perspectives in food science, nutritional science and preventative medicine. • Studies on interactions between fatty acids, flavonoids and cholesterol.

> Benefits

Potential to increase blood and tissue concentrations of Omega 3.

> References

• Michel de Lorgeril and Patricia Salen, Acute Coronary Syndromes, A companion to Branwald’s Heart Disease, Saunders • Michel de Lorgeril and Patricia Salen, Nutrition and Heart Disease, Causation and prevention, CRC Press • Michel de Lorgeril et Patricia Salen, Le pouvoir des Omega 3, éditions Alpen

> Contact

> Applications

Véronique SENDRA

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 30 – Fax : +33 (0)4 76 00 70 38 veronique.sendra@floralis.fr www.biotech-pipeline.com

> Food technology > Human and animal nutritional sciences > Healthcare (preventative medicine for cardiovascular illness) > Environmental sciences

42


A new marker for the detection of insulin resistance Titration of the circulating domain of IRAP > Introduction

Type 2 diabetes touches 8% and insulin resistance 20% of the population of industrialised countries. The prevalance of these two pathologies is constantly increasing, in particular in emerging countries. They represent major risk factors for morbidity and cardiovascular mortalities and in such a sense represent a major problem for public healthcare. The detection of insulin resistance would enable a strategy centred on prevention, for an affliction where the social and economic costs are growing incessantly (by means of an example, the global cost of diabetes healthcare has been estimated at 132 billion dollars in the United States in 2002).

> Services and Product Offerings Our offering centres on a diagnostic method based on the titration of the circulating domain named IRAPe of the IRAP protein (insulinregulated AminoPeptidase). IRAP protein is a transmembrane protein which colocolises with the glucose trnasporter GLUT4. The translocation of GLUT4 to the plasmic membrane allows the capture of glucose and is regulated by insulin. At the moment the GLUT4 is inserted in the plasmic membrane, the extracellular domain of IRAP (IRAPe) is cleaved and secreted in the blood. Where insulin resistance occurs, the translocation of GLUT4 and IRAP is reduced, and as a result, so is the secretion of IRAPe in the blood. The plasmatic concentration of IRAPe is therefore inversely proportional to the degree of insulin resistance.

A

Sensitivity to normal insulin

IRAP is translocated towards the membrane. IRAPe is secreted in the blood.

B

Insulin resistance:

Insulin receptor

IRAP is no longer translocated towards the membrane. IRAPe is no longer secreted

insulin

> Contact

Véronique SENDRA

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 30 – Fax : +33 (0)4 76 00 70 38 veronique.sendra@floralis.fr www.biotech-pipeline.com

ELISA, IRMA and ICMA testing kits are currently in development. We have already developed: > 5 monoclonal antibodies targeting different IRAPe epitopes > Recombinant human IRAPe > Specific ligands that have been radioactively marked > An ELISA prototype

Titration of IRAPe Dosage d’IRAPe: ELISA ELISAsandwich Sandwich 2. IRAPe 5. Read OD

+ 1.  Capture: anti-IRAPe mAb1

43

figure 2

+

TMB

4.Révélation : + TMB 3.Détection HRP-anti-IRAPe mAb2

Calibration : IRAPe humaine recombinante


A new marker for the detection of insulin resistance Titration of the circulating domain of IRAP > Benefits

Our method is the first simple, specific and quantitative detection system for a direct marker of insulin resistance (IRAPe) in the blood.

[4] Keller, S.R. et al. (2002) Mice deficient in the insulinregulated membrane aminopeptidase show substancial decreases in glucose transporter GLUT4 levels but maintain normal glucose homeostasis. J Biol Chem 277: 17677-17686.

The detection of IRAPe as well as the monoclonal antibodies and ligands are patented.

> Applications

• Detection of insulin resistance and type 2 diabetes • Longterm analysis of insulin resistance and diabetes

> References

[1] Maianu, L. et al. (2001) Adipocytes exhibit abnormal subcellular distribution and translocation of vesicles containing glucose transporter 4 and insulin-regulated aminopeptidase in type 2 diabetes mellitus: implications regarding defects in vesicle trafficking. J Clin Endocrinol Metab 86:5450-5456.

> Contact Véronique SENDRA

[2] Keller, S.R. (2004) Role of the insulin-regulated aminopeptidase IRAP in insulin action and diabetes. Biol Pharm Bull 27:761-764.

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 30 – Fax : +33 (0)4 76 00 70 38 veronique.sendra@floralis.fr www.biotech-pipeline.com

[3] Keller, S.R. (2003) The insulin-regulated aminopeptidase: a companion and regulator of GLUT4. Front Biosci 8:s410-420.

Titrationd’IRAPe: of IRAPe Dosage ELISA ELISA sandwich Sandwich 2. IRAPe 5. Read OD

+ 1.  Capture: anti-IRAPe mAb1

44

+

TMB

4.Révélation : + TMB 3.Détection HRP-anti-IRAPe mAb2

Calibration : IRAPe humaine recombinante


Flogentec

Safe, fast & user-friendly high speed wholemount labelling device > Introduction

Developments in gene sequencing over the past ten years have helped us to map the human genome, resulting in data that will play a vital role in providing healthcare solutions for years to come. The wholemount labelling process can contribute massively towards a clear understanding of how individual genes express themselves at particular times and in particular locations. Flogentec is an automated device that can determine with a high degree of accuracy, the expression of genes or proteins in biological samples.

> Flogentec : Automatic and

> Product Benefits

Flogentec’s revolutionary new device uses a patented process to subject multiple samples to a continuous, computer controlled flow of reactants. Bespoke hardware ensures that solvents wash through 3D embryo samples at optimum temperatures, maximizing the transfer of solvents to the specimens’ core and reducing analytic lead time. Similarly, because the device needs less highly concentrated levels of RNA probe and antibodies, research results can also be improved significantly.

The final result is a highly efficient, automatic system which can radically improve both the speed and the quality of Wholemount mapping research projects.

fast

> At a Glance

Whereas mRNAs are specifically targeted using the in situ hybridization «wholemount» principle, proteins are detected with specific antibodies and secondary antibodies.

> Commercial Opportunities To find out more about this innovative device, please contact us for more information.

• Reduces analytic lead time by up to 400% • Higher rates of solvent dillution can increase quality of results • User-friendly • Highly compact • User settings/Experiment results can be imported/ exported via USB port • Suitable for industrial and academic research and all healthcare markets

45

> Contact

Nicole GIRAUD

6 Allée de Bethléem – F- 38610 Gières Tel. +33 (0)4 76 00 78 42 – Fax : +33 (0)4 76 00 70 38 nicole.giraud@floralis.fr - www.biotech-pipeline.com


Flogentec

Safe, fast & user-friendly high speed wholemount labelling device > How it works etc. Constant flow of reactant

3D biological samples are submitted to a permanent flow of solvent which ensures that the solution is transferred to their core. A constant supply of reactant is pumped through the chamber ensuring that no stagnation occurs and that the integrity of the samples is preserved

Recycling Process

Constant recycling of the solvent results in ARN and antibody probes that are ten times weaker than normal ensuring that background signaling is minimized and helping to reduce significantly the time that is needed to wash samples. The solvent is collected at the end of the session and can be re-used for future experiments.

Total autonomy

The user settings for each experiment are imported into the Flogentec device via a USB port. The machine is then able to function in its own right without the need to be connected to a PC. Once the experiment has finished a summary of the session can be exported back to the PC via the USB port for further analysis.

Compact size

The Flogentec device works entirely on low voltage (24 Volts). A back up power supply (batteries) ensures that the system can continue to function following a power cut. Its compact size makes it easy to use.

Quartz flow Cells

The incubation chamber or «flow cell» is made out of quartz which helps ensure highly precise levels of thermoregulation. The chamber can hold between 10 to 20 samples. However, dependent on their size, between 40 and 300 samples can be analyzed in one experiment in 24 hours.

Ability to multi-task

Four individual experiments can be carried out simultaneously with different probes and temperatures. It is possible to test in one session, a probe with four different hybridization temperatures.

46

> Contact Nicole GIRAUD

6 Allée de Bethléem – F- 38610 Gières Tel. +33 (0)4 76 00 78 42 – Fax : +33 (0)4 76 00 70 38 nicole.giraud@floralis.fr - www.biotech-pipeline.com


Epstein Barr Virus R Transactivator (RTA) Technology A novel antibody enabling the detection and qualification of the RTA protein, a key factor in the detection of early Epstein Barr Virus.

