With a bold approach, including next-generation DNA sequencing (NGS) and state-of-the-art biobanking systems, Norway is pushing forward personalised cancer treatments in its national health care system. Clinical-quality genome sequencing still isn’t widely used yet, but the country has already begun tracking every patient diagnosed with carcinoma. In mid-February, the Research Council of Norway launched a new programme to couple analysis results with data from health surveys and registers. “The main objective of the programme is to develop research-based knowledge about human health and disease through better use of human biobanks and health data as unique resources,” said Rolf Bergen, who chairs the programme. Norway has a head start in using NGS to look for tumour mutations in the clinic. Projects underway in the UK and elsewhere still use conventional genetic testing, but that might change soon. China’s BGI, the world’s largest genomics centre, has opened its first European Genome Research subsidiary in Copenhagen (Denmark). Kicked off at the beginning of February, the institute is the cornerstone of a collaboration between BGI and top Danish research institutes. “The vision is to create the best facilities in the field for genomics and bioinformatics,” said Thomas Bjønholm from the University of Copenhagen, who wants to begin development on a vaccine against cancer.
The human race is at war with another species, and has been for thousands of years. Each of us in Europe swats dead dozens of the enemy every summer, and in the tropics they kill thousands of people with infectious diseases...
The human race is at war with another species, and has been for thousands of years. Each of us in Europe swats dead dozens of the enemy every summer, and in the tropics they kill thousands of people with infectious diseases hidden within their bodies. As in all wars, the battle for public opinion plays a key role in hostilities, along with the latest high-tech weaponry. The newest front in our battle with bloodsucking insects is now a matter of public debate. Innovative and powerful bioengineering technologies are providing Homo sapiens with a potential game-changer in the war against disease-carrying mosquitos. Unfortunately, at some point the weapons have to be tested out in the field. Exactly how careful and transparent do researchers have to be in large-scale studies involving transgenic animals?
Since 2009, Oxford-based biotech company Oxitec Ltd has released millions of genetically altered Aedes mosquitoes – which transmit both yellow fever and dengue fever – in a field test on the island of Grand Cayman. In 2010 and 2011, the British bioengineers also began large-scale experiments in both Brazil and Malaysia. A long list of other countries where the diseases pose a major health concern are lining up to host field tests of their own. Strikingly, it took more than a year for the little-publicised studies to begin making headlines. But when they did, the ensuing uproar was loud, and many scientists have sided with environmental groups in voicing concerns about inadequate oversight in the emerging field. The mosquitoes used in the Grand Cayman study were altered using Oxitec’s RIDL® technology, which produces insects that can only survive if as larvae they are also fed a particular supplement. Larvae born of matings between RIDL and wild-type mosquitoes live for awhile, competing with ‘healthy’ offspring. Without access to the supplement, however, these die before reaching maturity. The release of successive waves of transgenic adult male mosquitoes, so the theory, can help decimate populations of the dangerous disease-carriers. And in fact, the first results from the Caribbean look positive. “We monitored the mosquito population very thoroughly for several months after the pilot study was conducted, and found an initial reduction in the population of around 80%,” said Bill Petrie, the Director of Cayman’s Mosquito Research & Control Unit. He also told the country’s news service in January that “these data refute any allegation that the released mosquitoes persisted in the environment.” Fears in the general public might revolve around being bitten by GM mosquitoes, but for experts, the persistence of the implanted genes in the wild population would be a worrying indicator that everything was not going according to plan. A grave lack of transparency Although the experiment has apparently gone well, Oxitec was widely condemned by NGOs and environmental organisations for not being more forthcoming about the study, even though it was approved by the Caymans government. Scientists are also concerned about gray areas and a lack of standards. In a paper published at the end of January in the open-access journal PLoS – Neglected Tropical Diseases, researchers from the Max Planck Institute for Evolutionary Biology took a close look at how different countries cope with oversight and public access to information on large-scale field tests with GM mosquitoes – and found them seriously lacking. In “Scientific standards and the regulation of genetically modified insects”, their assessment of the regulatory apparatus found that in field experiments performed with transgenic insects in the US so far, little was done to inform the public