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The spatial innovation biography of a successful monoclonal antibody

The spatial innovation biography of a successful monoclonal antibody. Christian Zeller April 17, 2007 CIRUS Workshop on Innovation, Institutions, and Path Dependency, Forum Chriesbach, Eawag, Dübendorf. Presentation. Theoretical bases and questions The pharma-biotech-complex

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The spatial innovation biography of a successful monoclonal antibody

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  1. The spatial innovation biography of a successful monoclonal antibody Christian ZellerApril 17, 2007CIRUS Workshop on Innovation, Institutions, and Path Dependency,Forum Chriesbach, Eawag, Dübendorf

  2. Presentation • Theoretical bases and questions • The pharma-biotech-complex • Antibodies: slow breakthrough of a new technology • The spatial innovation biography of the drug • Conclusions Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  3. 1. Theoretical bases Industrial organization in the pharmaceutical and biotech industries Research Development Production Sales Universi-ties Until mid-1970s Pharma-cies,clinics Transnational pharmaceuticals National pharmaceuticals Pharma-cies,clinics 1980s and 90s Transnational pharmaceuticals Universities Biotech companies Specialized pharmaceuticals Contract manufacturing Contract Research Org. Pharma-cies, clinics Transnational pharmaceuticals Possible tendency Universities Specialized pharmaceuticals HMOs Biotech companies Contract manufacturing Contract Research Org. Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  4. 1. Theoretical bases Question • How influence the changes of industrial organization innovation systems as well as research, development and commercialization of new technologies and therapeutic active substances? Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  5. 1. Theoretical bases Theoretical framework Macro-societal and economic context Mode of regulation Accumulation regime Technology generation and evolution technological system Industrial organization in a sector, markets sectoral innovation system Design space Institutional rules Actors and organizations Market conditions, industrial organization

  6. 1. Theoretical bases Sectoral, national and regional innovatio systemstechnological systems Financial system Knowledge base Learning process through interaction Organizations Inputs Sectoral innovation system Demand Technological system Companies Technologies Individuduals RegulationInstitutions, rules, coordination, cultural context Regional innovation system Nationalinnovation system Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  7. 1. Theoretical bases More precise questions • How are organized and structured the flows of resources, knowledge and values in a technological system? (power relations) • How institutional changes, particularly at intellectual property rights, influence the organization and dynamics of innovation systems? Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  8. Theoretical bases and questions • The pharma-biotech-complex • Antibodies: slow breakthrough of a new technology • The spatial innovation biography of the drug • Conclusions Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  9. 2. The Pharma-Biotech-Complex Arenas of innvation and north-atlantic innovation relations Quebec / Montreal Lund/Kopenhagen Boston c a Oxford / Cambridge a a b C New Jersey Rheinland A Bay Area b Rhein / Main / Neckar Paris München c a b b B Basel Maryland b Research Triangle Park 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 A a c a b San Diego 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 Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  10. 2. The Pharma-Biotech-Complex 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. “As a ‘pharma guy’ who makes therapies I compbine the keys and I play the music” (Interview, March 6, 2001). Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  11. Theoretical bases and questions • The pharma-biotech-complex • Antibodies: a slow breakthrough of a new technology • The spatial innovation biography of the drug • Conclusions Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  12. 3. Antibodies: a slow breakthrough of a new technology Technological paths Markets Products Three key technologies in the 1970s 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 Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  13. 3. Antibodies: a slow breakthrough of a new technology 1975: Monoclonal antibodies from hybridoma cells • 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 Sang Melanoma cells B-cells from spleen Fusion Hybridoma cells Selection of hybridoma cells with antibody activity, culture of selected cell lines (clones) from positive cell cultures monoclonal antibodies Quelle: Der kleine LaRoche (2003: 15)

  14. 3. Antibodies: a slow breakthrough of a new technology At the beginning no patents!Then multiplication of intellectual property monopolies! • 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. Soon, each aspect of their production was enclosed by patents. Subsequent users are forced to pay royalties (cf. Zeller 2007). Institutional change Currently, about 100 recombinant biotech drugs are on the market, 21 of them are monoclonal antibodies. Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  15. 3. Antibodies: a slow breakthrough of a new technology Monoclonal antibodies approved by the FDA First product: 11 years after invention of basic technique. Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  16. 3. Antibodies: a slow breakthrough of a new technology Intellectual property monopolies on each aspect of production Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  17. 3. Antibodies: a slow breakthrough of a new technology 1975 1984 1986 1990 1994 2006 Panitumumab (Vectibix) • 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