> Introduction

The R Transactivator (RTA) is one of the two main transactivators originating from the Epstein Barr Virus (EBV). It acts in synergy with the Zebra protein in the switch-latency productive cycle. The transactivator demonstrates significant potential as a marker for the early detection of EBV infection. This technology is available to license to organisations working in the field of monoclonal antibody distribution.

> Benefits

> Scientific Data

• Monoclonal Antibody > Highly targeted • Validated for use in immunofluorescence/western blotting/flow cytometry > Facilitates use in a research environment • UVHCI (Unit of Virus Host Cell Interactions), laboratory renowned at a European level > Specialists in the understanding of EBV biology

Name

Anti EBV R transactivator (Rta)

Clone

5A9 (IgG) // 8c12 (IgG) //4C1 (IgG)

Host species

Mouse

Ig subclass

Mouse monoclonal IgG

Culture medium

RPMI 1640 with FCS GIBCO (Invitrogene) 10%

> Applications

• Detection of early Epstein Barr Virus infection • The technology has significant potential within a research environment

> Commercial Opportunity

> Contact

This technology is available to license to organisations working in the field of monoclonal antibody distribution.

Bruno TILLIER

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 34 – Fax : +33 (0)4 76 00 70 38 bruno.tillier@floralis.fr – www.biotech-pipeline.com

> Reference Imbert-Marcille et al. Clin. Diagn. Lab Immunol. 7 : 206211.2000 Feederle R. et al. EMBO J. 19 : 3080-3089.2000

47


Anti 5 - Methylcytidine Antibody A research tool enabling researchers to determine levels of DNA methylation - an important factor in the characterisation of cell states

> Introduction

Antibody from this clone recognizes the modified base 5-methylcytidine (5-MeCyt) found in the DNA of plants and vertebrates. DNA methylation is a DNA modification process which is involved in the control of gene expression. The clone has been developed to discriminate between the modified base of 5-MeCyt and its normal counterpart. As a result, this technology can help researchers to determine DNA methylation levels, an important factor in the characterization of cell states.

> Features/Benefits • Monoclonal Antibody > Highly targeted

• Validated for use in immunoblotting/ immunohistochemistry/cytochemistry/ELISA/ Flow cytometry/cytogenetics > Suitable for use within a research environment • UVHCI (Unit of Virus Host Cell Interactions), laboratory renowned at a European level > Specialists in the understanding of EBV biology, the team is able to provide a high level of technical support.

> Refences

More than 40 publications referring to this Antibody are available including: - M.Weber et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nature Genetics. 37, 853-862, 2005 - Mayer W. Niveleau A. Walter J. Fundele R. Haaf T. Demethylation of the zygotic paternal genome. Nature. 2000 3:403 (6769): 501-2.

> Applications

This research/diagnostic tool shows significant potential in the following fields: • Cytogenetics • Cancer Research

> Scientific Data Name

5-Methylcytidine

Specificity

Specific marker of DNA methylation status (5 methylcytidine)

Clone

3A3

Host species

Mouse

Ig subclass

Mouse monoclonal IgG1

Culture medium

RPMI 1640 with FCS GIBCO (Invitrogene) 10%

> Contact Bruno TILLIER

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 34 – Fax : +33 (0)4 76 00 70 38 bruno.tillier@floralis.fr – www.biotech-pipeline.com

> Commercial Opportunity

This technology is available to license to organisations working in the field of monoclonal antibody distribution.

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A new marker for the chemo resistance Titration of IRAP protein > Introduction Many different forms of cancer affect over 25 million people in the world and are the cause of death for around 7 million each year. Breast cancer is the most frequent representing 13.5% of all cancers. An identification of the extent to which cancers are chemoresistant (including breast, ovary, and endometrial cancers) using diagnostic tools, would enable a better identification of high risk patients and help develop treatments that are better suited to these specific illnesses. The malignancy and chemo resistance of cancerous cells are directly correlated to the expression of the glucose transporter GLUT4 which proves to be extremely useful as a diagnostic marker for certain cancers.

> Services and Product Offerings

A

Sensitivity Our offering centres on a diagnostic method to normal insulin based on the titration of the IRAP protein (insulin-

regulated AminoPeptidase), a transmembrane protein which co-localises with the glucose trnasporter GLUT4. It has been proved that the expression of IRAP is directly correlated to that of GLUT4 and that it increases according to the level of cancer (endometrial and breast cancers). At the moment it is inserted in the plasmic membrane the extracellular domain of IRAP (IRAPe) is cleaved and secreted in the blood. The plasmatic concentration of IRAPe is therefore proportional to its degree of expression and translocation to the membrane and should therefore be increased in proliferating tumours.

IRAP is translocated towards the membrane. IRAPe is secreted in the blood.

B

Insulin resistance:

Insulin receptor

IRAP is no longer translocated towards the membrane. IRAPe is no longer secreted

insulin

> Contact

ELISA, IRMA and ICMA testing kits are currently in development.

Véronique SENDRA

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 30 – Fax : +33 (0)4 76 00 70 38 veronique.sendra@floralis.fr www.biotech-pipeline.com

We have already developed: > 5 monoclonal antibodies targeting different IRAPe epitopes > Recombinant human IRAPe > lSpecific ligands that have been radioactively marked > An ELISA prototype

Dosage d’IRAPe: ELISA Sandwich 2. IRAPe 5. Read OD

+ 1.  Capture: anti-IRAPe mAb1

49

figure 2

+

TMB

4.Révélation : + TMB 3.Détection HRP-anti-IRAPe mAb2

Calibration : IRAPe humaine recombinante


A new marker for the detection of insulin resistance Titration of the circulating domain of IRAP > Benefits

Our method is the first simple, specific and quantitative detection system for a direct marker of insulin resistance (IRAPe) in the blood. The detection of IRAPe as well as the monoclonal antibodies and ligands are patented.

> Applications

[4] Shibata, K. et al. (2007) P-LAP/IRAP-induced cell proliferation and glucose uptake in endometrial carcinoma cells via insulin receptor signaling. BMC Cancer 7: 15 [5] Pilar Carrera, M. et al. (2006) Insulin-regulated aminopeptidase/placenta leucil Aminopeptidase (IRAP/ P-IAP) and angiotensin IV-forming activities are modified in serum of rats with breast cancer induced by N(methylnitrosourea. Anticancer Res 26: 1011-1014.

• Detection and medical prognosis of cancers • Longterm analysis of insulin resistance and cancers

> References

[1] Ito, T. et al. (1998) Expression of facilitative glucose transporter isoforms in lung carcinomas: its relation to histologic type, differentiation grade, and tumor stage. Mod Pathol 11:437-443. [2] Medina, R.A. et al. (2003) Estrogen and progesterone up-regulate glucose transporter expression in ZR-75-1 human breast cancer cells. Endocrinology 144: 45274535

> Contact Véronique SENDRA

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 30 – Fax : +33 (0)4 76 00 70 38 veronique.sendra@floralis.fr www.biotech-pipeline.com

[3] Keller, S.R. (2004) Role of the insulin-regulated aminopeptidase IRAP in insulin action and diabetes. Biol Pharm Bull 27:761-764

Titrationd’IRAPe: of IRAPe Dosage ELISA ELISA sandwich Sandwich 2. IRAPe 5. Read OD

+ 1.  Capture: anti-IRAPe mAb1

50

+

TMB

4.Révélation : + TMB 3.Détection HRP-anti-IRAPe mAb2

Calibration : IRAPe humaine recombinante


Ecrins Therapeutics Effective services and products dedicated to various research programs targeting the microtubule cytoskeleton

> Introduction

The microtubule cytoskeleton plays several major roles in cells. It is particularly important during mitosis, when the microtubule-based bipolar spindle assures chromosome partitioning between daughter cells. Failure to properly segregate chromosomes in mitosis is frequently associated with cancerogenesis and tumour progression. Due to its importance during mitosis, the microtubule cytoskeleton is a natural target for many of the currently available antiproliferative drugs. Most of the currently known anti-mitotic drugs act by inhibiting tubulin assembly or depolymerisation, arresting mitosis and eventually killing fast dividing (cancer) cells.

