Mikhail Sitkovsky Skolkovo im modernization of medicine
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Skolkovo in modernization of medicine and fostering the cutting
edge biomedical enterprise in Russia
• The next 5 years…
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The Cutting Edge Treatments and Technologies that stimulate and/or enable the world-class IP-generation In Russia.
• The thoughtfully arranged “repertoire” of networking Skolkovo companies…
• But how to ensure that the Skolkovo-generated IP is NOT lost!
• Because it is NOT validated in vivo!• Skolkovo Institute of Translational Medicine• =SITM: • But which Treatments and Technologies?• The Recruitment of Top Talent to Skolkovo
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One of the desirable Skolkovo aims: to develop what
“everybody wants and nobody has”.
• But Skolkovo also should develop what USA has, but Russia does not have
• Or does not have IP to produce the needed treatment…
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The “Cutting Edge” technologies
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What is it that “everybody wants and nobody has”?
• For example, the effective immunotherapy of cancer.
• Requires combined use and improvement of many medical technologies..
• Immunotherapy is the Biomedical “Decathlon”!
• Immunotherapy can serve as an unifying focus in selecting and offering priorities…
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• Attacking tumor with patient’s own anti-tumor CD8+ T-killer cells and Natural Killer Cells
• To get rid of the residual tumor and metastases…
• FDA USA: = 27 april 2010, “Provenge” Cancer Vaccine, Dendreon,
• But the success rate is still low: ~ + 4 months?
• Why?-Tumor protects itself from anti-tumor T-killer cells;
• “Hellstrom Paradox”…
Immunotherapy of Cancer( “Our last hope”…)
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In vivo tumor seems to be protected:
T-killer
T-killer
T-killer
T-killer
The “Hellstrom” Paradox”, Nature, 1968;
?
Anti-tumor T cells destroy tumor cells in vitro:
T-killerT-killer
T-killer
The “Hellstrom-Schreiber” Paradox: -“Equilibrium lesions”(Nature, 2007)
The Motivation: 1974, Moscow University
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Hypoxictumor
Adenosine
Adenosine
Adenosine
Adenosine
Adenosine
Adenosine
T-killerT-killerT-killerT-killerT-killerT-killerT-killer
Adenosine puts anti-tumor T killer cells to sleep …
The SolutionOhta and Sitkovsky, Nature 2001
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• Moscow University: 1974-1981• Mass.Inst. of Technology: 1981-1984• National Institute of Health, Lab.Immunology: : 1984-
2004• New England Inflammation and Tissue Protection
Institute, NU: 2004-present :• Dana Farber Cancer Institute, Harvard Institutes of
Medicine: 2005-present• “Invisible “College” of Multiple Tough Reviewers:
Nature, J.Exp.Med., J. Biol. Chem; PNAS; J. Immunol ,..)
• “NewVac”: 2010-present
Where the study was done…
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• Based on Solution of Hellstrom Paradox…
• RedoxTherapies and ChemRar: • Founders of “NewVac” in Skolkovo.• The IP-Creating and the IP-
attracting enterprise in Skolkovo
Tumor Defense CounterMeasures
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Hypoxictumor
Adenosine
Adenosine
Adenosine
Adenosine
Adenosine
Adenosine
T-killerT-killerT-killerT-killerT-killerT-killerT-killer
Tumor Defense Countermeasures
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Hypoxictumor
T-killerT-killerT-killerT-killerT-killerT-killerT-killer
Tumor Rejection
Survival
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Anti-Tumor Hypoxia Drug
Competitive A2AR AntagonistTumor Hypoxia [O2]Low
Ecto-Enzymes [CD39]High
[CD73]High
ATP-->[Adenosine]High
Elimination or Blockade of CD73
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Preclinical evidence of tumor rejection and immunological memory to rejected tumordue to the action of the A2AR antagonist in different animal models of cancer
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The Anti-Tumor Hypoxia Drug enables anti-tumor T killer cells to reject lung tumors
21%
40%
60%
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• If there is In Vivo Evidence No IP, No patents!• The decisive solution:• SITM • Skolkovo Institute of Translational
Medicine
The importance of animal models of diseases
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• =SITM develops cutting edge novel ideas• =SITM makes great ideas patentable by
validating them in vivo• =SITM has Department of Animal Models of
Human Diseases• =“Humanized” and KO mice • =SITM coordinates clinical trials of Skolkovo
companies• Who can collaborate in launching SITM?
