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The spatial innovation biography of a successful
monoclonal antibody
Christian Zeller
April 17, 2007CIRUS Workshop on
Innovation, Institutions, and Path Dependency,Forum Chriesbach, Eawag, Dübendorf
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
1. Theoretical bases and questions
2. The pharma-biotech-complex
3. Antibodies: slow breakthrough of a new technology
4. The spatial innovation biography of the drug
5. Conclusions
Presentation
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
Research Development Production Sales
Until mid-1970s
Transnational pharmaceuticalsUniversi-
ties
1. Theoretical bases
National pharmaceuticals
Pharma-cies,
clinics
1980s and 90s
Possible tendency
Transnational pharmaceuticals
Contract Research Org.Contract manufacturing
Universities
Biotech companiesSpecialized pharmaceuticals
Pharma-cies,
clinics
Transnational pharmaceuticals
Biotech companiesContract Research Org.
Universities
Specialized pharmaceuticals
Pharma-cies,
clinics
HMOs
Contract manufacturing
Industrial organization in the pharmaceutical and biotech industries
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
• How influence the changes of industrial organization
innovation systems as well as research, development
and commercialization of new technologies and
therapeutic active substances?
Question
1. Theoretical bases
Design space
Actors and organizations
Institutional rules
Market conditions, industrial organization
Mode of regulation
Accumulation regime
Macro-societal and economic context
Technology generation and evolution technological system
Industrial organization in a sector, markets sectoral innovation system
1. Theoretical bases
Theoretical framework
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
Sectoral, national and regional innovatio systemstechnological systems
Knowledge base
Inputs
Demand
Individuduals
RegulationInstitutions, rules, coordination, cultural context
Organizations
Companies
Regional innovation system Nationalinnovation system
Sec
tora
l inn
ovat
ion
syst
em
Learning process through interaction
Technological system
Financial system
Technologies
1. Theoretical bases
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
• How are organized and structured the flows of
resources, knowledge and values in a
technological system? (power relations)
More precise questions
• How institutional changes, particularly at
intellectual property rights, influence the
organization and dynamics of innovation systems?
1. Theoretical bases
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
1. Theoretical bases and questions
2. The pharma-biotech-complex
3. Antibodies: slow breakthrough of a new technology
4. The spatial innovation biography of the drug
5. Conclusions
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
ResearchTriangle Park
a
A
a
a
a
b
Bbb
b
b
b
C
c
c
c
Bay Area
San Diego
Boston
New Jersey
Maryland
Oxford / Cambridge
München
Paris
Rheinland
Basel
Rhein / Main / Neckar
Arenas of innvation and north-atlantic innovation relations
A
a
Big pharma: headquarters and most important Centers of Excellence
Big pharma: Centers of Excellence
Biotech companies
Financial institutions
Research institutes
Innovation arenas and hubs
Innovation relations structured by oligopolistic rivals
Quelle: Zeller, Christian (2004): North Atlantic innovative relations of Swiss pharmaceuticals and the importance of regional biotech arenas, Economic Geography 80 (1): S. 83-111
Quebec / Montreal
a
Lund/Kopenhagen
2. The Pharma-Biotech-Complex
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
“As a ‘pharma guy’ who makes
therapies I compbine the keys
and I play the music”
(Interview, March 6, 2001).
Paul Herrling, Global Head of Research of Novartis
Pharmaceuticals, compared himself with a piano player.
Each biotech firm represents a key and large
pharmaceutical company puts the piano together.
2. The Pharma-Biotech-Complex
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
1. Theoretical bases and questions
2. The pharma-biotech-complex
3. Antibodies: a slow breakthrough of a new technology
4. The spatial innovation biography of the drug
5. Conclusions
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
Three key technologies in the 1970s
Technological pathsMarkets
Products
3. Antibodies: a slow breakthrough of a new technology
Recombinant DNA technologies
(Arber 1970; Nobel prize in medicine 1978),Boyer/Cohen 1973; Berg Nobel prize in chemistry 1980
Monoclonal Antibodies
(Jerne, Milstein/Köhler 1975; Nobel prize in medcine 1984)
Polymerase Chain Reaction (PCR)
(Mullis 1983; Nobel prize in Chemistry 1993)
Multiplication of biotechnologies
1975: Monoclonal antibodies from hybridoma cells
Quelle: Der kleine LaRoche (2003: 15)
• Georges Kohler and Cesar Milstein (1975) in Nature:
• Monoclonal antibodies are artificially produced against a specific antigen.