> Services offerings

--> Key Benefits

• Quick and reliable tubulin polymerization assays, carried out with the hit and/or lead molecule, can potentially save a a significant amount of time and money in a drug development programme.

> A/ Products available

• Highly purified brain tubulin (purity >99%), • Fluorophore-labelled bovine brain tubulin (Rhodamine, FITC, Cy3 and Alexa™ fluorophores) • Other fluorophores may be coupled to tubulin on request.

• Identification and elimination of tubulin interfering compounds at the earliest stage of a drug development program. • Tubulin screening should not be overlooked, taking into account that in some commercial small molecule libraries the percentage of chemicals that interfere with tubulin and/or microtubules could be as high as 5%.

> B/ Drug screening services

In vitro tubulin polymerization assays Two major reasons to test your compound in a tubulin polymerization assay: a) You have identified an antiproliferative molecule and wish to make sure it affects tubulin b) You have a hit/lead molecule-candidate drug and wish to ensure that your compound does not intefer with tubulin. 0,7

Microtubule-stabilizing drug (Taxol) 0,6

Control curve (DMSO)

0,5

0,4

0,3

Microtubuledestabilizing drug (colchicine)

0,2

0,1

0

100

Onset OD = 10 Well B7 Onset Time Limits-

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

Time (secs) D8

D9 Limits-

Limits-

Turbidimetric assay of tubulin polymerization in the presence of drugs

figure 1

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Indirect immunofluorescence on fixed HeLa cells. Microtubules are in green, nuclei in red. Control (DMSO-treated) cells are on figure 1, drug-treated cells with depolymerized microtubules are on the figure 2.


Ecrins Therapeutics Effective services and products dedicated to various research programs targeting the microtubule cytoskeleton Live cell-based assay for small molecules interfering with microtubule cytoskeleton This assay allows to estimate: a) effects of test compounds on cell proliferation b) mitotic index c) organization of the microtubule cytoskeleton in different stages of the cell cycle

--> Key Benefits

• Cell-based assays allow an evaluation of the microtubule cytoskeleton in drug-treated cells. This test is complementary to the turbidimetry assay, as some drugs may depolymerize microtubules indirectly (without binding to tubulin).

Custom production of monoclonal antibodies (mABs) for microscopy Services available: a) development of microscopy-friendly mABs against your favourite protein (YFP) (tests of supernatants from antigen-specific hybridomas on fixed cells). b) isolation of hybridomas with predicted intracellular reactivity c) uncovering unique populations of the same protein (conformational epitopes).

--> Key Benefits

• At the same time, polyclonal antibodies are often inconvenient for several reasons: > They are more likely then mABs to recognize different proteins with the same epitopes, > They stain all populations of the same protein, making it difficult to evaluate the relative contribution of such populations in diverse cellular functions. • In microscopy, mABs have some additional advantages aver polyclonal reagents: > mABs are usually more specific; > mABs give less background; > mABs produce more reproducible results.

> Applications

• Cell biology • Developmental Biology • Immunochemistry and immunocytochemistry

> Commercial Opportunities

Floralis is currently looking for industrial partners who may benefit from this exciting new technology as part of their R&D programs.

• Screening of hybridoma supernatants by indirect immufluorescence avoids frequent problems:

> Antibodies developed using reactivity in ELISA and immunoblotting often fail to recognize their target(s) in fixed cells or give a staining incompatible with localization(s) observed in live cells (for example expressing a fluorescent fusion of a protein).

> Contact

Florence ALESANDRINI

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 35 – Fax : +33 (0)4 76 00 70 38 florence.alesandrini@floralis.fr www.biotech-pipeline.com

figure 2

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Indirect immunofluorescence on fixed HeLa cells. Microtubules are in green, nuclei in red. Control (DMSO-treated) cells are on figure 1, drug-treated cells with depolymerized m i c rot u b u l e s are on the figure 2.


Anti-Translation Eukaryotic Factor (eIF3b) Antibody A valuable research tool that demonstrates significant potential with regards to the characterization of proliferating cells that over ex press eIF3

> Introduction

Antibody from this clone recognizes the RNA recognizing motif (RRM) of subunit b of the eukaryotic Initiation Factor 3 (eIF3) molecule. eIF3 binds specifically to mRNA and some viral RNA genomes and plays an essential role in the translation initiation process. This antibody shows significant potential with regards to the characterization of proliferating cells that over express eIF3.

> Features/Benefits • Monoclonal Antibody > Highly targeted

> Scientific Data Name

eIF3b MRR

Specificity

Cell proliferation marker (for over expression of eIF3. Recognizing the RNA recognizing motif (RRM) of eIF3.

Clone

2D3D9

• UVHCI (Unit of Virus Host Cell Interactions), laboratory renowned at a European level S > Specialists in the understanding of EBV biology, the team is able to provide a high level of technical support.

Host species

Mouse

Ig subclass

Mouse monoclonal IgGs

Applications

> Applications

The antibody is effective in immunoblotting, cytochemistry, immunohistochemistry

Culture medium

RPMI 1640 with FCS GIBCO (Invitrogene) 10%

• Validated for use in immunoblotting/ immunohistochemistry/cytochemistry > Suitable for use within a research environment

This research/diagnostic tool shows significant potential in the following fields:

> Contact

• Fundamental Virology • Cancer Research

Bruno TILLIER

> Commercial Opportunity

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 34 – Fax : +33 (0)4 76 00 70 38 bruno.tillier@floralis.fr – www.biotech-pipeline.com

This technology is available to license to organisations working in the field of monoclonal antibody distribution.

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EBV ZEBRA Transactivator A Monoclonal antibody that demonstrates significant potential as a research and/ or diagnostic tool (virology, cancer research, immune-biology)

> Introduction

The ZEBRA transactivator is an Epstein-Barr Virus (EBV) protein transactivator controlling the switch of the viral cycle from a latent to productive phase. The Zebra transactivator acts by binding to the promoters of genes involved in lytic DNA replication and activating their transcription. This protein transactivator demonstrates significant potential within a research environment (virology, cancer research, immune-biology) as well as in diagnostics.

> Benefits

> Commercial Opportunity

• Validated for use in immunofluorescence/western blotting/Flow cytometry > Especially useful within a research environment

> Scientific Data

• Monoclonal Antibody > Highly targeted

• UVHCI (Unit of Virus Host Cell Interactions), laboratory renowned at a European level > Specialists in the understanding of EBV biology, the team is able to provide a high level of technical support.

> Applications

This research/diagnostic tool shows significant potential in all of the following fields: • Virology • Cancer Research • Immune biology

> References

Le Roux et al. J. Gen. Virol. 77 : 501-509, 1996 Segouffin et al. J. Gen. Virol. 77 : 1529-1536, 1997 Drouet E. et al. J. Med. Virol. 57 : 383-389, 1999 Imbert-Marcille et al. Clin. Diagn. Lab. Immunol. 7 : 206211. 2000

This technology is available to license to organisations working in the field of monoclonal antibody distribution.

Name

EBV - Zebra Transactivator

Description

Two hybridomas have been developed to target this protein: one against the p130 epitope, a ZEBRA DNA-binding domain, and a second targeting the p125 epitope.

Specificity

Specific marker for the early detection of EBV infection

Clone

AZ125 (IgG) // AZ130 (IgG)

Host species

Mouse monoclonal IgGs

Ig subclass

The antibody is effective in immunoblotting, cytochemistry, immunohistochemistry

Culture medium

RPMI 1640 with FCS GIBCO (Invitrogene) 10%

> Contact

Bruno TILLIER

6 Allée de Bethléem – F-38610 Gières Tél. +33 (0)4 76 00 78 34 – Fax : +33 (0)4 76 00 70 38 bruno.tillier@floralis.fr – www.biotech-pipeline.com

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Anti-Translation Eukaryotic Factor (eIF3g) Antibody A valuable research tool that demonstrates significant potential with regards to the characterization of proliferating cells that over ex press eIF3.

> Introduction

Antibody from this clone recognizes the RNA recognizing motif (RRM) of subunit g of the eukaryotic Initiation Factor 3 (eIF3) molecule. eIF3 binds specifically to mRNA and some viral RNA genomes, and plays an essential role in the translation initiation process. This antibody shows significant potential with regards to the characterization of proliferating cells that over express eIF3.

