Modern Biopharmaceuticals: Recent Success Stories

This collection of high-profile contributions provides a unique insight into the development of novel, successful biopharmaceuticals.

Outstanding authors, including Nobel laureate Robert Huber as well as prominent company researchers and CEOs, present valuable insider knowledge, limiting their scope to those procedures and developments with proven potential for the biotechnology industry. They cover all relevant aspects, from the establishment of biotechnology parks, the development of successful compounds and the implementation of efficient manufacturing processes, right up to the establishment of advanced delivery routes.

• Language: English
• Publisher: Wiley
• Release date: May 7, 2013
• ISBN: 9783527669431

Book preview

Foreword by Andreas Busch

History and Future of Modern Biopharmaceuticals

It is my real pleasure to write a short welcoming note for the new book Modern Biopharmaceuticals – Recent Success Stories.

In the fashion of the first four volumes Modern Biopharmaceuticals – Design, Development and Optimization, when an introduction on the historical development of biopharmaceuticals was given by Nobel Laureate Robert Huber [1], this new edition starts with an historical outline of the evolution from traditional biotechnology 20 000 years ago to modern biotechnology as of today, presented by the editor [2]. Altogether, the book provides an overview of the most exciting innovations in biopharmaceutical development for the most pressing therapeutic areas with a high medical need. Each chapter highlights emerging research from some of the world's most respected scientists and managers who divulge their knowledge on how to transform the respective biotechnological treatment paradigms into cures for specific therapeutic areas. Modern Biopharmaceuticals also explores the current environment in healthcare and the pharmaceutical industry and examines drivers and challenges for the use of innovative biotechnologies for biopharmaceutical development.

Overall Biopharma Business

A snapshot of current biotechnology in Europe is given by some sector-specific diagnostic benchmarks from London-based Tefen Management Consulting [3] – similar to the first edition, which described the status of biopharmaceuticals in 2005 [4], and the impact of an ever-changing environment for pharmaceutical development, at that time from the perspective of McKinsey [5].

Process Optimization

In the first edition, the Bayer experience with different biopharmaceutical production systems was presented [6] and the industrial scale production of insulin by Novo Nordisk [7]. In this book, companies such as GE Healthcare Biosciences share their experience to cope with the increasing pressure by improving strategies and workflows [8], and Sartorius describe how they improve biopharmaceutical production by developing new and innovative process technologies [9].

Acceleration of Biopharmaceutical Development

This is followed by other technological improvements to design and produce modern biopharmaceuticals, for example, to increase cloning efficiency: previously the Gateway® system from Invitrogen was described [10], this time innovative technologies such as FastDigest® from Fermentas [11], and the IBA StarGate® expression cloning system [12]. Another approach to accelerate biopharmaceutical development is directed evolution to design smarter genetic libraries for effective biopharmaceuticals. Two examples were nicely described in the previous book by Nobel Laureate Manfred Eigen and colleagues from DirEvo (now a part of Bayer corporation) [13], and also by colleagues from Roche [14], now followed by another innovative technology with the same goal, applying a brute force method approach, Massive Mutagenesis® [15]. In addition, a new method of quantitative real-time PCR is presented to accelerate biopharmaceutical development [16].

Innovative Production of Biopharmaceuticals

Once the genetic blueprint of the modern biopharmaceutical is optimized and cloned into a high-level expression vector, the protein needs to be produced in an attractive host at a large and commercial scale. Besides the common commercial expression platforms, some highly innovative plant-based technologies were previously presented, for example, the moss bioreactor from greenovation [17], or the transient tobacco expression system magnICON™ from Icon Genetics [18]. Both systems are capable of designer glycosylation, (post-translational modification, PTM) and meanwhile, Icon Genetics was part of the Bayer Corporation to manufacture non-Hodgkin's lymphoma vaccines for phase I clinical trials. In this book, another striking example of plant-derived biopharmaceutical antibodies is presented: the world's first approved plantibody for human therapeutic use: all Cuban citizens born after 1980 received the hepatitis B vaccine, Heberbiovac. Over 12 million doses have been administered since 1992 in Cuba, and as a consequence, the Hepatitis B cases have fallen from more than 2000 per year (before vaccination began in 1992) to less than 50 a year now. This fantastic case study on vaccination against hepatitis B in Cuba shows how to efficiently apply biotechnology to foster economic growth and public health at the same time, also in developing countries [19].

Adjoining to transgenic plants, transgenic animals can also be used to cost-efficiently produce biopharmaceuticals. This was nicely shown with ATryn®, a human antithrombin III (AT) which is produced in transgenic goats, followed by easy downstream processing, that is, extraction from the goat's milk by cross-flow filtration which is used in the dairy industry since decades [20]. In the meantime, ATryn was approved in 2006 by the European Medicines Agency (EMA) for use in preventing clotting conditions during surgical procedures in patients with hereditary AT deficiency.

PTM

Regardless of the type of expression system (being it common commercial or designer), the main criterion to select a certain technology is the capability to perform specific PTMs – if required at all for the given biopharmaceutical. This important topic, including the genetic engineering of expression hosts to perform a particular type of PTM, is addressed by Gary Walsh, a real expert for biopharmaceutical development [21].

New Business Models and CROs

Since there are so many different hosts available, which have certain advantages over others for a given project, obviously not every pharma company can hold available all of them. Having said that, many companies source out the manufacturing of their biopharmaceutical to specialized CROs, as described in the chapter from Chemgineering [22]. To provide sufficient production capacity, and to be competitive with the growing number of CROs, some companies heavily invest into their bioreactor park. One imposing example is the new 6 × 15 000 liter facility from Boehringer Ingelheim [23]. One technology for easy downstream processing of such huge fermentation runs (with just one single step) was developed by Qiagen and is nicely described for large-scale purification of various biopharmaceuticals [24].

HIV, Clotting, Vaccination

Modern Biopharmaceuticals focuses on urging diseases such as HIV, hepatitis, pandemic influenza, cardiovascular, and clotting impairments. Some innovative approaches against HIV were previously described applying gene therapy [25] or combinatorial RNAs [26]. In this context, also RNA interference (RNAi) as one among the most significant scientific discoveries at the turn of the twenty first century (both for its impact on fundamental genetic research and on biotechnology and the development of biopharmaceuticals) was described, especially the rational design of siRNA by the leader in this emerging field, Dharmacon [27]. Due to the high relevance, Andrew Z. Fire and Craig C. Mello were awarded the Nobel Prize in Physiology or Medicine 2006 for their discovery of RNA interference – gene silencing by double-stranded RNA.