SITM
Skolkovo Institute of Translational Medicine
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The Structure of Dana-FarberThe Structure of Dana-Farber
• Bone and Sarcoma
• Cancer Genetics
• Cutaneous and Mohs
Surgery
• Gastrointestinal
• Women’s Cancers
• Head and Neck
• Genitourinary
• Thoracic
• Hematology
• Neuro
• Experimental
therapeutics
• Psychosocial
DISEASE CENTERS
• Center for Cancer
Vaccines
• Center for Clinical
Translational Research
• Center for
Experimental Pathology
• Center for Cancer
Genomics
• Center for Cancer
Systems Biology
• Center for Applied
Cancer Science
INTEGRATIVE
RESEARCH CENTERS
• Proteomics
• Genomics
• Chemistry
• Computational
Biology
• ImagingTECHNOLOGIES
How Dana-Farber Cancer Institute at Harvard Organizes its 50:50 Balance of Clinical Care and Basic Research
An Innovative Model for Cancer
Research and Care
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Some of the promising opportunities for Skolkovo
Specific Examples…
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• For example, the NewVac in Skolkovo will have drug that may also improve the antibody-targeting therapies of breast cancer…
• Monoclonal Antibody Herceptin.• But How to get it to Skolkovo?
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• DFCI, Harvard and U. Penn, Mark Greene. M.D.
• The Skolkovo may have chance to develop the most superior treatment using the next Generation Herceptin;
•
The answer #1: Recruiting the Discoverer of Herceptin
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S22-Fc - a multi-specific binder to EGFR, Her3 and Her2/neu
MCF7 NE91
T6-17
S22-Fc
Binding to T6-17 (Her2) and NE91(EGFR) cells by S22-Fc
S22Fc
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“Creation of a trivalent antibody like molecule with picomolar activity
against EGFr, HER2/neu and HER3”The molecule is already fully “human” …;
Has potential to help all HER+ breast cancer patients as compared with 25% for original herceptin Ab…
as compared with Zero with no “old” herceptin.
Is not it something that “everybody wants and nobody has”?
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Drugs that are not novel, but are much needed…
and can be “novel again”…
• These drugs can be also very lucrative• Multi-$ Billion market• -The IP- is getting “old”…• But the international IP on them is still
possible!
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Not “Cutting Edge” on the first look…
• But these actually ARE cutting edge technologies…
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Fabrazyme Amevive
Xolair Bexxar Raptiva
Fabrazyme Amevive
Xolair Bexxar Raptiva
Chronology of Key Biotech Product Approvals 1982 - 2007
20031987 199819971995 19961988 1989 1990 1991 1992 1993 1994 1999 20012000
CBER (N=48)
CDER (N=14)
Activase
19861985
Nutropin
Glucagon
Thyrogen
Mylotarg
Ovidrel
NatrecorProtropin CerezymeCeredase
Follistim
Forteo
Epogen/ProcritEpogen/ProcritNeupogen
Leukine
Actimmune
Proleukin
Pulmozyme
Betaseron
ReoPro
Intron AAbatacept
Galsulfase
Abatacept
Galsulfase
Avonex
Retavase
Benefix
Infergen
Neumega
Rituxan
Zenapax Regranex
Simulect
Synagis
Remicade
Herceptin
Enbrel
NovoSeven
Ontak
Refacto
Zevalin
Elitek
Humira Rebif
Humulin R (1982)
Achieved $1 Billion Annually in International Sales
2002
Campath
Kineret
Xigris Aranesp
2004 2005 2006
Avastin
Erbitux
Tysabri
Lucentis
Myozyme
Elaprase
Vectibix
HumatropeHumatrope
IncrelexIncrelex
Products Most Likely Off Patent
by 2018
2007
2018
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Why would you want to have a drug that is out of IP protection?
• Because it is proven to be safe…
• Because it works!
• It will bring you $$!
• And it did not cost you $$$$ to develop!
• Competition: China, India…
• But safety still must be proven..
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Biosimilars in Skolkovo
• Our Chance?• New IP-based methods of inexpensive
evaluation of Innovative and “Biosimilars”…• “Evergreening” of drugs on the market…• -New combinations• -New delivery• -New formulations• E.g. ChemRar and Sanofi-Aventis..
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“The Potential Skolkovo Enterprise:
• New IP-based Technologies to evaluate “Biosimilar” biotech products;
• Less expensive validation of BioSimilars• Also minimize the $$$ risk with innovative
drugs..• “Immunogenicity”… • -”scale-up”…. “omics” …• E. Reinherz, Harvard and Barry Karger, NU
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GENERAL PRINCIPLE:Skolkovo must have strong requirement:
The IP-generating technological platform
• The Example:• Monoclonal antibody/ Proteomics based and• The disease-specific diagnostic or outcome-
predicting assays;
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• If there is NO need in immunotherapy!• Early diagnosis!• Need in superior biomarkers.• Proteomics and bioinformatics platforms• Not just for immunotherapy!• For any disease!
What is even better than EFFECTIVE immunotherapy of
cancer?