> Benefits

> Scientific Data

• Monoclonal Antibody > Highly specific with regards to its target

Name

eIF3g MRR

Specificity

Marker of cell proliferation (with over expression of eIF3. Recognising the RNA recognizing motif (RRM) of eIF3.

Clone

Four clones secreting IgG antibodies

• UVHCI (Unit of Virus Host Cell Interactions), laboratory renowned at a European level > Specialists in the understanding of EBV biology, the team is able to provide a high level of technical support.

Host species

Mouse

Ig subclass

Mouse monoclonal IgGs

Applications

> Applications

The antibody is effective in immunoblotting, cytochemistry, immunohistochemistry

Culture medium

RPMI 1640 with FCS GIBCO (Invitrogene) 10%

• Validated for use in immunoblotting/ immunohistochemistry/cytochemistry > Suitable for use within a research environment

This research/diagnostic tool shows significant potential in the following fields:

> Contact

• Fundamental Virology • Cancer Research

Bruno TILLIER

> Commercial Opportunity

6 Allée de Bethléem – F-38610 Gières TEl. +33 (0)4 76 00 78 34 – Fax : +33 (0)4 76 00 70 38 bruno.tillier@floralis.fr – www.biotech-pipeline.com

This technology is available to license to organisations working in the field of monoclonal antibody distribution.

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An implantable, in vivo, miniature dosimeter

Safety in radiotherapy : a highly innovative technology that enables the measurement of radiation in situ and in real time

> Introduction

160,000 radiotherapy procedures are carried out every year in France. Around a third of these are highly-complex treatments {multiple arcs, intensity modulated radiotherapy, etc} resulting in a high margin of error with regards to dosages. A highly-innovative in-vivo implantable dosimeter for external radiotherapy and radiodiagnostics has been developed to counter this problem which is currently being tested.

> Technology Overview

The control and measurement of radiation delivered throughout a course of radiotherapy is an essential part of ensuring both the patient’s safety as well as the overall effectiveness of the treatment. This innovative dosimeter answers the requirements put in place by the French ministry of health in March 2007 regarding the systematic use of dosimeters, in vivo. An implantable device (with a diameter less than 800 μm), it allows the measurement of radiation, in-situ and in real time. The device consists of an invasive fibre optic probe incorporating a radio luminescent semi-conductor material and a luminescence detection module connected to the control booth by means of a fibre-optic connecting cable.

> Key Benefits This innovative system centres on the radio luminescent qualities of a semi-conductor material. The very small nature and associated low cost of the probe allows its use in situ and can enable the production of a disposable device. Similarly, the high radio-luminescent output of the material ensures highly accurate measurement of radioactive dosages in real-time.

> Additional Documentation Press release issued by the Ministry of Health (www. sante.gouv.fr/htm/actu/31_070306.pdf). Circular DHOS/E4 n°2007-230 dated 11/06/07 with regards to the practice of radiotherapy in oncology

> Intellectual Property French Patent pending n° 0752962 and European extension in progress

> Stage of Development Several prototypes have been developed and are currently being evaluated at Grenoble University Hospital (Team led by J Balosso)

> Contact Bruno TILLIER

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 34 – Fax : +33 (0)4 76 00 70 38 bruno.tillier@floralis.fr - www.biotech-pipeline.com

• Disposable low-cost probe • Highly compact probe can be used in situ • Enables highly accurate measurement of radioactive dosages in real time

> Applications • Radiotherapy • Radiodiagnostics

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â&#x20AC;˘ Testing Systems

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Uniplastomic

Innovative solutions for the analysis of plastid gene ex pression > Introduction

Leveraging the expertise of the Plastid Laboratory of the University Joseph Fourier (UJF), Grenoble, Uniplastomic develops strong and innovative tools for the relevant analysis of plastid gene expression allowing an understanding of the response of plants to environmental factors. Uniplastomic focuses on the chloroplast, the main organelle responsible for most of the physiological mechanisms involved in plant functioning such as photosynthesis, lipid synthesis, hormone and amino acids production.

> Uniplastomic : highlighting

> The Uniplastomic offering

the link between plastid gene ex pression and plant function

Amongst its main activities, Uniplastomic offers: • A wide range of specific antibodies targeted at plastid proteins of interest in genetic research (ribosomal proteins, RNA polymerase subunits, cytochrome subunits etc)

Environmental factors trigger a chain of physiological reactions resulting in the activation of specific genes giving the plant the ability to counter the negative effects of stress and adapt to its environment. Uniplastomic’s genetic approach centres on the understanding of the expression of plastid genes that play a key role in plant physiology.

• Innovative macroarrays kits dedicated to the plastid genome of a large number of plants such as tomato, tobacco, spinach, Arabidopsis etc. Such macroarrays have a high specificity and reliability rate and allow the study of sense and anti sense RNA.

> Applications

• Expertise and services for the analysis of plastid genes and all questions related to the area of gene expression in plants

The expertise and tools of Uniplastomic match requirements for all research areas where living plants are used, such as agronomy, agrochemistry, plant genetics and ecology (controlling the gene expression profiles of genetically modified mutants in plant enhancement activities, highlighting the effects of herbicides on seedling development, monitoring the effects of drought, temperature or other environmental factors during plant development etc)

> Contact

Mathieu TILQUIN

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 41 – Fax : +33 (0)4 76 00 70 38 mathieu.tilquin@floralis.fr - www.biotech-pipeline.com

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NOVITOM - Innovative applied micro-tomography 3D imaging of the inner micro-structure of biomaterials with unprecedented quality for industrial R&D and control

> Introduction X-ray computed micro-tomography is a high resolution, non-invasive and non-destructive 3D imaging technique. It benefits from the penetrating power of X-rays to reveal the inner structure of any type of material at a micrometer scale. It does not require any sample preparation and can be carried out under natural or controled environment.

> Services available

> Applications

NOVITOM uses the exceptional properties of X-ray beams delivered at synchrotron radiation centers to provide its clients with the highest quality microtomographic analyses of biomaterials and composite materials. The technical characteristics include: • sub-micron spatial resolution imaging, • real-time follow up of structural modifications under various treatments, • imaging in controled environment: temperature, humidity, mechanical stress • unparalleled contrast, even with poorly absorbing materials.

The domain of applications comprise various types of materials like polymers, colloids, raw vegetal and animal tissues as well as transformed products, implants etc.

NOVITOM’s service offer encompasses rapid qualitative characterization, quantitative image analysis and development of à la carte equipments.

The industrial sectors that are concerned are :

The generated digital 3D images of a product allows for: • visualizing the distribution and micro-architecture of its components, • separating and quantifying the distribution of its phases, • following process-induced changes, • assessing the effects of stress, fatigue, ageing, • modelling the relationship microstructure-properties

> Biotechnologies > Pharmaceuticals > Cosmetics > Health > Agriculture

> Key Benefits X-ray microtomography provides insight to hidden structures in products and materials. It generates high-resolution 3D-images while preserving sample integrity. NOVITOM provides its clients with the best quality “all-inclusive” microtomographic analyses.

> Contact

> Food > Pulp > Plastics > Environment

Nicole GIRAUD

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 42 – Fax : +33 (0)4 76 00 70 38 nicole.giraud@floralis.fr - www.biotech-pipeline.com

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Spygen

Identification of vegetal species in complex substrates > Introduction

Identification is based upon the use of universal primers (patented in 2004) which present at the same time, variations of size and sequence according to the vegetal species.

> Ex perimental protocol Universal primers

Damaged DNA DNA amplification --> Extraction --> Standardised protocol

> Services • Sample analysis (mixed or pure) • Bioinformatic analysis • Research projects • Consultancy

Analysis of DNA polymorphism --> High-throughput sequencing/bioinformatics --> Cloning and sequencing/hybridisation/electrophoresis

> Ex ample: analysis of nut oil

The presence of potato and wheat indicates a stage implicating the use of starch during the manufacturing process of this nut oil.

> Key benefits

Intensité de fluorescence

Taille du fragment

• Comprehensive: The same experimental protocol can be used to identify most plant species. • Powerful: The method is highly effective even with transformed or highly damaged substrates. It can be used to identify every kind of matter containing vegetal substances. • Highly Accurate: It is possible to analyse substrates containing a mix of several plant compounds and to estimate the relative proportion of each compound. • Easy to analyse: After amplification, classical methods of DNA polymorphism analysis can be carried out.