In addition, the important role of vaccines in the fight against human diseases was highlighted by the use of novel adjuvants to combat a widespread disease such as hepatitis [28]. In this new edition, two other innovative vaccination approaches from global players are presented: Chiron Vaccines/Novartis describe the design of HIV vaccines based on the HIV envelope immunogens [29], and Baxter present a case study on their fast production of a pandemic influenza vaccine [30]. Although the last outbreak was not as drastic as expected, it is only a question of when (rather than if) will there be other more vigorous outbreaks in the near future – morituri te salutant.

Clotting Cascade

Some contributions were focusing on clotting impairments and the underlying mechanisms such as serine protease activation [31] and possibilities to increase the activities of involved enzymes by rational design using 3D X-ray structures [32]. In addition, an efficient treatment for hemophilia was presented: the biotechnological production of Factor VIII from Baxter, ADVATE® [33], now followed by Kogenate® and its production in Bayer's unique high-throughput perfusion culture [34].

Molecular Imaging

Molecular imaging is an important technology platform for biopharmaceutical development, and its application for individualized medicine and use as theranostic were demonstrated by colleagues from Philips [35] and Schering (now Bayer corporation) [36]. Another important application is the in vivo molecular and functional imaging of cancer and cancer therapies with PET [37] or the specific targeting (and subsequent killing) of tumor cells, as described by Dario Neri from ETH Zurich, also founder of Philogen [38].

More recently, very exciting new modalities for imaging were developed and are presented by Andreas Briel, CEO of nanoPET [39], and also the innovative quantitative multispectral optoacoustic tomography (MSOT) [40].

mAbs

Dat census honores: With a global monoclonal antibodies (mAbs) market of about $15.6 billion in 2010, and a compound annual growth rate (CAGR) of 36.7% between 2002 and 2010, mAbs are the mainstay of modern biopharmaceuticals. Monoclonals are used in almost all disease areas, such as bone metastases and bone loss (due to cancer therapy), relapsing-remitting multiple sclerosis, metastatic nonsmall cell lung cancer (NSCLC), rheumatoid arthritis (RA), and HER2 breast cancer. Treatment for the latter disease with a monoclonal was highlighted in a contribution from Roche on Herceptin® and its role in individualized cancer therapy [41]. The big picture and a review of 30 years of monoclonal antibodies was pictured by a joint chapter of Amgen and Sartorius [42] and the impact of mAbs for drug development were described by Andreas Plückthun and Simon Moroney, founders of the leading company MorphoSys [43]. And in fact, just recently Morphosys reported good clinical activity of its anti-GM-CSF in phase 1b/2a clinical trial evaluating its previously described HuCAL antibody MOR103: the positive data make MOR103 the first anti-GM-CSF antibody to demonstrate clinical efficacy in RA. Of particular importance was the fast onset of action observed: within two weeks, up to 40% of patients achieved the required score – the antibody was safe and well-tolerated at all doses administered.

As we can see from these examples, mAbs are successfully used in almost all indications, and this is why the entire market is forecast to grow at a CAGR of more than 10% and to reach over $30 billion by 2017. This excellent perspective is also reflected in the current contribution from Amgen, focusing on advanced technologies in commercial mAb production [44].

Gene Therapy and Delivery

It goes without saying that gene therapy is a powerful approach to combat various diseases. Of utmost importance for gene therapy – and at the same time a challenge – is to introduce the gene of choice into the cells, and even more important, at the right position within the genome. A real expert in this demanding field is Bob Langer from MIT, who is also a member of the Alnylam Scientific Advisory Board (together with Nobel Laureate Phillip Sharp and Thomas Tuschl), who shared the experience with DNA delivery from microspheres [45]. This time Bob provides some new and exciting results from his experiments applying high-throughput biomaterials-mediated delivery of DNA and siRNA biopharmaceuticals [46].

One formidable gene therapy approach to not just cure a disease, but rather avoid mortality per se (or at least lead to longevity) would be a molecular fountain of youth. But is this really possible? As we age, the dying cells in our body are replenished through cell division. Unfortunately, with each cell division the parts of DNA at the ends of chromosomes – the telomeres – deteriorate. At some point, the shortened telomeres signal to the cell to stop dividing (and hence renewing), leading to tissue degradation. The responsible enzyme that keeps our chromosomes/telomeres (and thus our cells – and finally the entire body) young is called telomerase. Human telomerase is regulated during development by dramatically reduced expression in many somatic cells during embryonic development, and therefore, chromosome ends shrink with successive cell divisions. Thus, the roles of telomerase in both, cellular immortality and cancer, are vibrant areas of current research.

Nobel Laureate Thomas R. Cech previously divulged his knowledge on telomerase and its role of reaching longevity: if one could introduce more telomerase into the cells by gene therapy, this would be a silver bullet for longevity [47]. And in fact, just recently scientists injected mice with the telomerase gene, which then slowed the cellular aging process by extending the dwindling telomere ends. This gene therapy with one-year-old mice (considered adults) extended their lifespan by 24% – and so far it is completely safe. Not only did the mice live longer, but they reaped beneficial effects across a range of conditions associated with aging, including insulin sensitivity, osteoporosis, and physical coordination. But is this approach also applicable for men? Adding telomerase to human cells in culture allowed them to extend their lifespans by at least an extra 20 divisions. And genetically engineered (transgenic) mice lived 40% longer and showed improved glucose tolerance, coordination, and less inflammation compared to normal mice. But genetically engineering people (transgenic human) is obviously not an option (yet), so telomerase gene therapy (such as the injectable virus in the current study, extending the lifespans of mice) is a much more conceivable approach for humans.

Other approaches for longevity in humans (especially the application of sirtuins) are discussed by Nobel Laureate Robert Huber together with his former student, the editor, Jörg Knäblein.

Rather than treating mortality, other approaches focus on gene therapy to treat specific diseases such as chronic myocardial ischemia [48] and other human chronic diseases [49]. In this context, smart minimal genetic vectors were previously described [50] and now tools are presented to precisely introduce the genetic information of choice at the right position in the genome [51].