• Production of monoclonal antibodies with hybridoma technique.
• With this technique a group of lymphocytes producing all the same antibody protein is obtained.
revolutionizing diagnostic medicine.
Medicaments against cancer and infections.
Antigen
Melanoma cellsB-cells from spleen
Fusion
Sang
Selection of hybridoma cells with antibody activity, culture of selected cell lines (clones) from positive cell cultures
Hybridoma cells
monoclonal antibodies
3. Antibodies: a slow breakthrough of a new technology
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
Milstein und Köhler did not try to patent their invention!
Basic technology was freely accessible for subsequent scientists.
Revolution in immunology laboratories.
Foundation of numerous young companies and institutes which wanted to transfer monoclonal antibodies into efficient therapies.
At the beginning no patents!Then multiplication of intellectual property monopolies!
Soon, each aspect of their production was enclosed by
patents. Subsequent users are forced to pay royalties (cf. Zeller 2007).
Currently, about 100 recombinant biotech drugs are on
the market, 21 of them are monoclonal antibodies.
Institutional change
3. Antibodies: a slow breakthrough of a new technology
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
Monoclonal antibodies approved by the FDA
1. Appr. Product Companies Indication Royalties to
6/86 Orthoclone OKT3 Ortho Biotech (J&J) Verhinderung aktuter Abstoßung bei Nierentransplantation
-----
12/94 ReoPro Centocor (J&J); Lilly Vorbeugung gegen Verengung der Blutgefäße
Celltech
11/97 Rituxan IDEC Pharmaceuticals (Biogen Idec); Genentech; Roche
CD20-positives B-cell Non-Hodgkin's Lymphom
Celltech
12/97 Zenapax Protein Design Labs, Roche Vorbeugung aktuter Abstoßung bei Nierentransplantation
Celltech
5/98 Simulect Novartis Vorbeugung akuter Abstoßung bei Nierentransplantation
Celltech
6/98 Synagis MedImmune; Abbott Laboratories Vorbeugung ernster Erkrankun-gen der unteren Atemwege
Protein Design Labs, Celltech, Genentech Centocor
8/98 Remicade Centocor (J&J); Schering-Plough Hemmt Entzündungen,vermeidet Gelenkzerstörung
Genentech, Celltech
9/98 Herceptin Genentech; Roche Metastatisierender Brustkrebs Protein Design Labs, Celltech
5/00 Mylotarg Wyeth; Celltech Group akute myeloische Leukämie Protein Design Labs
5/01 Campath Genzyme (Ilex Onco-logy); Berlex Laboratories (Schering)
Chronisch, lympathische Leukämie
Cambridge University; BTG
First product:11 years after invention of basic technique.
3. Antibodies: a slow breakthrough of a new technology
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
1. Appr. Product Companies Indication Royalties to
2/02 Zevalin IDEC Pharmaceuticals (Biogen Idec); Schering
B-cell Non-Hodgkin's Lymphom GSK (Corixa)
12/02 Humira Cambridge Antibody Technology; Abbott Laboratories (Knoll/BASF)
Moderate bis ernsthafte rheumatoide Arthritis
CAT; MRC, Scripps und Stratagene (über CAT); Genentech
6/03 Bexxar Corixa (Coulter Pharmaceutical); GlaxoSmithKline
CD20-positive non-Hodgkin's lymphoma
University of Michigan
6/03 Xolair Genentech; Tanox; Novartis bis schwerem Asthma Bronchiale
Protein Design Labs
10/03 Raptiva Genentech; Xoma; Serono mittelschwerer bis schwerer Plaque-Psoriasis
Protein Design Labs
2/04 Avastin Genentech Darmkrebs Protein Design Labs
2/04 Erbitux ImClone Systems; Bristol-Myers Squibb
Dickdarmkrebs Genentech
11/04 Tysabri Biogen Idec; Elan Multiple Sklerose Protein Design Labs
06/06 Lucentis Genentech altersbedingte Makuladegeneration
Protein Design Labs, Xoma
09/06 Vectibix Abgenix (Amgen) fortgeschrittenem Darmkrebs nach erfolgloser Chemotherapie
03/07 Soliris Alexion Pharmaceuticals paroxysmal nocturnal hemoglobinuria
Protein Design Labs filed patent infringement
Intellectual property monopolies on each aspect of production
3. Antibodies: a slow breakthrough of a new technology
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
3. Antibodies: a slow breakthrough of a new technology
2006 Panitumumab (Vectibix)
1975
1984
1986
1990
1994
Technologies to reduce immunogenicity of monoclonal antibodies:
TIS:
• technological evolution towards
humanization, human antibodies
• innovation biography of drugs
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
1. Theoretical bases and questions
2. The pharma-biotech-complex
3. Antibodies: slow breakthrough of a new technology
4. The spatial innovation biography of the drug
5. Conclusions
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
Verkaufsentwicklung Rituxan/MabThera: ein Blockbuster
0
500
1000
1500
2000
2500
3000
3500
1997 1998 1999 2000 2001 2002 2003 2004 2005
mill
ion
US
D
Quelle: Informationsdienst Biotechnologie (http://www.i-s-b.org/business/rec_sales.htm)
4. The spatial innovation biography of the drug
Sales of Rituxan / MabThera: « a blockbuster »
The most successful biotech drug!
