Future trends and perspectives in modern pharmaceutical biotechnology

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PharmaCon2007 Congress, Dubrovnik, Croatia "New Technologies and Trends in Pharmacy, Pharmaceutical Industry and Education" http://www.pharmacon2007.com
Abstract is available at http://www.pharmaconnectme.com

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  • it is a fantastic representation in the biopharmaceutical techology
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  • good information in biopharmaceutical
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Future trends and perspectives in modern pharmaceutical biotechnology

  1. 1. FUTURE TRENDS AND PERSPECTIVES IN MODERN PHARMACEUTICAL BIOTECHNOLOGY Prof. Borut Štruk elj Faculty of Pharmacy, UL, Slovenia BWP, EMEA London Ph. Eur. Strasbourg
  2. 2. Pharmaceutical biotechnology Traditional biotechnology -secondary metabolites -antibiotics -steroids -vitamins, etc Modern biotechnology -recombinant proteins -monoclonal antibodies -gene therapy -transgenic organisms
  3. 3. What is a modern pharmaceutical biotechnology? keyword: “ PHARMACEUTICAL BIOTECHNOLOGY” GOOGLE 1996: app. 35.000 hits GOOGLE 2006: app: 3.220.000 hits ! Pharmaceutical biotechnology: the use of living things or parts in order to create or modify drugs Modern pharmaceutical biotechnology: the use of living things or parts by means of recombinant DNA technology in order to create or modify drugs and physiological targets
  4. 4. From the starting point of protein pharmaceuticals…. 100 Years ago Serum Therapy 1893 Emil von Behring immunizing a “ serum-horse”
  5. 5. … .to modern biotech
  6. 7. Trends and perspectives <ul><li>1 st generation of biopharmaceuticals </li></ul><ul><li>2 nd generation of biopharmaceuticals </li></ul><ul><li>Introduction of biosimilars </li></ul><ul><li>Novel technologies for R&D and advanced drug delivery </li></ul><ul><li>Gene therapy and tissue engineering </li></ul><ul><li>Personalised drug therapy </li></ul>
  7. 8. Biopharmaceuticals or protein drugs have proven to be safe and effective therapies in many disease indications The 1 st generation biopharmaceuticals Replacement therapies (mimic the normal function of a protein) “ Antagonist” therapies (in which protein function is inhibited - usually antibodies) Many successful products: Erythropoietin, insulin, human growth hormon (HGH), interferons (IFNs), granulocyte colony-stimulating factor (G-CSF), etc.
  8. 9. Cytokines Hormones Coagulation factors/ Antibodies Vaccines and antagonists and peptides Inhibitors Abciximab Hepatitis Vaccine Interferon alfacon-1 Insulin Eptacog alfa Adalimumab LymeDiseaseVaccine Interferon alfa-2a Antihemophilic Alemtuzumab Diphtheria/Tetanus/ Interferon alpha-2b Factor (3) Arcitumomab Pertussis Vaccine Moroctocog alfa Basiliximab Rotavirus Vaccine (FVIII mutein) Bevacizumab Interferon beta-1a Epoetin alfa Nonacog alpha Gemtuzumab Enzymes Interferon beta-1b Epoetin beta Desirudin Ibritumomab Alteplase (t-PA) Interferon gamma-1b Lepirudin Infliximab Reteplase Aldesleukin (IL-2) Drotrecogin-alfa Palivizumab Tenecteplase (TNK-t-P) Filgrastim (G-CSF) Follitropin alfa (Protein C act.) Rituximab Monteplase Follitropin beta  1-Proteinase Trastuzumab Dornase-alfa (RNase) Lenograstim (G-CSF) Somatropin i nhibitor Omalizumab Imiglucerase Molgramostim (GM-CSF) Glucagon Efalizumab Agalsidase alfa and beta Sargramostim (GM-CSF) Teriparatide (PTH 1-34) Catuximab Laronidase Tasonermin (TNF-a) Salmon Calcitonin Daclizumab Rasburicase Becaplermin (PDGF-BB) Thyrotropin-alfa Panitumumab Oprevelkin (IL-11) Choriogondotropin A2 Ranibizumab Anakinra (IL-1-RA) Osteogenic Protein-1 Fusion Proteins Dibotermin alpha (BMP-2) Denileukin diftitox Pegvisomant (hGH antagonist) Etanercept Nesiritide (natriuretic peptide) Alefacept Lutropin-alfa 1st generation of biopharmaceuicals
  9. 10. Limitations of the 1 st generation biopharmaceuticals: <ul><li>Marketed drugs are differently produced nature proteins, with unoptimized physico-chemical properties. Native proteins have not evolved to be human drugs, but to serve a specific function in the body. As such they are often deficient in important drug qualities such as solubility, stability, half-life, potency, recombinant expression yields, reduced immunogenicity. </li></ul><ul><li>Drug activity is largely restricted to nature’s existing repertoire of biological activities. Agonists are not easily transformed into antagonists. </li></ul>