Embryonic and Other Stem Cell Research

Cell therapy and transplantation medicine is another very powerful and promising field of modern biopharmaceuticals. Although organ transplantation has been one of the major medical advances of the past 40 years, it is becoming increasingly apparent that the supply of organs is limited and will not improve with current medical practice. Another issue is that donor and patient have different genetic make-ups, which can lead to rejection of the transplanted organ by the recipient. Also, it cannot be ruled out completely that contaminations with viruses or other adventitious agents occur in the course of transplantation. Organogenesis represents a welcome alternative to combat organ shortage, possible rejection, and also to prevent that the recipient will be infected with whatever contamination from the donor. Therapeutic cloning, or the creation of regenerative biopharmaceuticals from the patient's own cells, is the solution of choice. But organogenesis of complex tissues, such as the kidney, requires a coordinated sequential transformation process, with individual stages involving time-dependent expression of cell–cell, cell–matrix, and cell–signal interactions in all three dimensions. Embryonic precursor tissues are composed of functionally diverse stem/progenitor cell types that are organized in spatially complex arrangements. The theme of temporal–spatial patterning of progenitor cell interactions is programed in precursor tissues leading to their growth and development. Two striking examples to repair infarcted myocardium with stem cells were previously presented by colleagues from Harvard using mesenchymal stem cells [52] and from Israel Institute of Technology using embryonic stem cells [53]. The creation of an entire organ, namely an artificial kidney, was pictured by Yair Reisner from the Weizmann Institute of Science [54]. We now even present an artificial heart: engineered human heart tissue which spontaneously starts pumping [55].

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) could also be used to directly help repair damaged heart muscle. Studies in rats and mice have already shown that transplanted hESC-CMs can improve the function of heart muscle damaged by an infarction. In addition, at the University of Washington's Institute for Stem Cell and Regenerative Medicine, respective studies in immunosuppressed guinea pigs were performed. These pigs have a lower natural heart rate than rats or mice, and as such represent a more easily analyzed model for studying hESC-CM transplantation. In the study it was confirmed that transplanting hESC-CMs into hearts with damaged left ventricles resulted in a significant amount of remuscularization (and far fewer episodes of ventricular tachycardia compared with the control heart-damaged animals). In fact, the control animals demonstrated 785% more ventricular tachycardic episodes than those implanted with the hESC-CMs [56]. To also confirm that the transplanted hESC-CMs really couple to and beat in synchrony with the recipient's myocardium, the researchers created ESC-CMS that effectively fluoresced each time they contract. Encouragingly, results from imaging studies of grafted hearts in fact showed that the hESC-CM transplants were capable of contracting completely in synchrony with the animals' own heart muscle, indicating true host–graft coupling. Thus, these intravital imaging studies are the first direct demonstration that human cardiomyocytes can integrate and contract synchronously with host myocardium. This demonstration of electromechanically coupled grafts in injured hearts supports the idea of Wolfram Zimmermann [56] that hESC-CMs can improve mechanical function by creating new force-generating units (not only on the petri dish), obviously a sine qua non for heart regeneration also in humans.

For the creation of entire organs, obviously the biggest challenge is to provide enough cell material. Woo Suk Hwang was hyped when he cloned the first human embryo by somatic-cell nuclear transfer (SCNT) as an unlimited source of stem cells for therapeutic cloning [57]. Then it was found out that he manipulated experimental data and he was accused for fraud. Looking back, but moving forward: this time another well recognized pioneer, Miodrag Stojcovic (who cloned together with Ian Wilmut the first sheep Dolly), shares his experience and addresses the question, if SCNT can be replaced by induced pluripotent stem cells (iPS cells) [58]. The importance of innovative technologies to create stem cells was emphasized when two researchers were awarded this year's Nobel Prize for Medicine: Sir John B. Gurdon and Shinya Yamanaka for the discovery that mature cells can be reprogramed to become pluripotent. They had converted mature cells into embryonic-like stem cells by taking a skin cell, insert it with DNA, and get it to reverse back to an embryonic state. Applying this new biotechnology, they were able to create that kind of stem cells needed by researchers and stem cell investigators, who had previously to rely on the controversial practice of destroying embryos for their research materials, or using egg donations as Woo Suk Hwang did for SCNT.

Biomarker/Multimarker

Another tool with an ever-increasing importance for biopharmaceutical development (and also for approval) are biomarkers. There are several types of biomarkers, being it risk indicator, predictive, diagnostic, prognostic, or predictive biomarkers. These can be implemented for example on a protein chip [59], or the samples can also be analyzed by a spectrometer to, for example, detect lung cancer just from the breath [60]. To develop the different types of biomarkers, there is a need for pharmaceutical and biotech companies for animal and human samples – in particular, in the fields of target and biomarker identification and validation, enabling development of new generations of biopharmaceuticals, diagnostics, and medical products, this is evident [61].

Transgenic Animals Welfare: Farewell or Welcome?

As discussed earlier, transgenic animals are key to study medical interventions before these are applied to humans. Nevertheless, it is often a matter of debate whether animals should be used for development of new medicines. The truth is that there is no alternative for testing drug candidates before they can move into clinical trials, but it is possible to significantly reduce the number of utilized animals by smart design of the required experiments. As genetic engineering advances, also transgenic animals become more and more important for biopharmaceutical development, for example, the creation of specific disease models mimicking the human situation. How KO mice are used as disease models to discover true physiological gene functions was portrayed in a contribution from Max Planck Institute [62]. To create and apply transgenic animals on an industrial scale is now described by Peter Stadler and his colleagues from TaconicArtemis, a global player for functional mouse genomics [63].

From Bench to Bedside: Approval of Biopharmaceuticals and Biosimilars

In the end, after all development efforts, what counts is the approval of the biopharmaceutical and its launch in the respective market. As mentioned earlier, approval has become more difficult over the years with increasing regulatory requirements for agencies such as FDA and EMA. A comprehensive view on regulatory aspects for the US market was given by Kurt Brorson from FDA [64] and from Axel Wenzel, President of TOPRA (global organization for Professionals in Regulatory Affairs) for the EU [65].

At that time already, global manufacturers were exploring the possibility of producing biosimilars or follow-on biologics to extend product pipelines and increase availability of lower cost products. As biopharmaceuticals are large, complex molecules, manufacturing changes may alter clinical efficacy and safety of the biologic product, complicating their development and approval. This became evident during the long period with no binding guidelines available from the authorities for the approval of biosimilars. And, although the guidelines for approval of biosimilars were not completely harmonized/finalized at that time, one example, the biogeneric version of G-CSF from Dragon Pharmaceuticals, was illustrating the impact on healthcare economics [66].