in advance that the tests were taking place, and there was no real public debate on the issue. There was also no estimate of possible hazards prior to the releases in the Caymans, Brazil or Malaysia. “We noted that public access to scientific information is highly restricted throughout the world, particularly information made available before releases start,” said Guy Reeves, the paper’s lead author, who also pursues fundamental research in how to combat disease-carrying insects effectively with the help of bioengineering techniques. “We argue for transparency – not for transparency’s sake – but for clearly articulated strategic reasons that promote acceptance of the value of evaluating this promising technology,” he says. Trying not to repeat mistakes According to the WHO, up to 100 million people are infected with dengue fever every year. Around half a million of them, mostly children, end up in hospital. Up to 30,000 people die of the disease annually. Yellow fever kills around the same number. While there is an effective vaccine available for yellow fever, the only way to fight dengue at the moment is through vector control. Scientists in the field agree that bioengineered insects could prove an effective weapon in controlling that host vector, but are divided on the best ways to move forward with the research. Oxitec has defended its quiet pursuit of large-scale testing by pointing out that government agencies in the affected countries approved the trials well in advance. And the company’s initial success has paid off in more than scientific terms. In February, Oxitec received £8m in fresh cash from investment fund Oxford Capital, and has also increased staff numbers. But many other scientists and companies are desperate to avoid a media debacle like that surrounding GM crops in Europe. By ignoring public concerns in the early days of that technology, firms like Monsanto drove European consumers firmly into the anti-GMO camp, where they have remained to this day. Researchers active in the field of transgenic insects don’t want to see those mistakes repeated. “While it may appear naïve to argue for pre-release access to accurate scientific information and a high quality multi-disciplinary approach,” concludes the MPI researchers’ paper on standards, “it is in our opinion even more naïve to expect that the development of GM insect technologies will progress far in its absence.”B
The Philogen group is a specialist for therapies against cancer. Unlike other private companies, the Swiss-Italian firm has developed a rich pipeline of antibodies consisting of five different molecules being tested in 15...
The Philogen group is a specialist for therapies against cancer. Unlike other private companies, the Swiss-Italian firm has developed a rich pipeline of antibodies consisting of five different molecules being tested in 15 different clinical trials. The R&D facility in Zurich is run by Philogen subsidiary Philochem, which has specialised in many areas. One of them is the chemical modification of immunomolecules called ‘armed’ antibodies.
The development of antibody-drug conjugates has recently been receiving a lot of attention, and not only at Philochem, but in the whole biotech industry. With growing generic competition and a lack of new targets, many companies are looking for ways to make antibodies against known targets more efficient. Antibody-drug conjugates represent an interesting therapeutic approach that combines the desirable properties of monoclonal antibodies with the cell-killing activity of cytotoxic drugs, reducing systemic toxicity and increasing therapeutic benefit for patients. In this area, Philogen and its R&D subsidiary Philochem have demonstrated for the first time that a non-internalising vascular targeting ADC can be used to mediate strong anti-tumour activity in vivo. The scientists believe that bio-orthogonal reactions that modify proteins at specific sites using cleavable linkages are essential for the development of antibodydrug conjugates. Philochem has developed proprietary traceless site-specific linkage technologies to conjugate novel drugs to clinical-stage human monoclonal antibodies.
Phase III in planning
At present, Philogen has four anti-cancer antibody derivatives in clinical studies, as well as an antibody-derivative for the treatment of rheumatoid arthritis. Two registrational studies (one in Phase III and one in Phase II) are in planning. Since it was founded in 2006, Philochem has worked on the following methods for biotechnological product development: – isolation of human monoclonal antibodies from large combinatorial libraries. – development of armed antibodies (immuno-cytokines and antibody-drug conjugates). – discovery and validation of vascular markers of pathology using a perfusion-based chemical proteomics approach. – design, construction and screening of DNA-encoded chemical libraries of unprecedented quality and size. Since its inception in 1996, the mother company Philogen has focused on the development of new biopharmaceuticals for the treatment of angiogenesis-related disorders. Angiogenesis – the formation of new blood vessels – is a characteristic feature of many severe pathologies such as cancer, rheumatoid arthritis and age-related macular degeneration.