> Contact

Nicole GIRAUD

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 42 – Fax : +33 (0)4 76 00 70 38 nicole.giraud@floralis.fr - www.biotech-pipeline.com

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Spygen Identification of vegetal species in complex substrates > Applications

• Tests of the composition of raw materials : authenticity, traceability • Contaminant research • Tests for the presence of trace elements in production • Test of the composition of transformed products during manufacturing processes • Diet studies

> Field of applications

> > > > >

Agribusiness Cosmetics Healthcare Public health Ecology

> Contact Nicole GIRAUD

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 42 – Fax : +33 (0)4 76 00 70 38 nicole.giraud@floralis.fr - www.biotech-pipeline.com

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Ecological Biodiversity Impact of Global Change on Microbial, Vegetal and Functional Diversity in Alpine Ecosystems > Introduction

As part of the French National Research Agency’s (Agence Nationale de la Recherche) « BIODIVERSA » call for projects, we have put together a consortium of European laboratories to study the relationship between microbial, vegetal and functional variations on a landscape scale. One of the objectives of this study is the development of a simple and standardised method for analysing ecosystem biodiversity based on on-site sampling followed by high throughput laboratory analysis.

> Target Audience

> The Project’s core objectives

• Research agencies or other organisations specialising in biodiversity analysis • Researchers specialising in field ecology

> Key Benefits

This truly global approach to the analysis of ecosystems enables researchers or scientists to simplify and standardize current methods of understanding biodiversity. The fact that this approach involves three levels of analysis (vegetal, microbial and functional) can enable a clear understanding of ecosystem functioning by providing strong biodiversity indices.

> The Consortium

• Identification of the best estimators of microbial, vegetal and functional diversity in order to build robust diversity indices • Develop an understanding of the impact of global change by analyzing the evolution of these indicies across an altitudinal gradient. • Develop an evaluation method for biodiversity based on on-site sampling and the use of molecular and statistical tools. The unique nature of the project lies in a three-pronged approach (vegetal, microbial, functional) coupled with the use of high throughput analytical tools.

> Developmental Opportunities

• The Ecological Alpine Laboratory (University Joseph Fourier) • The Institute of Biology, University of Tromsø Norway • The University of St Andrews, Department of Biology (UK) • Life and Environmental Sciences Division, Austrian Research Center (Austria).

We are currently looking for an industrial partner working in the fields of ecology or conservational biology, or other potential users of this technology, to enable us to drive the project towards the development of a powerful diagnostic biodiversity system.

> Contact

> Our Skill-set > Field ecology > Molecular ecology > Microbiology > Statistics > Bioinformatics > Modeling

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Mathieu TILQUIN

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 41 – Fax : +33 (0)4 76 00 70 38 mathieu.tilquin@floralis.fr - www.biotech-pipeline.com


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Galentech

New Method for optimizing formulations and processes > Introduction

An innovative process (the sample thermal activity trace - TAT) that provides valuable information and radically increases preformulation, formulation and manufacturing cost efficiencies in biotechnology, pharmaceutical, food and cosmetics industries.

> Description

The department of Formulation and Pharmaceutical Engineering led by Professor Aziz Bakri has thirty years experience in the field of galenic chemistry. It has developed a methodology together with a highly sensitive analytic device that can adapt specifically to the study that is being carried out. The sample thermal activity trace (TAT) is detected and recorded under precise controlled vapour pressure. This approach allows the implementation of physical, (bio)-chemical or biological studies concerning stability, compatibility, ingredient interactions, studies, and population growth experiments. It provides precise results within a short timeframe. Professor Bakri’s team can offer its expertise in all of the following areas: • Trouble-shooting and resolution of issues relating to product development, manufacture and storage • API-Cyclodextrines inclusions, API-proteins/Polymer binding, Antigen-antibody interaction studies etc. • Effect of xenobiotics upon Inhibition/stimulation of cell/growth evaluation. • (Bio) reactor optimization • Consultancy relating to the choice of formulation and implementation processes • Training sessions relevant to the field of formulation and thermal methods

product-cyclodextrines inclusions in order to fully optimize the formulation and manufacturing process. The method is highly applicable to • Pharmaceutical • Food • Cosmetic industries (product aging) • Fine Chemistry • Characterization of new materials, vapor diffusion, polymer hydration/swelling/reticulation • Biotechnology for evaluating interactions in complex media (liposome, vaccine formulations,etc.) • Water activity, water content assessment in complex media, • Amorphous crystallization and quantification, polymorphism The system provides solutions to production problems when issues arise regarding: > process control, > scale up (granulation, micronization, freeze/spaydryingetc.) > handling/storage conditions (temperature/vapor pressure).

> Contact

> Applications

Nicole GIRAUD

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 42 – Fax : +33 (0)4 76 00 70 38 nicole.giraud@floralis.fr - www.biotech-pipeline.com

At the pre-formulation stage, the method will assess common physical and chemical compatibilities and stability issues and allow interaction studies between active product-excipient, protein-ligand and active

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Galentech

New Method for optimizing formulations and processes > Benefits

• Speed of analysis The technique provides rapid and highly reliable results within hours as opposed to several weeks or even months usually required for conventional methods. • Purpose-built equipment The research laboratory has developed purpose-built equipment which enables the resolution of different problems relating to, for example, vapor-powder interaction and their consequences upon the physical stability of amorphous products (Patent N.Khalef and Bakri A., device and process for crystallization control n° 08/06918). The GPCD-IDTC approach was presented at the annual meeting of the royal academy of chemistry (BAKRI, A) • No treatment required The third key benefit of the approach relates to fact that the method is non invasive and the product does not need to be treated prior to testing.

> References - Khalef N. and Bakri A., Recent Methods for stability and compatibility studies in pharmaceutical preformulation, STP Pharma, volume, 2005 (15), 342-353.BHUGRA C., S. RAMBHATLA , A. BAKRI , S.P DUDDU , AND D. P MILLER , M.J Pikal, D.Lechuga-Ballesteros, Prediction of the onset of crystallization of amorphous sucrose below the calorimetric glass transition temperature from correlations with mobility, J Pharm Sci. 2007, (5),1258-1269. - Khalef N., Bakri A., Contributions méthodologiques et instrumentales aux études d’interaction solide-vapeur et transformations cristallines induites en recherche et développement pharmaceutique, Récents Progrès en Génie des Procédés, Numéro 97 - 2008, ISBN 2-910239-71-3, Ed. SFGP, Paris, France. - Khalef N., Bakri A., Etude comparative de cristallisation par calorimétrie isotherme en système ouvert et en système fermé et détermination de faibles taux d’amorphe, Récents Progrès en Génie des Procédés, Numéro 97 - 2008, ISBN 2-910239-71-3, Ed. SFGP, Paris, France. - Khalef N., Bakri A., Caractérisation des matériaux par un système calorimétrique isotherme double jumeau ouvert : mesures des énergies de surface, établissement des isothermes de sorption et études des phénomènes de recristallisation d’amorphes, Récents Progrès en Génie des Procédés, Numéro 97 - 2008, ISBN 2-910239-71-3, Ed. SFGP, Paris, France. - Khalef N., Bakri A, Etude des interactions saccharose - humidité : optimisation des conditions de stockage des lyophilisats et nébulisats pharmaceutiques, Récents Progrès en Génie des Procédés, Numéro 97 - 2008, ISBN 2-910239-713, Ed. SFGP, Paris, France. - Khalef N., D.Avignant, F.Pilotaz Bakri A., Etude de la stabilité physique et de la recristallisation du cromoglycate de sodium en solution et à l’état solide, Récent progrès en Génie des Procédés, Numéro 97 - 2008, ISBN 2-910239-71-3, Ed. SFGP, Paris, France. - Khalef N., Hammad T., Bakri A., Optimisation de la stabilité chimique et physique de formulations solides de la benzocaïne par enrobage moléculaire et cristallisation, Récents Progrès en Génie des Procédés, Numéro 97 - 2008, ISBN 2-910239-71-3, Ed. SFGP, Paris, France.