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“In Skolkovo” mAB proteomics technology
New IP to be created for every new disease
• ~10 000 mAB / experiments for proteome profiling
• Disease specific mAB libraries detect the natural form of the proteome
• Easy to translate
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Immunogenpreparation
Hybridomageneration
ScreeningCloning
assay
Reagent characterization
Patent pending
proteome normalization (10,000 mABs / experiment)
No translation bottleneck
Record speed form bench
to market
Generation of the BSI mAb library against native human plasma proteins
using mAb proteomics (patent pending)
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“In Skolkovo” created mAb/Proteomics diagnostics
• A test for early detection of lung cancer is in late development phase– Expectation is improvement of survival from
16% to 50%
• Serum from patients with other diseases…
• What e.g. about early bacterial infections?
• What about prostate cancer?
• What about heart disease?
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• Targeting NOVEL targets by NOVEL small molecules and NOVEL biotech products:
• These are the most IP-rich technologies : • Must be based on “Breakthroughs in understanding
of molecular mechanisms of disease”.• Now is the good time to identify some of these
underfunded in USA/Europe breakthroughs.• Benefitting from failures of peer review at NIH..• Skolkovo has all to attract the top world
scientists!
The Recruitment of Top Talent to Skolkovo
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• Yes: -Emotional to some…-Interesting to many..• =Bad times in the West…
- $$$ = is the “strongest chemo attractant!”• No: -1990s stories about “Russian Partners”…• -Yes: Skolkovo will dispel fears by excellent
examples of Russian Partners!• Thus Skolkovo will play yet another great role for
Russia by challenging the wrong image stereotype!
Will The Top World Scientists Come to Russia with their
Best to synergize with Russian scientists ?
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What to Do?
• 1. Identifying top scientists with cutting-edge discoveries that have significant translational potential
• 2. =SITM:
• Skolkovo Institute of Translational Medicine
• Novel Treatments and drugs IP-Creating companies in Skolkovo
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Skolkovo is also uniquely qualified to catapult the medical care in Russia to the
much higher levels
• One can think about the MedTechSOP-Transfer enterprise in Skolkovo;
• The Medical Treatments, Standard Operating Procedures (SOP) and Technology transfer
• Top clinician-scientists of Dana Farber Cancer Institute, Harvard Institutes of Medicine,Harvard Medical School..
• A lot of people to persuade, but there is some initial interest..
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Molecular Weight
IgG Antibody
~ 25,000 atoms
hGH
~ 3000 atoms
0 200,000 350,000250,00050,000 150,000100,000 300,000
Factor VIII
~ 55,000 atomsN
eed
for
Tri
als
Biosimilars – Complexity leads to unknowns - If you don’t run trials – you won’t know the safety or efficacy
Aspirin
21 atoms
COOH
OCOCH3
Complexity of biotech products
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Drug Discovery from Uncultur-able before Microorganisms
● 99% of all species of microorganisms on the planet do not grow in the lab
● Millions of new species, an enormous untapped resource for drug discovery
● A general method to grow uncultured microorganisms developed based on
cultivation in situ in diffusion chamber and subsequent “domestication” for
growth in the lab
● Growth factors for many uncultured species identified, an additional tool for
growing them in the lab
Patent: US 7,011,957
Kaeberlein et al., Science 296:1127-1129.
Schumacher et al., 2009. Science 323:396-401.
Dörr et al., PLoS Biol 8(2): e1000317.
Lewis, K. 2007. Nature Rev. Microbiol. 5:48-56.
D’Onofrio et al., 2010. Chem. & Biol. 17: 254–264.
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IP-generating drug discovery in Russia
• “Fishing expeditions”….
• But fishing expeditions DO catch fish!
• Some times…
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Plasma
Collection
Plasma
Normalization
Patent pending
Shotgun
ImmunizationNascent library
generation
Library characterization
screening
HT Hybridoma
Cloning
mAb validation
ELISA
mAb
Production
mAb microarray
Production
Generation of the BSI mAb library against native human plasma proteins
using mAb proteomics (patent pending)
QuantiPlasma™
PlasmaScan™
Microarray
Libraries
>600 mABs
Characterization
mAb/epitope/protein ID
“10 000 mABs”
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An Open Forum on the Scientific and Regulatory Issues
of Biosimilars and Follow-on Biologics
Boston, MA USA
Copley Marriott Hotel
Address by:
Senator Edward Kennedy
Chairman of the Senate Health,
Education, Labor and Pensions
Committee
Plenary by:
Dr. Randall Lutter
Acting Deputy Commissioner
for Policy, US FDA
Organizing Chair:
Prof. Barry Karger
Director, Barnett Institute, and
James L. Waters Chair,
Northeastern University
Hosted by:
A high level meeting of the international biotechnology and generics industries, together with government regulators and academic laboratories, for an open
forum and collegial debate on the scientific and regulatory issues in the introduction of generic complex biological drugs.
www.barnett.neu.edu/biogenerics/
For additional information or to receive updates, email [email protected]
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BIOSYSTEMS INTERNATIONAL
The antibody technology company
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