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
Rituxan / MabThera (Rituximab)
XomaBerkeley
AntiCD20 patent
Milstein/Köhler, Cambridge, Basel
Hybridoma, Antibodies1975
Lee Nadler, Dana Farber, Boston
Antigen CD201980
Ronald Levy, Stanford Univ.,
Palo AltoIDEC, San Diego
1991
G./.F. Stevenson, Univ. Southampton
B-cell lymphoma1976
Glaxo-Wellcome (Coulter – SmithKline
Beecham 1998 Verkaufskooperation
Bexxar
Glaxo-Wellcome Patentstreit
Columbia Univ.)Patentstreit
IDECMitchell Reff et.al
Engineering of Rituximab
Preclinical (safety, toxicology) IDEC/
Genentech
Roche
Chugai
Zenyaku Kogyo
Genentech, Vacaville
Lonza Biologics, Portsmouth, NH
IDEC, San DiegoOceanside
IDECNabil Hanna,
A. Grillo-LópezPhase I/II1993-4Phase II 1994-95Phase III 1995-96Phase II 1995-98
Idec, OceansideUp-scaling
Genentech U.S.South San Franciso
Zenyaku Kogyo Japan
Collaboration with NCI: Extension to
further therapeutic potentials
Roche EUBasel
Celltech, GBpatent
(manuf. Antibodies)
Pharma. Partners Royalty Pharma
Schaffhausen
Patent
Patent sold 1997
Lizenzgebühren für Patent
Liz
enz
Lizen
z
Knowledge flows
Basic research
1970s
Applied research / discovery
1980s
Preclinical R&D
1991-93
Clinical devel., clinical trials
1993-19971997-?
Manufacturing
1993/1997-
Sales
1997-
4. The spatial innovation biography of the drug
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
Synthesizing explicit and tacit knowledge: Decisive phases of innovation trajectory happen in close social and spatial proximity
Biotech companies transform basic knowledge of universities in marketable knowledge.
Pharmaceutical companies appropriate knowledge and technologies and are responsible for commercialization.
Intellectual property rights can take independent properties and be a pure financial asset
What does us say this example?
Role and financing of universities
Hierarchies of innovation and production networks
Aspect of increased influence of placement (financial) capital
4. The spatial innovation biography of the drug
Knowledge and proximity
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
1. Theoretical bases and questions
2. The pharma-biotech-complex
3. Antibodies: slow breakthrough of a new technology
4. The spatial innovation biography of the drug
5. Conclusions
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
• Institutional forms such as the regime of intellectual property rights, shape the innovation networks.
Hunting for intellectual property monopolies leads to a complex landscape of property rights and cascades of royalties.
Strategies for extracting rents
Innovation systems
5. Conclusions
• Innovation systems consist of power hierarchies. TNC are on the top of these cascades of power, financial flows and governance of innovation systems.
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
5. Conclusions
• Innovation deficit
• Problem of contradicting cycles
• Which demand and which needs?
• Democracy
Societal challenges
• Technological systems and power relations in a changed configuration of capitalism!
• Consider financing and institutional changes!