  10. 11. The Problem with Proteins <ul><li>Generally </li></ul><ul><li>Very large and unstable molecules (prone to denaturation, a ggregation , p recipitation , a dsorption , d eamidation , o xidation , d isulfide exchange , p roteolysis ...) </li></ul><ul><li>Structure is held together by weak noncovalent forces </li></ul><ul><li>Easily destroyed by relatively mild storage conditions </li></ul><ul><li>Easily destroyed/eliminated by the body </li></ul><ul><li>Hard to obtain in large quantities </li></ul><ul><li>In the body </li></ul><ul><li>Elimination by B and T cells </li></ul><ul><li>Proteolysis by endo/exo peptidases </li></ul><ul><li>Small proteins (<30 kD) filtered out by the kidneys very quickly </li></ul><ul><li>Unwanted allergic reactions may develop (even toxicity) </li></ul><ul><li>Loss due to insolubility/adsorption </li></ul>
  11. 12. Desired Drug Properties <ul><li>Increased physico-chemical stability (thermal stability, longer shelf-life) </li></ul><ul><li>Improved solubility and formulation </li></ul><ul><li>Improved potency </li></ul><ul><li>Reduced immunogenicity </li></ul><ul><li>I ncreased proteolytic resistance </li></ul><ul><li>Improved half-life in serum </li></ul><ul><li>R educed toxicity </li></ul><ul><li>Increased bioavailability </li></ul><ul><li>Faster or slower onset of action </li></ul><ul><li>Elimination of degradation products </li></ul><ul><li>Introduction of novel functions </li></ul><ul><li>Alternative, non-parenteral routes of delivery (e.g. pulmonary, transdermal, nasal, oral..) </li></ul><ul><li>Economically favorable production systems </li></ul>
  12. 13. Trends and perspectives <ul><li>1 st generation of biopharmaceuticals </li></ul><ul><li>2 nd generation of biopharmaceuticals </li></ul><ul><li>Introduction of biosimilars </li></ul><ul><li>Novel technologies for R&D and advanced drug delivery </li></ul><ul><li>Gene therapy and tissue engineering </li></ul><ul><li>Personalised drug therapy </li></ul>
  13. 14. 2nd Generation Biopharmaceuticals: Transforming Proteins into Protein Drugs with Improved Properties Post-production modification derivatization, conjugation (PEGylation , polysialylation, HESylation, fatty acid group derivatization) Amino acid engineering From single mutations to large scale modifications (chimeric or humanized mAbs), introduction/removal of glycosylation sites, introduction/removal of cysteines, introduction of unnatural amino acids, alteration of protease sensitive regions, removal of agretopes to reduce immunogenicity, removal of deamidation-prone Asn, substitution of expoased non-polar amino acids, etc. Protein-protein fusions (IgG, IgG1 Fc, albumin, transferrin, Hsp 65, antibodies or their fragments) New drug delivery systems (liposomes, nanoparticles, microparticles)
  14. 15. <ul><li>PEGylation is currently the main approach for improving protein therapeutic value fulfilling many of the required protein drug properties: </li></ul><ul><li>Increases in vivo half life (4-400X) </li></ul><ul><li>Decreases immunogenicity </li></ul><ul><li>Increases protease resistance </li></ul><ul><li>Increases solubility & stability </li></ul><ul><li>Reduces depot loss at injection sites </li></ul>PEGylation In solution the PEG begins to move rapidly, sweeps out a large area (hydrodynamic volume) and protects in this way the protein from environmental influences . Protein  PEG-Protein In vitro activity: 100 % reduced In vivo activity: 100 % enhanced 30–50 nm 5 nm
  15. 16. Future trends : app 500 biotech drugs in clinical trials in 2007 480 are protein-based, 11 gene therapy, 14 antisense DNA or RNAi-based products
  16. 17. 2 nd generation: Insulins
  17. 18. 2nd generation: Darbepoietin
  18. 19. Trends and perspectives <ul><li>1 st generation of biopharmaceuticals </li></ul><ul><li>2 nd generation of biopharmaceuticals </li></ul><ul><li>Introduction of biosimilars </li></ul><ul><li>Novel technologies for R&D and advanced drug delivery </li></ul><ul><li>Gene therapy and tissue engineering </li></ul><ul><li>Personalised drug therapy </li></ul>
  19. 20. Proteins vs SCE: complexity Size Structure Modification Stability Epoetin Aspirin Denaturation, Aggregation, Degradation, Oxidation, ... Glycosylation, Acylation, etc.