> Contact Nicole GIRAUD

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 42 – Fax : +33 (0)4 76 00 70 38 nicole.giraud@floralis.fr - www.biotech-pipeline.com

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In Ovo Screening Assessment of Electromagnetic Radiation An Innovative technology that enables the fast and efficient evaluation of the impact of electromagnetic waves on embryonic development

> Introduction The ability to quickly and efficiently evaluate the effect of intense, long-term electromagnetic exposure on humans and on embryonic development is a key requirement in public healthcare. In ovo screening is an innovative technology that provides a solution to this problem: via an analytical model that works on both macroscopic and molecular levels. The in ovo model enables a clear understanding of the possible effects of electromagnetic exposure on humans as well as reducing the need to carry out scientific experiments on animals.

> Frequency / Ex posure

> Services Available

• Analysis of embryonic development at different stages of development (daily observation increases the accuracy of the final analysis) • Macroscopic analyses for the detection of potential malformations or mortality induced by treatment • Histological and molecular analyses (in situ hybridization, immuno-histochemistry, cell cultures, biomarkers, genotoxicityetc.) • Comparative analyses, correlation between phenotypic results and molecular pathway networks, databank analyses

> Contact

times

The model enables the evaluation of electromagnetic exposure on embryos and organs during development by first carrying out tests in-ovo (eggs can be exposed for up to 20 consecutive days and frequency/exposure times can be modified according to experimental demands).

Florence ALESANDRINI

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 35 – Fax : +33 (0)4 76 00 70 38 florence.alesandrini@floralis.fr www.biotech-pipeline.com

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In Ovo Screening

Assessment of Electromagnetic Radiation > The Benefits of In Ovo Testing

The model allows results to be obtained after embryos have been subjected to constant electromagnetic exposure (equivalent tests on animals prove less effective as they are prone to movement, thereby reducing levels of electromagnetic exposure). • Strong similarities with human embryonic development enables cross-tabulation with human based studies including all of the following - embryonic development - cellular differentiation - molecular pathways and organogenesis

> Potential Application

►Telephony: risk assessment ►High voltage networks: risk assessment ►Electric devices etc.

> Commercial Opportunities

Floralis is currently looking for industrial partners who may benefit from this technology as part of their R&D programs.

• Very strong/total similarity with mammals for - physiology - metabolism - molecular pathways

> Contact

• Possible to test on a very large number of samples at the same time

Florence ALESANDRINI

• Confirmation of results obtained from cells

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 35 – Fax : +33 (0)4 76 00 70 38 florence.alesandrini@floralis.fr www.floralis.fr

• Optimization of R&D programs focusing on electromagnetic exposure • Reduction of risk in R&D programs through a costeffective methodology

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In Ovo Screening

A valuable research and development tool for ecotox icology and environemental safety In Ovo testing process (on avian embryos): a fast, efficient and practical means of evaluating the inocuity/toxicity of chemical and environmental compounds (process is exempt from legislation concerning animal testing)

> Introduction The ability to quickly and efficiently evaluate the effect of chemical and environmental compounds on living organisms and to predict their impact at an early stage can prove a challenge with regards to the management of public health and the environment. In ovo screening (amniotic model), is an innovative technology that provides a solution to this problem through a process that enables testing to be first carried out on bird embryos. Embryonic toxicity when first tested on bird embryos both enables a clear understanding of possible effects on humans as well as reducing the number of tests that need to be carried out on animals. In ovo screening can prove to be highly beneficial in R&D programmes where the key objective is the identification of new molecules.

> The Testing Process

The process can be applied in three distinct ways: by exposing the surface of the embryo to the chosen molecule/sample, by means of injection into the embryo and finally, by targeting specific organs • Treatment by surface exposure The first level of testing gives researchers an understanding of the effects of environmental exposure to a molecule or sample. • Injection into embryonic egg (1 ml à 100 μl) The process can be implemented by means of an injection directly into the embryo. This level of testing ensures a clear understanding of the internal impact of a specific molecule or sample on the entire living organism.

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• By means of targeted injections into developing organs (25 nl) Injections can target the brain, muscles, skin, kidneys, amniotic fluid, pigmentary & digestive systems, bones etc. This, the most precise level of testing, gives R&D professionals the ability to understand with a very high level of detail the impact of molecules or samples on a specific organ.

> Contact Florence ALESANDRINI

6 Allée de Bethléem – 38610 Gières Tée. +33 (0)4 76 00 78 35 – Fax : +33 (0)4 76 00 70 38 florence.alesandrini@floralis.fr www.biotech-pipeline.com


In Ovo Screening

A valuable research and development tool for ecotox icology and environemental safety

> Key Benefits • Highly sensitive model - Low concentrations of molecules/samples in a small volume of injection required (from ml to nl) - Ability to detect multiple biomarkers simultaneously - Possibility to carry out several tests simultaneously • Study relevant to the whole organism - Model enables the implementation of physiological and metabolic/molecular process studies relating to pathways as well as studies of complex molecular pathways • Amniotic vertebrea Model - Similar results to those you would expect to find in humans • Ethical model - Complies with demands made by the REACH directive. Exempt from legislation regarding animal testing • Short, highly accurate and reproducible tests - Increases efficiency of process/more experiments can be carried out within the same time frame • Analysis of high throughput screening - Enables user to test molecules that have just been discovered to give a rapid indication of toxicity/innocuity • Breakdown of molecules suitable for testing : Chemical molecules, Nanostructures, Electromagnetic emissions, Water, effluents etc. - Highly versatile model

biomarkers, in situ hybridization, immunohistochemistry, cell cultures genotoxicity etc. • Comparative analyses, correlation between phenotypic results and molecular pathway networks, databank analyses • Analysis of results, explanation, interpretation and report delivery.

> Potential Applications ► Toxicological risk analysis ► Environmental risk analysis ► Analysis of risks in public health ► Water/effluent analysis

> Commercial Opportunities Floralis is currently looking for industrial partners who may benefit from this exciting new technology as part of their R&D programs

> Contact

> Service Available

Florence ALESANDRINI

• Customized services (bespoke testing available on demand) • Quantitative analyses of the impact on embryos at different stages of their development • Macroscopic Analyses for the detection of malformations or mortality induced by treatment • Histological and molecular analyses, follow up with

6 Allée de Bethléem – F-38610 Gières Tél. +33 (0)4 76 00 78 35 – Fax : +33 (0)4 76 00 70 38 florence.alesandrini@floralis.fr www.biotech-pipeline.com

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> Technological Platforms

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Extraction Platform Vegetal products > Introduction As part of the research and characterisation for new molecules of vegetal origin, the Molecular Chemistry department of the University Joseph Fourier can provide you with access to its platform in order to extract your natural compounds for samples up to 2Kg. The team can enable you to benefit from all its know-how and its expertise in chimio-taxonomy to study the chemical link between vegetal species belonging to the same botanic family, as well as through pharmacognosis in order to improve natural substances (raw extracts or pure compounds).

> 100 - 500g samples:

• Extractor mounted on a 6L flask with mechanical agitation and heating (finely controlled temperature) > Extractions with different organic or aqueous solvents • Soxhlet version: extraction via heating cycle, condensation repeats indefinitely until complete exhaustion of the solid > Very efficient (compared to soaking)

> Samples up to 2kg:

• Large extractor with a 20L flask with mechanical agitation and controlled heating • Soxhlet version (continuous)

> Other equipment:

• Mixer and continuous liquid/liquid extractor on a pilot scale for the purification of raw extracts obtained by sold/liquid extraction > Extraction by solvent density difference > Up to 150 litres (following solvants’ density) • Rotating evaporators (1L, 3L, 10L) allowing the concentration and evaporation of organic or aqueous solvent extracts • Freeze drying from 1 and 5L of trapped water

> Applications: • Pharmaceuticals • Cosmetics • Agribusiness

• Version adapted to essential oil extraction by water vapour

> Contact Nicole GIRAUD

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 42 – Fax : +33 (0)4 76 00 70 38 nicole.giraud@floralis.fr - www.biotech-pipeline.com

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Ecometrix Environmental Platform > Introduction

Ecometrix is expert in the field of atmospheric chemistry and the meteorology of volatile organic compounds (VOC) and, in particular, the industrial emissions resulting from combustion and incineration processes. The technology exploits an innovative high performance sampling methodology that is particularly suited to this application. Ecometrix is also developing in parallel, new analytical tools that aim to improve the efficacy of sampling processes for VOCs in harsh industrial conditions and which answer growing concerns to convert biomass into energy and reduce industrial gaseous emissions.