Now, after some years of uncertainty regarding the approval of biosimilars, approval procedures are available. With a new US biosimilars approval pathway imminent, and the expiration of many top-selling biopharmaceuticals on the horizon, existing biosimilar developers, and newcomers are highly motivated to invest in the biosimilar field and are turning their attention to more complex biopharmaceuticals, such as monoclonal antibodies. Altogether, global sales of biopharmaceuticals are projected to reach $200 billion in 2014 (from $138 billion in 2010), making it a really lucrative market for developers and manufacturers of biosimilars. These developments are described along with the introduction of the first ever-approved similar biopharmaceutical product: Omnitrope®, from Sandoz [67].

This new book Modern Biopharmaceuticals – Recent Success Stories displays interesting case studies and new technologies along the entire value chain of biopharmaceuticals. It starts with an historical outline of the evolution from traditional biotechnology 20 000 years ago to modern biotechnology as of today, and also addresses the challenges of our current health systems for the development of innovative biopharmaceuticals. The book is an outstanding collection of highlights from various stages of biopharmaceutical development and sharpens our understanding how to come up with real breakthrough innovations – despite this challenging environment. Modern Biopharmaceuticals is written by brilliant, creative thinkers and can be strongly recommended as a comprehensive basic reference source for this exciting field to biotechnologists, clinicians, physicians, pharmacists, pharmaceutical chemists, molecular biologists, medicinal chemists, and anyone working in the biotechnological and pharmaceutical industries or in medicinal institutes.

Berlin, January 2013

Prof. Dr. Andreas Busch

Member of the Board of Management of Bayer Pharma AG

References

1. See also Huber, R. (2005) History of modern biopharmaceuticals: where did we come from and where will we go, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

2. See also Knäblein, J. (2013) Twenty thousand years of biotech - from traditional to modern biotechnology, in Modern Biopharmaceuticals - Recent Sucess Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

3. See also Caldwell, P. (2013) BioBenchmarking: the global perspective to ensure future success of biopharmaceutical development, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

4. See also Walsh, G. (2005) Current status of biopharmaceuticals: approved products and trends in approval, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

5. See also Moscho, A. et al. (2005) Health-care trends and their impact on the biopharmaceutical industry, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

5. See also Apeler, H. (2005) Preparing for success - the Bayer experience with a broad range of expression systems, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

6. See also Diers, I.V. and Andersen, A.S. (2005) Advanced expression of biopharmaceuticals in yeast at industrial scale: the insulin success story, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

7. See also Jagschies, G. (2013) Bright future outlook and huge challenges to overcome: an attempt to write the short story of the biopharma industry with current status, selected issues, and potential solutions in discovery, R&D, and manufacturing, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

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10. See also Janulaitis, A. (2013) Cut & Go – FastDigest® with all restriction enzymes @ same temperature and buffer: a new paradigm in DNA digestion to speed-up biopharmaceutical development, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

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14. See also Sylvestre, J. et al. (2013) Massive Mutagenesis®: the path to smarter genetic libraries for effective biopharmaceuticals, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

15. See also Loffert, D. (2013) Standardized solutions for quantitative real-time PCR to accelerate biopharmaceutical development, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

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20. See also Walsh, G. (2013) Posttranslational modifications to improve biopharmaceuticals, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

21. See also Hempel, J.C. (2005) Contract manufacturing of biopharmaceuticals, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

22. See also Werner, A. (2013) Large-scale manufacturing of biopharmaceuticals - speed up the road to market by scale up: 6×15 000 l BI bioreactors, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

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24. See also Vázquez, F.L. (2005) AIDS gene therapy: a vector able to selectively destroy latently HIV-1 infected cells, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

25. See also Rossi, J. (2005) Combinatorial RNA based therapies for the treatment of HIV infection, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

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29. See also Barrett, P.N. (2013) Superfast biopharmaceutical development: Vero cell technology and pandemic influenza vaccine production, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

30. See also Friedrich, R. (2005) Mechanisms of serine proteinase activation: insights for the development of biopharmaceuticals for coagulation and fibrinolysis, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

31. See also Brandstetter, H. (2005) Releasing the spring: cofactor- and substrate-assisted activation of factor IXa - triple mutant of factor IXa shows 7000 times increased activity, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

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33. See also Boedeker, B.G.D. (2013) Recombinant factor VIII (Kogenate®) for the treatment of hemophilia A: the first and only worldwide licensed recombinant protein produced in high-throughput perfusion culture, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

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36. See also Aboagye, E. (2005) Design and development of probes for in vivo molecular and functional imaging of cancer and cancer therapies by positron emission tomography (PET), in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

37. See also Neri, D. (2005) Ligand-based in vivo targeting of disease: from antibodies to small organic (synthetic) ligands, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

38. See also Briel, A. (2013) More to discover with VISCOVER™ - science fiction and science facts: the whole truth of in vivo whole animal imaging to speed up drug discovery and pharmaceutical development, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

39. See also Ntziachristos, V. and Razansky, D. (2013) Revolutionizing biopharmaceutical development with quantitative multispectral optoacoustic tomography (MSOT), in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

40. See also Gutjahr, T. (2005) The development of Herceptin®: paving the way to individualized cancer therapy, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

41. See also Gottschalk, U. and Mundt, K. (2005) 30 years of monoclonal antibodies: a long way to pharmaceutical and commercial success, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

42. See also Plückthun, A. and Moroney, S. (2005) Modern antibody technology: the impact on drug development, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

44. See also Zhou, J. et al. (2013) Implementation of advanced technologies in commercial monoclonal antibody production, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

45. See also Langer, R. et al. (2005) DNA delivery from poly(ortho ester) microspheres, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

46. See also Langer, B. and Anderson, D. (2013) High-throughput biomaterials-mediated delivery of DNA and siRNA biopharmaceuticals, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

47. See also Cech, T.R. (2005) Beginning to understand the end of the chromosome, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

48. See also Rubanyi, G. and McCaman, M. (2005) Therapeutic angiogenesis with adenovirus 5 fibroblast growth factor-4 (Ad5FGF-4) in patients with chronic myocardial ischemia, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

49. See also Gould Rothberg, B.E. et al. (2005) A systems biology approach to target identification and validation for human chronic disease drug discovery and development, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

50. See also Wittig, B. (2005) MIDGE vectors and dSLIM immunomodulators: DNA-based molecules for gene therapeutic strategies, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

51. See also Pingoud, A. et al. (2013) Precision genome surgery with meganucleases: a promising biopharmaceutical for gene therapy, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

52. See also Mangi, A. (2005) Repair of infarcted myocardium by genetically enhanced mesenchymal stem cells, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

53. See also Kehat, I. et al. (2005) Myocardial regeneration strategies using human embryonic stem cells, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

54. See also Reisner, Y. (2005) Applying human cells for organogenesis and transplantation - how to create an artificial kidney, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

55. See also Zimmermann, W.-H. (2013) BIOheart: an engineered heart tissue spontaneously starts pumping, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

56. Shiba, Y., Fernandes, S., Zhu, W.Z., et al. (2012) Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature, 489, 322–325.