  20. 21. IgG Antibody ~ 25,000 atoms Aspirin 21 atoms hGH ~ 3000 atoms Large Biologic Small Molecule Drug Large Molecule Drug Car ~ 3000 lbs F16 Jet ~ 25,000 lbs (without fuel) Bike ~ 20 lbs Proteins: Size, Structure & Complexity Complexity Size Source: Genentech
  21. 22. Manufacturing of recombinant Proteins is a complex p rocess DNA Vector Cloning into DNA Vector Large-scale Fermentation Downstreaming Transfer into Host Cell, Expression, Screening/Selection e.g., bacterial or mammalian cell Formulation
  22. 23. Biosimilars Manufacturers: Different Process – different Product Maybe the same genetic sequence (Probably) a different DNA vector A different recombinant cell expression system A different fermentation process A different downstreaming protocol Different in-process controls Maybe a different formulation A second manufacturer uses... DNA Vector Cloning into DNA Vector Large-Scale Fermentation Downstreaming Formulation Transfer into Host Cell, Expression e.g., bacterial or mammalian cell
  23. 24. Two complex biopharmaceuticals cannot be „the same “ but „similar“ <ul><li>IDENTICAL </li></ul><ul><li>The product attributes are the same as those of the comparator drug (difficult for complex products) </li></ul>Therefore, “Biogenerics” cannot exist. Pictures taken from: http://savingsandclone.com/news/press_room.html <ul><li>SIMILAR </li></ul><ul><li>The product attributes are similar enough to establish the same safety and efficacy as the comparator drug </li></ul>
  24. 25. Trends and perspectives <ul><li>1 st generation of biopharmaceuticals </li></ul><ul><li>2 nd generation of biopharmaceuticals </li></ul><ul><li>Introduction of biosimilars </li></ul><ul><li>Novel technologies for R&D and advanced drug delivery </li></ul><ul><li>Gene therapy and tissue engineering </li></ul><ul><li>Personalised drug therapy </li></ul>
  25. 26. Phage display technology <ul><li>Development of: </li></ul><ul><li>-recombinant antibodies </li></ul><ul><li>New peptidic ligands </li></ul><ul><li>Peptidomimetic drugs </li></ul>
  26. 27. Trends and perspectives <ul><li>1 st generation of biopharmaceuticals </li></ul><ul><li>2 nd generation of biopharmaceuticals </li></ul><ul><li>Introduction of biosimilars </li></ul><ul><li>Novel technologies for R&D and advanced drug delivery </li></ul><ul><li>Gene therapy and tissue engineering </li></ul><ul><li>Personalised drug therapy </li></ul>
  27. 28. Future trends: Gene therapy 1939 2007
  28. 29. Gene therapy
  29. 30. Future trends: Gene therapy <ul><li>Viral </li></ul><ul><li>Non-viral </li></ul>a) In vivo b) In vitro, c) Ex vivo a) Somatic b) Stem cell Target cells: Technology: DNA transfer:
  30. 31. Gene therapy-delivery
  31. 32. “ Ex vivo” gene therapy of severe combined immunodeficiency (SCID)
  32. 33. Gene therapy-gene silencing
  33. 34. Cell and tisssue engineering
  34. 35. Trends and perspectives <ul><li>1 st generation of biopharmaceuticals </li></ul><ul><li>2 nd generation of biopharmaceuticals </li></ul><ul><li>Introduction of biosimilars </li></ul><ul><li>Novel technologies for R&D and advanced drug delivery </li></ul><ul><li>Gene therapy and tissue engineering </li></ul><ul><li>Personalised drug therapy </li></ul>
  35. 36. … .and long-term future perspective? ???

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