> Areas of Ex pertise

• Analysis of organic volatile compounds emitted from combustion processes (pyrolisis, combustion and incineration) • Online sampling via solid phase micro extraction SPME, followed by a highly sensitive analytical process • Identification and analysis of tracer molecules from complex chemical families

> Recent Studies

• Analysis of tar emitted in combustible pyrolitic biomass processes (CEA – Commissariat à l’Energie Atomique, IFP – Institut Francais du Petrole) • Analysis and identification of volatile organic compound tracers on household waste tips (major environmental group) • Air quality studies relating to the presence of domestic wood-heating systems (fires, wood stoves, etc)

Compounds

Sampling

Analysis

Sensitivity

Hydrocarbons, BTEX, PAHs, Carboxylic acids, Organochlorides, Amines, Esters, Ethers, Ketones, etc.

C2-C20 Volatiles Semi-volatiles

SPME (solid phase micro-extraction)

Thermal desorption GC/MS, GC/FID

1ppbv-100ppmv

Hydrocarbons, BTEX, Carboxylic acids, Organochlorides, Amines, Esters, Ethers, Ketones, etc.

C2-C20 Volatiles

SPE cartridge (solid phase micro-extraction)

Thermal desorption ATD/ GC/MS, ATD/GC/FID

50ppv-1000ppmv

Aldehydes

C1-C10

DNPH silica cartridge

Solvent Extraction HPLC/UV/VIS Absorption

1-5000 ppbv

> Contact Mathieu TILQUIN

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 78 41 – Fax : +33 (0)4 76 00 70 38 mathieu.tilquin@floralis.fr - www.biotech-pipeline.com

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Grenoble Medical Proteomic Platform Clinical Bias > Introduction

Expert in the processing and analysis of clinical assays, this leading proteomic platform capitalizes on its integration within Grenoble University Hospital to advance research in proteomics

> Overview

(iTRAQ techniques) and multiple proteomic analyses • Unique proteomic and peptide separation processes • Industrial training sessions: the team can carry out training sessions on request • Research contracts established with the platform conform to BPL (bon pratique de laboratoire) standards. The team is currently working towards gaining an ISO accreditation • Core competencies acquired around the analysis of complex biological samples, notably in a clinical environment (diagnostic markers, therapeutic targets, marker validation, cohort studies, technological developments) • A wide range of cutting-edge equipment available (see list below) this truly global approach to the analysis of ecosystems enables researchers or scientists to simplify and standardize current methods of understanding biodiversity.

Expert in a wide variety of cutting-edge proteomic techniques such as peptidic fractioning using OFFGEL and quantification by iTRAQ the platform has also developed an excellent reputation for protein analysis of liquid biological samples (plasma for example). The expertise in analyzing liquid biological samples is due, in no small part, to the team’s close working affinity with Grenoble University Hospital. The combination of cutting-edge equipment available at the platform and its close alliance with Grenoble CHU results in a high-quality medical proteomic service that is of specific interest to private and public sector research organisations. With Grenoble as its base, the platform also has close links with nano and biotech research programmes (Nanobio). The platform is one of the few centres in France that is able to combine two types of sources of ionization for mass spectrometry and has already managed over 15 highly complex projects (some examples can be found below).

> Contact

> Key Benefits

Marie-Gabrielle JOUAN

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 00 61 – Fax : +33 (0)4 76 00 70 38 marie-gabrielle.jouan@floralis.fr www.biotech-pipeline.com

• Clinical focus: the platform has been developed specifically to manage clinical research programmes • Grenoble CHU: located at the heart of Grenoble University Hospital, the platform continues to maintain its close working relationship with the CHU, a factor that facilitates the exchange of medical/clinical data as well as enabling access to a biological resource centre. • Development of specific techniques relating to clinical samples (plasma, tissues) • Specialists in post-marker quantitative techniques

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Grenoble Medical Proteomic Platform Clinical Bias

> Laboratory Infrastructure

The platform boasts an impressive infrastructure (over 20 specialist laboratory machines and applications) including: > MALDI TOF TOF mass spectrometer (Abi 4800) > Electrospray (4000 QTrap) > 1 and 2D Nanochromatographers > Multi dimensional HPLC (Dionex) > Low pression chromatography system

> At a glance: Ex amples of

> Quantative and differential analysis

The platform can use the iTRAQ technique to identify and quantify proteins from several samples in one single experiment. iTRAQ is used in proteomics to study quantitative changes in the proteome. • • • •

Identification of specific biomarkers Analysis of the effects of drugs Investigation of pathological mechanisms Cinetic analysis

past/current projects

• Identification of proteins demonstrating pharmacological activity originating from snake venom • Identification of proteins secreted by pulmonary tumor cell lines • Characterisation of synthetic peptides demonstrating pharmacological activity • Proteome stem cell research within the context of reparative vascular therapy • Research into biomarkers in plasma for chronic sleep apnea • Validation of tryptic digestion bioreactor in complex biological sample

> Contact Marie-Gabrielle JOUAN

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 00 61 – Fax : +33 (0)4 76 00 70 38 marie-gabrielle.jouan@floralis.fr www.biotech-pipeline.com

> Potential Applications

> Protein identification in complex biological samples > Post translational modification studies > Protein Characterisation > Biomarker detection > Protein mapping

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2D and 3D in vivo optical imaging platform for small animals

From Bioluminescence to Fluorescence > Introduction

The small animal optical imaging platform offers a range of services that can be especially useful for lifescience organizations, notably those involved in Biomedical R&D where the need for non-invasive, spatio-temporal analyses of biological processes can be carried out directly within living organisms in real time.

> Key Benefits

• A fast, cost-efficient alternative to «conventional techniques» that can be both difficult to implement and necessitate a large number of animals for testing • Access to a wide-range of cutting-edge equipment some of which is unique on a global scale • A multidisciplinary approach - backed up years of highly relevant experience • The ability to interact with a network of private and public sector academics reputed to be leaders in their field • The potential to benefit from the platform’s close working relationship with Grenoble’s Microscopic Optical Network • Account management: a longterm , personalized approach to ensure that your needs are met from the beginning of your project up until the development of your brief, outlining the protocols and modalities that match your requirements

> From Bioluminescence

& 3D Fluorescenceetc.

to 2D

Whatever the imaging modality required for your research project, the Optical Imaging Platform, Grenoble, has the people and the equipment to ensure that your project runs smoothly from the development of your brief to the final analysis. The following examples demonstrate the strength in-depth of the platform and the wide range of research services that it is able to provide across different imaging platforms

Gene therapy: Evaluation of vectors relating to gene transfer • Colour images depicting reporter gene over a given period of time • Quantification of areas of interest on the same animals over a prolonged period of time Regulation of gene expression: Ongoing analysis of the regulation of gene expression in transgenic mice • Images illustrating reporter gene expression over a given period of time • Quantitative analysis relating to ≤ three animals at the same time

> 2D Fluorescence of the entire

body (Drug Development)

Biodistribution and pharmacokinetic studies in-vivo • Longterm biodistribution analysis of compounds of interest (new drugs, proteins, nano particles etc) • In-vivo films in real time analyzing different means of injection • Series of images illustrating biodistribution • Quantification of areas of interest on animals over prolonged periods of time • Relative quantification of the signal obtained from the organs after dissection, as well as in plasma

Bioluminescence (Cancerology: characterization of tumor models) • Colour images can be developed depicting tumor and metastatic cancer growth • Quantification of areas of interest on the same animals over a prolonged period of time

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(photo CEA-LETI)


2D and 3D in vivo optical imaging platform for small animals From Bioluminescence to Fluorescence > Imaging at cellular levels

> Resources Available

Macro and microscopic fluorescence

> Highly-detailed 3D

• Cell culture room (numerous cell lines available) • Specially adapted animal house for nude and trans genic mice • Five gas anesthetic systems equipped to work between the ranges of 480nm and 690nm • The potential to benefit from the platform’s close working relationship with Grenoble’s Microscopic Optical Network

Fluorescence

Cancerologie : in-vivo tomographic fluorescence • Long term quantitative and longitudinal analysis of deep tumors (lung, brain, abdomen) • Long term analysis of anticancer drugs