The company and its founder Dario Neri have been pioneers in the isolation, engineering and clinical development of lead products capable of targeting angiogenesis in vivo. These technologies are integrated into drug discovery programs. The most promising candidate products are further developed in the Siena-based Philogen facilities. Here production according to GMP standards and clinical trials is conducted with the aim of developing superior products for the imaging and treatment of serious angiogenesis-related diseases. Philogen and Philochem run three different collaborations with big pharma. Together with Pfizer Inc., Philochem is active in the field of target discovery. It assists Merck Serono in the search for biomarkers by generating monoclonal antibodies. And self-assembling chemical libraries are in the focus of a co-operation with MedImmune. Philogen is also in negotiations with other pharma partners to out-license its clinical-stage compounds.
The majority of drugs are currently prescribed empirically, but advances in research focusing on the molecular mechanisms of specific diseases have opened new pathways to matching patients with drugs that are more likely to be...
The majority of drugs are currently prescribed empirically, but advances in research focusing on the molecular mechanisms of specific diseases have opened new pathways to matching patients with drugs that are more likely to be effective and safe. The term ‘personalised medicine’ is currently used to summarise different levels of this process. The route to approval for a drug/diagnostic combination, however, continues to be rocky.
In extreme cases, individualised medicines vary from patient to patient. Such therapeutic concepts include, for example, cell-based cancer vaccines. A less extreme level of personalisation is the concept of stratified medicine. Here, a patient can be classified according to a specific cohort that shows an efficient differential response to a given drug. This stratification is achieved through the use of a clinical biomarker that has been correlated to a differential response.
Improving on empirical medicine
To be implemented in stratified medicine as a companion diagnostic, a clinical biomarker should be predictive for the efficacy and safety of the treatment. The most frequently-used predictive clinical biomarker concepts at the moment include techniques such as gene-expression pattern, individual protein expression (on histology) and even imaging. A stratified medicine regime adds a clinical biomarker assessment to empirical medicine practice, and associates a patient with the best therapy available with respect to efficacy and safety. That helps to avoid treatments with toxic side effects and low or even no benefit for the patient. For the application of stratified medicine, the following three prerequisites are required: I) underlying disease with variability reflecting multifactorial aetiology, II) multiple treatment options and III) a predictive clinical biomarker.
Cetuximab – a pioneer in the field
Successful anti-cancer treatment requires not only a potent drug, but also finding the right drug for a specific patient in a timely manner. The concept of stratified medicine has so far therefore focused on cancer treatment where both quality and time are critical. In 2004, the approval of Cetuximab by the US Food & Drug Administration (FDA) added another option for the treatment of colorectal cancer through chemotherapy. However, subsequent clinical experience indicated benefit for patients in only 10 -20% of the cases. In the years that followed, an intensive search for a predictive biomarker led to stratification of the treatment with Cetuximab. Retrospective analysis revealed a lack of benefit associated with Cetuximab treatment in colorectal cancer patients harboring mutations in the KRAS gene. These studies resulted in a label restriction from both the FDA and the EMA (in 2009) for patients without a KRAS mutation. In Europe, a diagnostic test for detection of the KRAS mutation recently (2011) received a CE label. Making the case-by-case decision Despite the fact that retrospective clinical biomarker analysis with subsequent development of companion diagnostic tests remains common practice, both the EMA and FDA favor co-development of drug and diagnostic. The concept of co-development envisages the approval of a diagnostic test at the time of drug approval. One of the most important consequences of this concept is that screening for suitable predictive biomarkers should occur at a very early stage of drug development, with implementation of the biomarker hypothesis in clinical trial design. In recent years, both the EMA and FDA have noted the need for regulations and clear concepts to support the development of stratified/personalised medicines along with appropriate diagnostic tests. However, in Europe the situation remains uncertain. Most importantly, current regulations and concept papers do not allow for a coordinated approval of a drug and its associated companion diagnostic. And in contrast to the situation in the US, cross-labeling of drug and companion diagnostics in Europe is not required. Additionally, self-certification by IVD manufacturers and a lack of harmonised quality regulations in clinical laboratories providing companion diagnostic testing may serve to widen the quality window of test results. Overall, the current regulatory landscape in Europe and in the US implements a case-by-case approach for the development of companion diagnostics that is in line with the advice for a very early consultation with the regulatory agency.
