29 Novembre 2011Università degli Studi di Milano

Via Golgi 19 aula G10

S. Di Giovine Business Development

Director

Corporate profile

TOP research team is specialized in the generation of vectors, cells and animals for Molecular Imaging using:

Bioluminescence

PET (Positron Emission Tomography)

NMR (Nuclear Magnetic Resonance)

TOP srl, originated in 2006 as a spin-off of the University of Milan and has been backed in 2007 by the NEXT fund managed by Finlombarda Gestioni SGR.

TOP is located at the Parco Tecnologico Padano in Lodi, near Milan.

TOP missionTo provide the scientific community with non-invasive tools for

the study of the activity of drugs and environmental or food contaminants

TOP aims at combining the power of physics, informatics and molecular biology to generate novel models for the bio-medical research and for the control of the environment and alimentary chain.

TOP strives to renew present investigational tools in the respect of animal rights to satisfy two conflicting needs: use of predictive biological models in the absence of animal distress.

The Company expertise: Molecular Imaging

Reporter green fluorescent dye

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Molecular imaging is based on the appropriate use of REPORTERS: molecules easily detectable and allowing to study spatio-temporally molecular events in living organisms.

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The Company unique and proprietary technology*: the use of insulator sequences to obtain generalized expression of the reporter

CCD

Camera

* EU patent No. EP 1298988B1 US patent No. 7,943,815

All TOP products are subjected to intense validation to ensure:

constitutive/ inducible

PREVENTION OF EPIGENETIC MODIFICATIONS

ACCURACY

TURN-OVER UBIQUITY

REPRODUCIBILITY NON-INVASIVENESS

SPECIFICITY

SATURNVALIDATION

REPRODUCIBLE and REGULATED EXPRESSION OF THE REPORTER REPORTER EXPRESSION MAINTAINED IN TIME AND GENERATIONS

TOP products enable to study your favorite molecular process along the whole life cycle

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TOP finds a response to a variety of research needs Pharma:

− identification of novel drug targets

− speeding of pre-clinical testing

− identification of drugs endowed of tissue specificity of action

− more predictable toxicological tests

− gender pharmacology

− pharmacology of infancy and aging

− new indications for drugs in the clinic or in the market

Environmental & Food toxicology:− identification of specific activities in mixtures of compounds− threshold effects in short and long term exposures

− identification of food contaminants

− threshold effects in short and long term exposures

− identification of the organs targeted by environmental pollutants

Biomedical research:− understanding the physiological effects of specific molecular events

One single tool for the multidimensional analysis of drugs in vivo.

TOP Reportersystem

Immediate readout;

Increased prediction power:

- holistic vs. reductionist approach;

- drug action, not only distribution.

Increased ability to perform multidimensional analysis of drug activity:

- space (organs, PD); - time (PK, longitudinal studies); - immediate evidence of undesired activity (toxicology).

Lower costs;

Decreased research time;

Significantly reduced number of animals.

Partnership

TOP srl is partner of Caliper Life Sciences (former Xenogen) , the world leader for in vivo optical imaging.

repTOP™ mice available at present:

Models Therapeutic areas:

repTOP™ ERE-Luc mouse (Estrogen Receptors)

•Aging-related pathologies•Depression•Inflammation

repTOP™ PPRE-Luc mouse (PPAR’s)

•Lipid metabolism alteration•Diabetes •Cancers and others

repTOP™ MITO mouse (“MITO as in MITOSIS”)

•Oncology•Regenerative medicine•Toxicology

repTOPTM Ubi-Luc2 (series) mouse + VivoGloTM

• Metabolism (CYP3A4) • Apoptosis (Caspase 3/7)

TOP reporter models - I

repTOP™ mice soon available

Models Therapeutic areas:

repTOPTM

NFkB-Luc2 mouserepTOP

TM TRAIL-EGFPLuc mouse

repTOPTM

P21-Luc /EGFPTK mouserepTOP

TM ARE Luc2

ApoptosisInflammationProliferationOxidative stress

TOP reporter models - II

In addition, TOP has generated a vast array of constructs for cell and animal engineering ready to be used and addressing most of current major needs in biological research. All of these constructs contain two or more reporters enabling bimodal and trimodal applications of molecular imaging

Custom- made repTOP™ mice: TOP’s technology platform and the standardized validation process are the guarantee of a rapid and reliable generation of an industry standard-compliant reporter system.

Founder mouse4-5 weeks 15 -18 weeks

GenerationFeasibility Characterization Validation

TOP reporter models - III

OUTSOURCING YOUR RESEARCH AT TOP

The expertise of TOP research team in molecular imaging is at our client’s service for advise and testing of compounds in a wide variety of therapeutic areas

TOP mice in the world Italy:

− Spedali Civili, Brescia

− Roma, University Tor Vergata

Europe:− Institut de Genetique et de Biologie

Moleculaire et Cellulare (IGBMC)

− Karolinska Institute

− Max Planck Institut fuer Psychiatrie Muenchen

− Dartmouth Medical School

− Leiden University Medical Center.

Australia:− Prince Henry’s Institute of Medical

Research

USA:− University of Kansas Medical Center

(KUMC)

− University of Miami, University of Chicago

− University of Illinois

− UT Southwestern Medical Center at Dallas

− University of Pennsylvania School of Medicine

− University of Tennessee

− Dana-Faber Cancer Institute

− Baylor College of Medicine.

Leading Pharmaceutical and Biotechnology companies worldwide.

TOP newest product:

repTOPTM mitoIRE to study proliferation in vivo

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The repTOPTM mitoIRE mouse to study proliferation in vivo

CCD

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Pro–proliferative stimuli

Anti – proliferative stimuli

NF-Y promoter

Cyclin B2 minimal promoter

repTOPTM mitoIRE validationcell proliferation induced by application of 7,12-dimethylbenz(a)anthracene to the skin of the left ear can be easily measured in vivo

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rapid detection

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COMPARING the sensitivity of Ki-67 immunohistochemistry and bioluminescence in the

MITO mouse

repTOPTM mitoIRE

following in time the development of chemically induce prostate carcinoma

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Combining repTOPTM and VivoGloTM technologies

Z-DEVD-Aminoluciferin, Sodium Salt

Induction of liver apoptosis 6h i.p. treatment with:

D-GalN (800mg/kg) + LPS (100 µg/kg )

Nakama T et al. Hepatology. 2001

repTOP™ Ubi-Luc2-M8

mouse