57. See also Hwang, W.S. (2005) The first cloned human embryo: an unlimited source of stem cells for therapeutic cloning, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

58. See also Stojkovic, M. (2013) iPS as substitute of SCNT? - the impact of induced pluripotent stem cells on drug discovery and regenerative biopharmaceuticals, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

59. See also Wiesner, A. (2005) Development of multi-marker based diagnostic assays with the ProteinChip® system, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

60. See also Baumbach, J.I. (2005) Early detection of lung cancer: metabolic profiling of human breath with ion mobility spectrometers, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

61. See also Swifka, J. et al. (2013) Pharma research biobanking: need, socioethical considerations, and best practice, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

62. See also Brakebusch, C. (2005) Knock-out mice as disease models and to discover true physiological gene functions, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

63. See also Stadler, P. (2013) Industrialization of functional mouse genomics for biopharmaceutical development, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

64. See also Brorson, K. et al. (2005) Regulatory aspects of approving biopharmaceuticals in the US - the FDA perspective, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

65. See also Wenzel, A.F. (2005) The regulatory environment for biopharmaceuticals in the EU, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

66. See also Harris, J. (2005) Biogenerics and the emergence of healthcare economics: G-CSF and bioequivalence, in Modern Biopharmaceuticals - Design, Development and Optimization (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

67. See also Berghout, A. et al. (2013) Basic concepts for the development of a biosimilar product: experience with Omnitrope®, the first ever approved similar biopharmaceutical product, in Modern Biopharmaceuticals - Recent Success Stories (ed. J. Knäblein), Wiley-VCH Verlag GmbH, Weinheim.

Foreword by Günter Stock

Biopharmaceuticals, molecular biology, and biopharmaceutical science have radically and completely transformed biomedical research to a hypothesis-based research and at the same time have also drastically changed the way the pharmaceutical research is being performed.

On top of it, biopharmaceuticals – in a strict sense – constantly add to our pharmaceutical armamentarium. Every year on average 20% of newly approved drugs are biopharmaceuticals.

Public–private partnerships and even private–private and public–public partnerships are now an essential part of drug finding endeavors. Taking together, all these developments have taken place during the past 10–15 years and have changed the business model within pharmaceuticals to a considerable extent.

The success of the four volumes of Modern Biopharmaceuticals – Design Development and Optimization published in 2005 necessitated a new edition devoted to recent success stories in this field.

The great hopes related to the practical realization of molecular medicine both in diagnostics and in therapeutics are however only partially fulfilled until today, not only with regard to the existing scientific progress made but also with regard to the number of successful products being launched on the market. However, this is almost characteristic for innovations in healthcare because nowadays highly complex targets and diseases are being worked upon. Furthermore, it needs more time to develop competitive drugs especially for diseases that so far could not have been treated at all or not properly. The complexity of pathophysiologies underlying such diseases is reflected in longer development periods.

Despite these facts, it is fascinating to see that our therapeutic armamentarium has considerably increased, especially in those areas where progress was anxiously awaited and needed by the patients. Looking, for example, at the number of orphan drugs that were successfully developed in the last years, it is obvious that we now have the means and the scientific basis to tackle diseases that are rare and have complex pathophysiologies.

It is my conviction that the advent of molecular biology and modern pharmaceuticals is not paralleled by an innovation gap as argued by some people, but rather we are confronted by failures in expectation management. As an example, we have today more realism in judging the potential of stem cells, irrespective of the fact that there has been a fantastic development in reprogramming procedures (see the Noble Prize in 2012) and also in high-tech fields such as genomics, epigenomics, metabolomics, and proteomics. Here, a development has taken place that will help us to much better understand which processes and pathways inside the cells have to be tackled in order to successfully diagnose and treat diseases. And above all, the fact that the genetic code of individuals can be analyzed for a very reasonable price today is paving the way for better preventive and therapeutic medicine in the future.

The amount of data that has to be handled is dramatically increasing and the question how this will be incorporated into daily medical practice is not yet solved.

Hence, this new edition of Modern Biopharmaceuticals provides a well-balanced basis for new results and trends in the biopharmaceutical arena. This is of utmost importance not only for the scientists working in the field but also for the patients suffering from chronic and severe diseases for which new therapeutic options may become available in the future. It is therefore hoped and expected that this new edition will be as successful as the first edition.

Berlin, January 2013

Prof. Dr. med. Dr. h. c. Günter Stock

President of the Berlin-Brandenburg

Academy of Sciences

Preface

We all know that since the remarkable ‘debut of modern biopharmaceuticals’, the field of pharmaceutical biotechnology has evolved tremendously. By comparison, when I follow how quickly (life) sciences advance, it would make Newton's apple appear to fall in slow motion.

J. Knäblein in Modern Biopharmaceuticals – Design, Development and Optimization, 2005

Inspiration

Back with more ... after so much encouraging feedback from readers all over the world – plus the publisher Wiley pushing – there was no other option rather than coming up with more exciting stories on modern biopharmaceuticals.

A real stimulus was, in fact, that the four volumes of Modern Biopharmaceuticals – Design, Development and Optimization were extremely well received by readers such as students, industry peers, teaching personnel, scientists – and notably Nobel laureates alike, who appreciated the outstanding collection of articles from groundbreaking scientists, impressive list of authors drawn both from world-renowned academic research laboratories and also from the world's leading biotech and pharmaceutical companies, comprehensive coverage provided by eminent investigators, important resource for students and researchers alike, for all experts in this field.