Success in the biopharmaceutical industry is mainly driven by the ability to innovate, and the continuous development of new products is crucial in that context. Shortening development times is key. The use of comprehensive...
Success in the biopharmaceutical industry is mainly driven by the ability to innovate, and the continuous development of new products is crucial in that context. Shortening development times is key. The use of comprehensive bioprocessing equipment supports the quick establishment of valid bioprocesses, and facilitates easy and reliable scale-up from lab to production plant. Genmab scientists have demonstrated how powerful methods can accelerate the development of antibody production processes.
Jolanda Gerritsen and her team at Genmab in Utrecht in the Netherlands have used a fourfold DASGIP Parallel Bioreactor System to shorten the development time of an antibody production process up to manufacturing level. In their laboratory, they carried out a screening process for a human monoclonal antibody (mAb) produced by CHO-cells in the 2L scale. Once the production procedure was established in the DASGIP Benchtop Bioreactor System, they successfully scaled-up the process to 100L in a first step (Fig. 1), and finally to the 1000L production scale, retrieving comparable results in regard to protein quantity and quality. Reliability and scalability are the crucial parameters in accelerating cell culture procedures for antibody production. Strictly parallel operation in cultivation processes facilitates fast process development and saves time during laboratory scale experiments. Using controlled benchtop bioreactors allows direct comparison of single-process parameters relevant in cell line development or optimisation of the antibody production process itself. Comprehensive data management can further promote effective use of time. The main objective was to establish a screening procedure for monoclonal antibody-producing CHO cell lines with reliable scale-up properties at the Genmab research facilities in Utrecht. The Cell Line Development team aimed to achieve the same antibody titers in large-scale production as were achieved in their small-scale screening cultures, which are fully up and running. They successfully scaled up their process 500-fold. Impact on the industry The case study discussed above demonstrates that the use of advanced parallel bioreactor systems can accelerate process development in biopharmaceutical science in a smart and comprehensive way. Parallel operations help save time, and lead to reliable results that are easy to scale up. Parallel design of experiments follows DoE principles, giving an extra plus when aiming for short time-to-market. Depending on the characteristics of the protein of interest, a parallel approach using benchtop bioreactor systems may deliver results that are precisely similar to large scale, allowing operators even to skip a common pilotscale development cycle.D
Contact Claudia M. Huether DASGIP AG c.Huether@dasgip.de Patrick Priem, Jolanda Gerritsen GenMab N.V. firstname.lastname@example.org, email@example.com
Zurich-based NeurImmune AG follows unconventional routes – for example, the company doesn’t rely on VC investors. And Neurimmune has also turned the drug discovery process upside down by taking its drug candidates from healthy...
Zurich-based NeurImmune AG follows unconventional routes – for example, the company doesn’t rely on VC investors. And Neurimmune has also turned the drug discovery process upside down by taking its drug candidates from healthy humans that have developed an immune response to pathogenic proteins like Abeta. Biogen Idec is building on NeurImmune’s expertise, and has already signed two agreements.