Challenges for innovation research
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
Xolair (Omalizumab)
Milstein/Köhler, Cambridge, Basel
Hybridoma, Antibodies
John Hopkins University
Baltimore
Texas UniversityHouston
Tse Wen Chang
TanoxTse Wen Chang
HoustonEngineering of Anti-IgE
1989
TanoxHoustonTNX-901
Genentech USA
Novartisexcept USA
Genentech, Vacaville
NovartisHuningue
GenentechSouth San Franciso
Phase I/II1994Phase II 1994-98
Phase III 1999-2003Up-scaling
Ciba / NovartisBasel
Phase II 1996Phase III 1999-2003
Up-scaling
TanoxHoustonTNX-901Phase I Phase II
Patent-streit
1993-2003Genentech verhindert
Entwicklung von TNX-901 gegen Erdnussallergie
Genentech Houston
Engineering of Anti-IgE1989
TanoxHouston
Royalities
Royalities
PDLFremont
RoyalitiesPatentstreit199?-2003
Grundlagen-forschung
1970s
Angewandte Forschung / Wirkstoff-findung1980s
Präklinische F&E
1991-93
Klinische Entw.
1994-2004
Produktion
2003-
Verkauf
2003-
Entdeckung IgE1968
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
Tamiflu (Oseltamivir) und Relenza (Zanamivir)
Gilead Sciences Nobert Bischoffberger
Foster CityGS 4071
Gilead SciencesFoster CityGS 4071GS4104
Gilead Sciences
RocheBoulderBasel
Tamilfu
DSMGrenzach
Intermediate Product(Shikimiacid)
RocheWelwynGS4104
Roche
Lizenzgebühren
Monash UniversityParkville, Aus
1983 mechanism of virus
Biota AustraliaGG167
GlaxoGG167
GlaxoSmithklineRelenza
GlaxoSmithKlineRelenza
GlaxoWellcomeGG167
Biota
EinlizenzierungSep. 1996
CIplaIndia
Indonesia
Vietnam
Patent Streitigkeiten?
Kooperation
Öffentlich zugängliches
Wissen
?
ChinaNatural Shikimiacid from Sternanis plant
Grundlagen-forschung
1980s
Angewandte Forschung / Wirkstoff-findung1990s-1995
Präklinische F&E
1994-96
Klinische Entw.
1996-99
Produktion
1999-
Verkauf
1999-
Lizenzgebühren
Monoclonal antibodies with hybridoma cellsKöhler & MilsteinCambridge 1975
drug target: malignant B-cell displays “marker” proteinG & F. StevensonSouthampton 1975?
Discovery of CD20, creation of an Anti-CD20 monoclonal antiibodyLee Nadler, Boston 1980
Chimerization of murine antibodiesMorrison, et. Al. New York, Palo Alto, Mountain View 1984
Expression vector
Kline & French Lab., Philadelphia
RituximabChimerization of murine anti-CD20Mitchell ReffSan Diego
Polymerase Chain Reaction (tool)Mullis et al.Emeryville 1984
Combined basic and applied technologies in the innovation path of rituximab
Anti-Idiotype monoclonal antibodiesRon Levy, Palo Alto 1981/82
CHO cell lineLarry ChasinNew York
Technology to make recombinant DNABerg, Boyer, Cohen 1972
tool
Manufacturing method based on CHO cell line expression vectorMitchell ReffSan Diego
4. The spatial innovation biography of the drug
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
Wirkstoff-findung
PräklinischeEntwicklung
Phase ISicherheitgesundeFreiwillige
Phase IIWirkung beiPatienten
Phase IIIVergleichstudienmit Standard-therap. Z
ula
ssu
ng
sp
rüfu
ng
Phase IVMarketingEntwicklungevtl. neueIndikationen
Klinische Studien
> 4 Jahre 1.5 Jahre 6 Jahre
Zentrale Arbeitsschritte in der F&E von Therapeutika
Geographie des Medikaments
Christian Zeller: The spatial innovation biography of a successful monoclonal antibody
Concentrated financial capital increasingly influences innovation systems
• Pension funds, investment funds, venture capital funds
• Liquid stock markets, Shareholder value-driven Corporate Governance
• Competitive regime shaped by TNCs
Power of concentrated placement capital
• New organizational forms and extension of financial markets
• Intellectual property rights
• Changed role of publicly funded research
Institutional changes
1. Theoretical bases