Modern Biopharmaceuticals was even acknowledged as a unique collection of reports by the world leaders in their fields, all encompassing, the chapters are authored by the ‘who is who’ of biotechnology experts, and the coverage is admirable. The ‘Knäblein’ should be a unique resource.

On top, and this is what really encouraged me to continue with this biopharmaceutical endeavor, were the very encouraging and stimulating critiques in several peer-reviewed scientific journals:

This is an extensive and unmatched compilation of comprehensive, in-depth current knowledge and history of biopharmaceuticals...the author is commended for this grand effort.

Veterinary Pathology, May 2006

I heartily recommend this authoritative, comprehensive reference to this new, exciting field dealing with the entire broad range of available biopharmaceuticals.

ChemMedChem, August 2006

These four volumes represent a highly valuable reference compendium for any practicing scientists interested in this sector of biotechnology.

Chemistry and Industry, September 2006

Motivation

Another real stimulus came from Professor Sir Aaron Klug (Nobel Prize laureate for Chemistry, 1982), MRC Laboratory of Molecular Biology, when he wrote

"The new book ‘Modern Biopharmaceuticals’ has an impressive list of authors drawn both from world-renowned academic research laboratories and also from the world's leading biotech and pharmaceutical companies. The experts from this coalition of world-class companies, institutes and universities have direct experience of the cutting edge technologies described and understand the various needs, met and unmet. This fantastic line up of authors make it a truly world class book – a four-volume educational platform covering the full spectrum of science from discovery to applications.

It is hoped, that there will also follow (an inexpensive) student edition, which would be more widely accessible."

Implementation

Following the wish of Aaron Klug and others, I am very pleased to announce that Modern Biopharmaceuticals – Design, Development and Optimization was elected by Wiley InterScience for online publication. Now the book is available worldwide and around-the-clock with comprehensive search functions and the CrossRef functionality. This new model approach together with Google and Amazon – and on top with all professional online providers – make Modern Biopharmaceuticals accessible to more than 25 million users!

Appreciation – and Excursion

During my career, I was traveling to Cuba several times and was always intrigued by the highly innovative level of biotechnology R&D. In fact, a small country undeveloped, such as Cuba, can be ranked with the world's best, not only in primary healthcare – but also in medical research, developing vaccines, and in tackling both HIV/AIDS and cancer. In earlier times though, Cuba has suffered a number of epidemics of meningitis B, and unfortunately at one time there was no vaccine available – but Cuba set about producing one. Necessity became the mother of invention and the Finlay Institute in Havana – a center of vaccine production – discovered an effective meningitis B vaccine in the 1980s, which remains to this day the only commercially developed vaccine. Encouraged by this success, a huge investment was made in the early 1980s, when the Fidel Castro administration made biotechnology a priority area for the country's social and economic development. The financial support granted to the sector was maintained even during the crisis of the 1990s, triggered by the break-up of the Soviet Union, Cuba's main trading partner. As a direct result, the Centro de Ingeniería Genética y Biotecnología (Center for Genetic Engineering and Biotechnology; CIGB) was established and inaugurated on July 1, 1986 by Cuban Revolution leader Fidel Castro – supported by my mentor Robert Huber, who shared his expertise to create such an impressive biotechnology institute. The center was eventually certified in 2001 by the World Health Organization (WHO). Later, the Center for Molecular Immunology (CIM) was created in 1994. The institutes have already contributed pharmaceuticals to diagnose, prevent, and treat nearly 30 different diseases. Some of the diseases treated with the Cuban biopharmaceuticals include chronic hepatitis, respiratory or laryngeal papillomatosis (a potentially fatal throat infection), condylomas or genital warts, and other virus-related diseases. They have also achieved a combined vaccine against diphtheria, tetanus, whooping cough, and hepatitis B, which has been introduced with good results in the National Vaccination Program.

Another focus area is oncology, and meanwhile, the Molecular Immunology Center is working on eight projects to produce biopharmaceuticals against different types of cancer. Three of the projects are undergoing phase III clinical trials. After highly successful clinical trials, cancer patients in China are receiving cancer treatment based on Theracim Hr3 formula discovered and developed at the CIM laboratories. Two biopharmaceuticals from CIM have aroused great interest and led to agreements for manufacturing in China and India under Cuban scientific supervision. Also, in Europe and Canada, international clinical trials are ongoing with positive results so far. Even an US company, Cancervax, has been granted a State Department waiver from provisions of the US embargo in order to carry out clinical trials for the US market.

Cuba is also a pioneer in transgenic plant biotechnology (e.g., producing antibodies in plants, plantibodies): one of the lead products of the Cuban biotechnology industry has been the hepatitis B vaccine (Trade name: Heberbiovac). The active pharmaceutical ingredient (API) of Heberbiovac is the hepatitis B surface antigen (HBsAg) recombinantly produced in yeast. A fundamental step in the purification process of this API from yeast is the affinity chromatography using the mice-derived monoclonal antibody CB Hep1, which is produced in transgenic plants [1].

All Cuban citizens born after 1980 received this hepatitis B vaccine; hence, over 12 million Heberbiovac doses have been administered since 1992 in Cuba. While more than four million Cubans have been protected against acute Hepatitis B, the vaccine is currently being administered in 40 nations of the world. As a consequence, in Cuba alone, Hepatitis B cases have fallen from more than 2000 per year (before vaccination began in 1992) to less than 50 a year now.

In summary, pharmaceuticals and biotech currently constitute the first and second non-traditional sectors of the Cuban economy (for their revenues), and altogether Cuba possesses 222 scientific research centers, employing 31 000 people, with six main institutes conducting the complete cycle: research, production, and marketing. The Cuban record of product innovation is 26 inventions with more than 100 international patents already granted. According to the published 2012 figures, over 100 Cuban high-tech medical products are being sold in about 40 countries and regions. The figures indicate that the biopharmaceutical drugs export had increased by 60% in the past two years alone with revenues of over US$500 million.

During one of my Cuba visits in 2006 at the CIGB for its 20 Years anniversary celebration, I had the honor (and pleasure) to discuss these advancements of modern biopharmaceuticals with my friends Carlos Borroto Nordelo, Robert Huber, and Fidel Castro, Jr. (Fidel Ángel Castro Diaz-Balart). Carlos serves as the Deputy Director of CIGB, and Fidelito (who studied nuclear physics in the Soviet Union in the 1970s) served as Executive Secretary of the Cuban Atomic Energy Commission from 1980 to 1992. Now, he is working as a consultant for the Ministry of Basic Industries, and as such is highly engaged in biotechnology as one of the Cuban scientific and economical cornerstones.