The deposition of pathogenic protein aggregates derived from physiological brain proteins is a common theme underlying most neurodegenerative diseases. These protein clusters deposited in the brains of human patients include, for example, Abeta (Ab)and tau in Alzheimer’s disease and Down syndrome, a-synuclein in Parkinson’s disease and dementia with Lewy bodies, and superoxide dismutase 1 in amyotrophic lateral sclerosis. Disease-causing mutations in the genes encoding these proteins point to their central roles in the etiology of neurodegeneration. Both genetic and the more frequent “sporadic” variants of neurodegeneration are associated with the conversion of misfolded physiological proteins into pathogenic aggregates. Prion-like mechanism Synaptic connections by which neuronal networks communicate are among the most vulnerable structures affected, resulting in the progressive deterioration of neuronal network activities. When released from affected cells, the pathogenic aggregates can enter unaffected neighbouring cells, bind to their cognate physiological protein counterparts, and force them to adopt pathological conformations as well. This thermodynamically driven process of prion-like infectivity drives the spatiotemporal spreading of protein aggregation from cell to cell and throughout the central nervous system. Unexpectedly, this metamorphosis from physiologic to pathogenic structural conformations of endogenous proteins can be accompanied by humoral immune responses generating B-cells encoding high-affinity antibodies that specifically bind and neutralise such pathogenic protein aggregates. This observation provides a basis for asking the questions of how healthy elderly subjects succeed in preserving intact cognitive functions during aging, and how such knowledge can be used pharmacologically to prevent neurodegeneration in subjects at risk. NeurImmune studied immune responses directed against pathogenic protein aggregates in cohorts of healthy elderly subjects with either excellent cognitive performance or recovery from initial signs of cognitive decline. Up to 80% of healthy elderly subjects had established B-cell memory against aggregated Ab, thus allowing for the cloning of human monoclonal antibodies targeting these aggregates. Recombinantly produced human monoclonal antibodies with high affinity and selectivity for aggregated Ab crossed the blood-brain barrier in transgenic mouse models of Alzheimer’s disease and accumulated on Ab deposits in the brain. Brain-resident microglial cells were recruited to antibody-labeled aggregates, and removed them by means of phagocytosis paralleled by signs of neuronal recovery and restored behavioral functions. The pharmacological effects of these human monoclonal antibodies are currently being studied in human patients with early signs of cognitive decline. In addition to immune responses against aggregated Ab, healthy elderly subjects also mounted immune responses against misfolded or aggregated forms of a-synuclein, superoxide dismutase 1, tau and TAR DNA-binding protein 43. The corresponding high affinity human monoclonal antibodies were cloned, sequenced, produced recombinantly and validated in vitro and in vivo. As an example, chronic treatment of transgenic mice with signs of amyotrophic lateral sclerosis established rescue of alpha-motor neurons along with increased overall survival. Likewise, recombinant human antibodies against a-synuclein decreased alpha-synuclein pathology and improved motor functions in transgenic mouse models of Parkinson’s disease. Pharmacological intervention using recombinant human antibodies against disease-causing toxic protein aggregates provides a promising concept for the treatment and prevention of neurodegeneration. In November 2007, Biogen Idec closed a first partnership with NeurImmune for the development of antibodies to treat Alzheimer’s disease. Neurimmune could receive an aggregate of US$380m in up-front and success-based milestone payments. In December 2010, Biogen acquired a NeurImmune subsidiary that contained the global rights to three preclinical candidates targeting neurodegenerative diseases.
The use of bispecific antibodies recognising two different targets may allow improvement of clinical efficacy. A bispecific antibody for two growth factors that stimulate the formation of blood vessels – Ang2 (Angiopoietin-2) and...
The use of bispecific antibodies recognising two different targets may allow improvement of clinical efficacy. A bispecific antibody for two growth factors that stimulate the formation of blood vessels – Ang2 (Angiopoietin-2) and VEGF-A (Vascular Endothelial Growth Factor A) – has been developed by Roche Pharma Research and Early Development (pRED). For the first time, single-use bioreactors (SUBs) in Roche’s fermentation plant have been used for production of this bispecific antibody for toxicological studies, successfully combining two emerging technologies.