> Procedural Fluorescence

Surgical procedures assisted by real time fluorescence imaging for: • Removal of lymphatic ganglions (for example sentinel ganglions) • Tumor removal • Removal of pulmonary or abdominal metastases • Vascular surgery

This Optical imaging platform is part of a European centre of excellence that includes EMIL, Nano to Life and CLARA (Canceropôle Lyon Auvergne Rhône-Alpes)

> Contact

> Available shortly: bi-modal

Marie-Gabrielle JOUAN

imagery

6 Allée de Bethléem – F-38610 Gières Tél. +33 (0)4 76 00 78 62 – Fax : +33 (0)4 76 00 70 38 marie-gabrielle.jouan@floralis.fr www.biotech-pipeline.com

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In Vivo Facility MRI Platform, Small Animal Optical Imaging, Small Animal in vivo Nuclear Imaging MRI Platform > Service Available

Small Animal in vivo Nuclear Imaging

A specialty of the MRI platform is that it is organized as a service-driven platform. Research teams using the MRI equipment and/or needing support from the platform staff are treated as «clients» of the platform. Services offered to clients cover a very broad spectrum. This can range from providing clients with access to the MR and/or biological equipment for the development of research contracts and subsequent research in areas specified by the client (i.e. the performance of MRI/ MRS experiments and/or biological analyses, histology, immunohistochemistry, cell cultures, etc)

The SANI platform is a pre-clinical platform dedicated to in-vivo nuclear imaging in small animals. Presently, the platform is based around two key pieces of equipment: a small-animal SPECT imager (Gamma Imager) housed at the medical campus of the Université Joseph Fourier, Grenoble. Research programs on this platform are developed along the following lines: • Development of nuclear imaging tracers • In-vivo pharmaco-kinetic studies of radioactive compounds • Evaluation of therapeutic trials at pre-clinical levels • Validation of new animal models in oncology, for the study of neurodegenerative diseases and of metabolism

> Equipment

The Animal MRI platform is currently equipped with four small animal MRI systems (2.5T, 4.7T, and 7.0T horizontal bore MR imagers and a vertical bore 4.7T MR imager). These systems are installed at the GIN. The Human MRI platform runs a 3T whole-body MR imager. The latter is installed in the immediate vicinity of the two clinical 1.5T MR imagers. The Animal MRI platform will be extended this year with a 3T whole-body imager while the equipment (3T Bruker system) from the Human MRI platform will be replaced by a system identical to the one to be installed in the Animal MRI platform.

Throughout the the course of 2009, the platform will be further extended with three new, small-animal cameras: a microSPECT-CT and a microTEP-CT to be installed on the Grenoble site.

> Contact Marie-Gabrielle JOUAN

6 Allée de Bethléem – F-38610 Gières Tél. +33 (0)4 76 00 00 61 – Fax : +33 (0)4 76 00 70 38 marie-gabrielle.jouan@floralis.fr www.biotech-pipeline.com

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Small Animal Platform Animal Facility > Introduction

Located in the Jean Roget Institute the experimental animal platform covers 1350m2 of floor space. It is divided into 5 areas maintained under pressurized conditions for the housing of up to 15,000 transgenic and immuno-deficient animals in an SPF (specific pathogen free) environment. A2 and A3 laboratories are available.

> Service Available

• Rearing, management and development of rodent lines bred for experiments and distribution to external laboratories and for use in training in an SPOF (specific opportunist pathogen free) and conventional environment. Housing and experimentation in microbiological confinement to levels A1 to A3. Manipulation of products requiring specific levels of confinement (pathogens, molecules of unknown incidence, nanoparticles)

> At outsourcing and consultancy level

• Embryo freezing/ storing • Consulting services for laboratories concerning analyses that need to be carried out on their animal lines • Expert advice on breeding strategies for animals destined for experiments and for associated experimentation techniques

• Decontamination and revival of animal lines by embryo transfer • Genotyping for the genetic characterisation and analysis of lines; • Cell reimplantation service by ES (embryonic stem cell) injection into blastocytes or cell aggregation Immunization service for antibody production (monoclonal and polyclonal) • Injections of antigens • Serum samples taken for tests carried out at laboratory level • Animal imaging services (proposed future development to place rodents in-house in imaging platform) • Experiments carried out by qualified technicians of the platform (with the potential to transfer know-how to the relevant laboratories) • Expertise acquired in animal experimentation (list of competencies available on request)

> Contact Marie-Gabrielle JOUAN

6 Allée de Bethléem – F-38610 Gières Tel. +33 (0)4 76 00 00 61 – Fax : +33 (0)4 76 00 70 38 marie-gabrielle.jouan@floralis.fr www.biotech-pipeline.com

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In Vitro Platform Microscopic, Cellular and Tissue based imaging services > Service on Offer • Fluorescent microscopy, spectral microscopy, (biphotonic, SHG) NLO microscopy, Holographic microscopy • Digital, micro spectrometry, Atomic force microscopy, NLO microscopy Electron microscopy, micro dissection The wide range of technological platforms available reflects the diversity of research that is carried out at the platform which extends from the study of molecular dynamics within the cell nucleus (normal and cancerous) to spatial and functional organization of cells in tissue (neuroscience, oncology and ontology).

Platform specialties: Developments in methodologies for confocal microscopy, biphotonic microscopy, FCS, FLIM, spectral fluorescent microscopy, oncology and ontology Technical platform ICTiss (cellular and tissue imaging) Services available: Confocal microscopy, spectral fluorescent microscopy, video microscopy, digital holographic microscopy, Atomic force microscopy Platform specialities: Expertise and development of image analysis, quantification in microscopy

> Overview by Site Technical platform (MBIOP) Biophysical Microscopy Services available: A collection of optical microscopes dedicated to molecular and cellular biophysical research which form the basis of study for developments in instrumentation and tracers (fluorescence etc) Platform specifics: Instrumental developments and methodologies in confocal microscopy (FCS) and TIRF for living cells and biochips; ultra sensitive microscopy for objects in turbid solutions Technical platform (IAB – Cellular Imaging) Services available: Management, use and updates for microscopy and microspectroscopy. Development and validation of new methods in fluorescent microscopy; Training and user support, assistance with protocol development; Set up for R&D projects with external teams; Dissemination of know-how, theoretic and practical development

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> Contact Marie-Gabrielle JOUAN

6 Allée de Bethléem – F-38610 Gières Tél. +33 (0)4 76 00 00 61 – Fax : +33 (0)4 76 00 70 38 marie-gabrielle.jouan@floralis.fr www.biotech-pipeline.com


In Vitro Platform Microscopic, Cellular and Tissue based imaging services Technical platform MBIG-MEC (Intravital biphotonic microscopy) Services available: Non-linear optical imaging, biphotonic (2ph) and second harmonic generation (GSH) on tissue and living animals and in particular for neuro-biological and neuro-oncological applications. Cellular imaging is not excluded from the moment that it is linked to invivo manipulations. Electronic microscopy and provision of equipment for experienced users. Preparation of biological samples for morphological studies (coloration, inclusion, ultra-thin cuts) Site Specialties: Development of animal models for intra-vital optical imaging, potential to temporarily stock and source mice and rats (to a maximum of 20) in the GIN quarantine (GIN – Grenoble Institute of Neurosciences) Technical platform DMICT (molecular detection for cells and tissue in-situ) Owner: DACP Centre Hospitalier Universitaire Albert Michallon Services available: Protein detection of DNA, RNA nucleotides in either healthy or pathological tissues. Intra-cellular or intra-tissue marker topography, histological services, automated immunohistochemical processes and in-situ hybridization, standardization of procedures for DNA chips, laser micro dissection (PALM LCS) combined with automated extraction (RNA) Site Specialties: in-situ identification of proteins in tissue (immunohistochemistry) and nucleotide sequences, genomic DNA, RNA, oncology

> Contact Marie-Gabrielle JOUAN

6 Allée de Bethléem – F-38610 Gières Tél. +33 (0)4 76 00 00 61 – Fax : +33 (0)4 76 00 70 38 marie-gabrielle.jouan@floralis.fr www.biotech-pipeline.com

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Biotechnology Opportunities in Grenoble  

Commercial Opportunities : - service based offerings - product based offerings - development opportunities Edited by Floralis, the Technolog...

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