Photograph showing from left: Nobel laureate Professor Robert Huber, Fidel Castro, Jr., and Jörg Knäblein during the 20 Years anniversary celebration of CIGB, Havana, in 2006.

In our lively discussions, we all agreed that for further fostering modern biotechnology (also especially in developing countries), it would be favorable to make Modern Biopharmaceuticals widely accessible for researchers and scientists in the biotechnology community. And in fact we did by making all four volumes available as online publication: today everybody can get access to the entire compilation (thanks to Wiley).

This is a great achievement and will help to make this project even more valuable for all people interested in the amazing development of modern biotechnology. As a matter of fact, the online publication helped a lot to improve visibility, availability, and coverage of Modern Biopharmaceuticals, as seen, for example, by the increasing number of citations of several chapters of this book in peer-reviewed scientific papers.

The Big Picture of Modern Biopharmaceuticals

The biotech industry translates more and more discoveries into safe, effective, and new biopharmaceutical medicines, as nicely described by Professor Günter Stock (President of the Berlin-Brandenburg Academy of Sciences) who describes the fantastic advancements of biopharmaceuticals in his preface for this book. In 2009, five of the 10 top-selling medicines were biopharmaceuticals, and market research firm EvaluatePharma predicts that, by 2016, there will be seven such bestsellers [2]. A small caveat though: a recent study of 4275 medicines moving through clinical trials to FDA approval suggests that the failure rate is actually increasing. Between 2003 and 2010, only one in 10 treatments reached the market, compared with a previous rate of one in five or six. [3], and the number of biopharmaceuticals approved by the FDA has stayed the same for the past three years – and it is still slightly lower than in 2002, when seven new biopharmaceuticals were approved.

Although it is hard to put an exact price tag to the development of a new drug, certainly it is an extremely expensive business. In 2006, the Tufts Center for the Study of Drug Development estimated the average cost at US$1.24 billion for a biopharmaceutical and US$1.32 billion for a small molecule compound [4, 5].

Big Pharma Cannot Bridge the Gap Alone

To compensate for increasing development prices and failure rates, some of the largest biopharma companies are now trying new approaches to fill their gaps. In 2011, they collectively contributed US$694 million – nearly 15% of the total venture capital invested in the US biotech sector that year [6], and the trend toward collaboration has been very pronounced. There are precompetitive discovery federations (where public and private institutions pool their resources to overcome bottlenecks in early stage biomedical research), as well as competitive development consortia (where rival biopharma companies form syndicates to develop the most promising molecules in their combined portfolios) [7].

So, closer collaborations matured over the last couple of years and are getting more popular to fill the gaps: if the biotech and pharma sectors join forces (but also academic with industry research, and all together with patient advocacy groups and medical charities), they are able to develop new medicines more effectively and capitalize together on the opportunities arising from each participant. Truly, there has been a significant rise in the number of alliances with academic institutions: between January and September 2011, there were 30 new biopharma alliances with academic bodies, nearly double the total for 2010 [8], and the US National Institutes of Health (NIH) has also just embraced crowd sourcing in an effort to teach old drugs new tricks [9]. The NIH's National Center for Advancing Translational Sciences and its industry partners are testing various compounds that have been studied in humans but shelved to see whether new uses can be found for them [7].

Having said that, patient money has received a more important role for drug development as a source of funding: for example, Cystic Fibrosis Foundation spent US$75 million for developing Kalydeco, and the Michael J. Fox Foundation agreed to pay for further testing of a therapy to Parkinson's disease [10]. Also, the Juvenile Diabetes Research Foundation funded a series of clinical trials on the effectiveness of a combination therapy for Type 1 diabetes [11].

This venture philanthropist model is now spreading outside the United States: in March 2012, Britain's Wellcome Trust launched a US$310-million fund to invest directly in healthcare and life sciences companies [12] and Cancer Research UK has also teamed up with a European venture capital firm to create a nearly US$50-million fund for boosting the development of new cancer treatments [13]. These moves mark a profound shift: medical charities and patient organizations have long supported basic research, but they are now moving down the pipeline jointly with the biotech industry.

Also, US venture capitalists are back on the scene: venture funding in the domestic biotech sector topped US$4.7 billion in 2011 (22% more than in 2010), but in 2011, there were only 8 initial public offerings (IPOs) in the US biotech sector (raising US$517 million), compared to 19 IPOs (raising US$1.2 billion) in 2007 (MoneyTreeTM Report from PwC and the National Venture Capital Association, based on data provided by Thomson Reuters).

In 2011, the FDA's Center for Drug Evaluation and Research (CDER) approved 30 new medicines – a higher number than at any time since Modern Biopharmaceuticals – Design, Development and Optimization – was published in 2005. Twelve of them were first-in-class therapies [14], and nine are expected to generate peak sales of more than US$1 billion a year (Consensus forecasts provided by EvaluatePharma).

Modern Biopharmaceuticals – Recent Success Stories

In this new edition of Modern Biopharmaceuticals – Recent Success Stories the attempt was again to give a good overview of the current developments within the field of biotechnology. I have tried to find a lineup of excellent authors describing with their contributions the amazing progress going on in this area and also reflecting scientific and economic trends. As perfectly summarized in his kind primer for this new book, Professor Andreas Busch (Member of the Board of Management of Bayer Pharma AG) shows that modern biopharmaceuticals are developing at a mind-boggling speed. He did an excellent job in outlining the content of this new book and bringing the specific contributions of their different kind in context to the previous four volumes of Modern Biopharmaceuticals – Design, Development and Optimization.

Finally, I hope that the readers will like this new compilation of cutting edge biotechnologies, written by the most knowledgeable experts from academia and industry. If the appreciation will be the same as for the previous four volumes, then Modern Biopharmaceuticals – Recent Success Stories will be a success already. Having said that, please enjoy reading these new and fascinating examples of Modern Biopharmaceuticals.

Berlin, January 2013

Dr. Jörg Knäblein

Technology Scouting

Bayer HealthCare Pharmaceuticals

References

1. Knäblein, J., Pujol, M. and Borroto, C. (2007) Plantibodies for human therapeutic use. BioWorld EUROPE, 1, 14–17.

2. EvaluatePharma World Preview 2016. EvaluatePharma (June 10). (2011).

3. Hay, M., Rosenthal, J., Thomas, D., et al. (2011) Trial and error: breaking down clinical trial success rates. 13th Annual Bio CEO Investor Conference, February 15, New York City, United States.