  18. Theoretical bases and questions • The pharma-biotech-complex • Antibodies: slow breakthrough of a new technology • The spatial innovation biography of the drug • Conclusions Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  19. 4. The spatial innovation biography of the drug Sales of Rituxan / MabThera: « a blockbuster » The most successful biotech drug! Quelle: Informationsdienst Biotechnologie (http://www.i-s-b.org/business/rec_sales.htm) Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  20. 4. The spatial innovation biography of the drug Rituxan / MabThera (Rituximab) Basic research 1970s Manufacturing 1993/1997- Preclinical R&D 1991-93 Clinical devel., clinical trials 1993-1997 1997-? Sales 1997- Applied research / discovery 1980s Lee Nadler, Dana Farber, Boston Antigen CD20 1980 IDEC Nabil Hanna, A. Grillo-López Phase I/II1993-4 Phase II 1994-95 Phase III 1995-96 Phase II 1995-98 Idec, OceansideUp-scaling Milstein/Köhler, Cambridge, Basel Hybridoma, Antibodies 1975 IDEC Mitchell Reff et.al Engineering of Rituximab Preclinical (safety, toxicology) Ronald Levy, Stanford Univ., Palo Alto IDEC, San Diego 1991 Genentech, Vacaville G./.F. Stevenson, Univ. Southampton B-cell lymphoma 1976 IDEC/ Genentech IDEC, San DiegoOceanside Genentech U.S. South San Franciso Roche Lizenz Roche EU Basel Lonza Biologics, Portsmouth, NH Chugai Zenyaku Kogyo Japan Zenyaku Kogyo Glaxo-Wellcome Patentstreit Columbia Univ.) Patentstreit Patent Lizenz Collaboration with NCI: Extension to further therapeutic potentials Lizenzgebühren für Patent Pharma. Partners Royalty Pharma Schaffhausen Celltech, GB patent (manuf. Antibodies) Glaxo-Wellcome (Coulter – SmithKline Beecham 1998 Verkaufskooperation Bexxar Xoma Berkeley AntiCD20 patent Patent sold 1997 Knowledge flows Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  21. 4. The spatial innovation biography of the drug What does us say this example? • 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 Knowledge and proximity Role and financing of universities Hierarchies of innovation and production networks Aspect of increased influence of placement (financial) capital Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  22. Theoretical bases and questions • The pharma-biotech-complex • Antibodies: slow breakthrough of a new technology • The spatial innovation biography of the drug • Conclusions Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  23. 5. Conclusions Innovation systems • Innovation systems consist of power hierarchies. TNC are on the top of these cascades of power, financial flows and governance of innovation systems. • 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 Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  24. 5. Conclusions Societal challenges • Innovation deficit • Problem of contradicting cycles • Which demand and which needs? • Democracy Challenges for innovation research • Technological systems and power relations in a changed configuration of capitalism! • Consider financing and institutional changes! Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  25. Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  26. Xolair (Omalizumab) Grundlagen-forschung 1970s Produktion 2003- Präklinische F&E 1991-93 Klinische Entw. 1994-2004 Verkauf 2003- Angewandte Forschung / Wirkstoff-findung 1980s PDL Fremont John Hopkins University Baltimore Texas University Houston Tse Wen Chang Patentstreit 199?-2003 Ciba / Novartis Basel Phase II 1996 Phase III 1999-2003 Up-scaling Royalities Milstein/Köhler, Cambridge, Basel Hybridoma, Antibodies Genentech USA Tanox Houston TNX-901 Royalities Tanox Houston TNX-901 Phase I Phase II Genentech, Vacaville Tanox Tse Wen Chang Houston Engineering of Anti-IgE1989 Tanox Houston Entdeckung IgE 1968 Royalities Novartis Huningue Patent-streit 1993-2003 Novartis except USA Genentech verhindert Entwicklung von TNX-901 gegen Erdnussallergie Genentech South San Franciso Phase I/II1994 Phase II 1994-98 Phase III 1999-2003 Up-scaling Genentech Houston Engineering of Anti-IgE1989 Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  27. Tamiflu (Oseltamivir) und Relenza (Zanamivir) Grundlagen-forschung 1980s Produktion 1999- Präklinische F&E 1994-96 Klinische Entw. 1996-99 Verkauf 1999- Angewandte Forschung / Wirkstoff-findung 1990s-1995 China Natural Shikimiacid from Sternanis plant Gilead Sciences DSM GrenzachIntermediate Product (Shikimiacid) EinlizenzierungSep. 1996 Lizenzgebühren Gilead SciencesFoster City GS 4071 GS4104 Roche Boulder Basel Tamilfu Gilead Sciences Nobert Bischoffberger Foster City GS 4071 Roche Welwyn GS4104 Roche ? CIpla India Patent Streitigkeiten? Öffentlich zugängliches Wissen Monash University Parkville, Aus 1983 mechanism of virus Vietnam Indonesia Kooperation GlaxoSmithkline Relenza GlaxoSmithKline Relenza GlaxoWellcome GG167 Biota Australia GG167 Glaxo GG167 Lizenzgebühren Biota Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  28. 4. The spatial innovation biography of the drug Combined basic and applied technologies in the innovation path of rituximab Monoclonal antibodies with hybridoma cells Köhler & Milstein Cambridge 1975 Discovery of CD20, creation of an Anti-CD20 monoclonal antiibody Lee Nadler, Boston 1980 Chimerization of murine antibodies Morrison, et. Al. New York, Palo Alto, Mountain View 1984 Rituximab Chimerization of murine anti-CD20 Mitchell Reff San Diego drug target: malignant B-cell displays “marker” protein G & F. Stevenson Southampton 1975? Anti-Idiotype monoclonal antibodies Ron Levy, Palo Alto 1981/82 CHO cell line Larry Chasin New York Manufacturing method based on CHO cell line expression vector Mitchell Reff San Diego Technology to make recombinant DNA Berg, Boyer, Cohen 1972 Expression vector Kline & French Lab., Philadelphia Polymerase Chain Reaction (tool) Mullis et al. Emeryville 1984 tool

  29. Geographie des Medikaments Zentrale Arbeitsschritte in der F&E von Therapeutika Klinische Studien Phase IV Marketing Entwicklungevtl. neueIndikationen Phase I Sicherheit gesunde Freiwillige Phase III Vergleichstudien mit Standard-therap. Phase II Wirkung bei Patienten Zulassungsprüfung Wirkstoff-findung Präklinische Entwicklung > 4 Jahre 1.5 Jahre 6 Jahre Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

  30. 1. Theoretical bases Concentrated financial capital increasingly influences innovation systems Power of concentrated placement capital Institutional changes • New organizational forms and extension of financial markets • Intellectual property rights • Changed role of publicly funded research • Pension funds, investment funds, venture capital funds • Liquid stock markets, Shareholder value-drivenCorporate Governance • Competitive regime shaped by TNCs Christian Zeller: The spatial innovation biography of a successful monoclonal antibody

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