the spatial innovation biography of a successful monoclonal antibody

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


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


• How influence the changes of industrial organization

innovation systems as well as research, development

and commercialization of new technologies and

therapeutic active substances?

Question


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


Theoretical framework


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



• 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?







5. Conclusions


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


“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




3. Antibodies: a slow breakthrough of a new technology


5. Conclusions


Three key technologies in the 1970s

Technological pathsMarkets

Products


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



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



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.



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




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






5. Conclusions


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)


Sales of Rituxan / MabThera: « a blockbuster »

The most successful biotech drug!


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-



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


Knowledge and proximity






5. Conclusions


• 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.


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


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


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



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


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


the spatial innovation biography of a successful monoclonal antibody

Documents

dynamics of innovation

dbendorfchristian zeller

questionsthe pharmabiotech

slow breakthrough

cirus workshop

forum chriesbach

path dependency

therapeutic active substances