4. DiMasi, J.A. Costs and returns for new drug development. FTC Roundtable on the Pharmaceutical Industry, October 20, Washington DC, United States. (2006) http://www.ftc.gov/be/workshops/pharmaceutical/DiMasi.pdf.

5. DiMasi, J.A. and Grabowski, H.G. (2007) The cost of biopharmaceutical R&D: is biotech different? Managerial and Decision Economics, 28, 469–479.

6. NVCA Today (2012) Corporate Venture Capital Activity On Three-Year Upward Trend. NVCA Today (February 23), http://nvcatoday.nvca.org/index.php/corporate-venture-capital-activity-on-three-year-upward-trend.html

7. PricewaterhouseCoopers (2012) Biotech What's next for the business of big molecules? (June 13), www.pwc.com/pharma.

8. Morrison, C. (2012) Biopharma in 2011: a year of transition. IN VIVO, 30 (1), 9.

9. Young, D. (2012). NIH-Industry Venture Taps. ‘Crowdsourcing’ for Teaching Old Drugs New Tricks. SCRIP Intelligence (May 4). http://www.scripintelligence.com/home/NIH-industry-venture-taps-crowdsourcing-for-teaching-old-drugs-new-tricks-330136

10. The Economist (2012) All Together Now: Charities Help Big Pharma. The Economist (Apr 21). http://www.economist.com/node/21553027.

11. Juvenile Diabetes Research Foundation (2011) JDRF and Amylin partner to investigate co-formulating two hormones for treatment of type 1 diabetes. Press release, May 10. http://www.jdrf.org/index.cfm?page_id=115726.

12. European Biotechnology News (2012) Wellcome Trust Launches Venture Capital Arm. European Biotechnology News (Mar 21). http://www.eurobiotechnews.eu/news/news/2012-01/wellcome-trust-launches-venture-capital-arm.html.

13. Jump, P. (2012). Cancer Research UK to Join Forces with Venture Capitalist. The Times Higher Education (Mar 31). http://www.timeshighereducation.co.uk/story.asp?sectioncode=26&storycode=419502&c=1

14. Morrison, C. (2012) Biopharma in 2011: a year of transition. IN VIVO, 30 (1), 9.

Quotes

"The making of pharmaceutical and diagnostic agents in cells has moved from edge to the center of their respective commercial development.

With ‘Modern Biopharmaceuticals’, Jörg presents an outstanding collection of articles from groundbreaking scientists, comprehensively describing the many novel ways cells so are being deployed toward human good."

Professor James D. Watson,

DNA code-breaker and Nobel Prize laureate

(Physiology or Medicine, 1962)

COLD SPRING HARBOR LABARATORY, New York

The new book ‘Modern Biopharmaceuticals’ has an impressive list of authors drawn both from world-renowned academic research laboratories and also from the world's leading biotech and pharmaceutical companies. The experts from this coalition of world-class companies, institutes and universities have direct experience of the cutting edge technologies described and understand the various needs, met and unmet. This fantastic line up of authors make it a truly world class book – a four-volume educational platform covering the full spectrum of science from discovery to applications.

It is hoped, that there will also follow (an inexpensive) student edition, which would be more widely accessible."

Professor Sir Aaron Klug,

Discoverer of the Phenylalanyl-t-RNA and Nobel Prize laureate (Chemistry, 1982)

MRC LABORATORY OF MOLECULAR BIOLOGY

Cambridge, United Kingdom

"The comprehensive coverage provided in ‘Modern Biopharmaceuticals’ by eminent investigators should stir the imagination of all scientists interested in possible medical applications of their own research. I wish you best of luck in your endeavors with this excellent biotech book."

Professor Stanley Cohen, Discoverer of Growth Factors

and Nobel Prize laureate (Physiology or Medicine, 1986)

VANDERBILT UNIVERSITY

SCHOOL OF MEDICINE Nashville, Tennesee

"We always seem to be right on the edge of solving all our health problems, just like we always seem to be on the verge of ultimately discovering the physical mysteries of the universe. It does seem like we are about to understand cancer, genetic diseases, infectious diseases – all the things that bring us discomfort on the personal level.

Gunther Stent decided in the late Sixties, in his wonderful lectures at Berkeley entitled the Rise and Fall of Molecular Biology, that all the interesting stuff in molecular biology had already been figured out. Only the boring details remained – just then biotechnology exploded. Our latest shocking advance, the ease of reading and manipulating DNA, is what is responsible, I suppose for our latest bout of thinking we know almost everything important. It turns out though, that there are always new things to discover.

You need to keep up on what is known already and you always need to know what's already known. So, read this book ‘Modern Biopharmaceuticals’ and you will get a very good overview of what is currently known in the exciting field of Life- Sciences."

Professor Kary Mullis,

Inventor of PCR and Nobel Prize laureate

(Chemistry 1993)

Newport Beach, California

"It is not easy to obtain a wide overview of the developing impact of new knowledge in the basic pharmaceutical sciences on medicine. This book, ‘Modern Biopharmaceuticals’, is an admirable attempt to meet that need, for all experts in this field, as well as for students who need an orientation for possibilities in academia, industry, and medicine."

Professor Paul Lauterbur,

Pioneer of MRI and Nobel Prize laureate

(Physiology or Medicine, 2003)

UNIVERSITY OF ILLINOIS

Department of Chemistry

"The new biopharmaceuticals that are being developed at present will provide important new opportunities in therapy and diagnosis that cannot be met in any other way. Jörg Knäblein has assembled in these four new volumes a unique collection of reports by the world leaders in their fields. They describe the present state of their field and the requirement for further research. ‘Modern Biopharmaceuticals’ will be an important resource for students and researchers alike."

Professor Ian Wilmut,

Clone-father of sheep Dolly

ROSLIN INSTITUTE, Scotland

Department of Gene function

and Development

"The explosion of biological products as novel human therapeutic agents is based on remarkable advances in the enabling sciences that comprise modern biotechnology. ‘Modern Biopharmaceuticals’ provides a broad, up to date analysis of the many facets of discovery and development required to successfully generate biopharmaceuticals. The scope is all encompassing, the chapters are authored by the ‘who is who’ of biotechnology