Bispecific antibodies incorporate the antigen-binding properties of two different monospecific antibodies. The basic principle underlying this technology involves transformation of the host cell line with the genetic information encoding for four different protein chains. Although the cell line produces the desired combination, it may also yield nine other antibody combinations. In order to avoid the mispairing of heavy and light chains, the protein chains have to be altered in a way that favors the formation of the correct molecule. This is achieved by two pivotal changes: first, the CH3 domains of two heavy chains are modified so that one exhibits a knob and the other a hole. The second alteration ensures the correct pairing of the light chains to their corresponding heavy chains. This is done via the crosswise exchange of CH1 and C in one arm of the antibody to produce a CrossMAb. The CrossMAb The bispecific antibody binding both Ang2 and VEGF-A is expected to weaken and ultimately eliminate a tumour by reducing the supply of nutrients from blood vessels, thereby suppressing tumour growth. Blood vessel formation requires a complex sequence of steps stimulated by Ang2 and VEGF-A. Because they are essential for angiogenesis, inactivating these two growth factors should allow the bispecific antibody for Ang2 and VEGF-A to strike the tumour effectively. Different challenges had to be addressed when developing the CrossMAb . The most important prerequisite was that the four protein chains be expressed in the correct, stable stoichiometric relationship. To do this, two DNA plasmids, each carrying the genetic information of one light and one heavy chain, were transferred into CHO cells. Both plasmids were mixed in different ratios, and the resulting cell clones were analysed. Twelve of the best candidates were subcloned and 23 of these subclones were characterized intensely in shake flasks and 2L bioreactors. The most important parameters for selecting the clones and subclones were IgG quantification and the analysis of unwanted byproducts, such as incomplete antibodies or heterodimers of two light chains. The best clones were further tested for expression stability, product quality, glycosylation pattern, structural integrity, antigen binding and bi-functionality. In order to produce material for preclinical toxicological studies, the selected clone was cultivated in 100L and 250L SUBs. During these fermentation processes, cells reproducibly reached densities of up to 8 x 106 mL-1 and maximal product concentrations of 4g/L-1. Design of the SUB plant The conceptual design phase of the SUB plant revealed that cell growth and product yield in different types of SUBs are comparable to those in stainless steel fermenters. The rocker and stirred tank vessels that were ultimately chosen are combined in such a way that their split ratio is 1:5, and each pre-fermentation line supports two main fermenters. The plant consists of 50 L, 100 L and 250 L fermenter lines (see Figure). Because each reactor has ports for feeding nutrients, all of the pre-fermenters can also function as main fermenters. Flexible tubes connect the different reactors. Depending on the desired combination, split ratios between 1:2 and 1:10 can be realized. Fermentation systems
and processes The cell-culture media are prepared in stainless steel vessels with working volumes of 60-600L for single or multiple fermentations. Finally, the media are passed through sterile filters into storage bags or directly into fermenter bags. The cells are cultivated in 10-20L bags, which are fixed on a rocking system that is aerated through the head space. SUBs with a working volume of 50, 100 und 250L are cylindrical, and contain a marine impeller for mixing the culture. The bag is aerated via submerged gas injection. All fermentation units are mounted on wheels and are supplied with the required media (gases, electricity) from the ceiling, which allows them to move when desired. Temperature, pH and pO2 are recorded and controlled in every fermentation bag. Some types of bags contain only optical sensors with a disposable sensor patch to measure pH and pO2, while others also allow users to insert electrochemical probes. Additional single-use sensors control pressure in the bags and enable monitoring of foam formation. The pressure control prevents overpressure, which can cause disruption of bags. Online and offline data are recorded and visualised, with different parameters of several fermenters shown in a single plot. This allows it to make fast comparisons, even between ongoing fermentations. 10-50L cultures are harvested using depth filtration or swing-head centrifuges with a capacity of 6-12L. In 100-250L fermentations, the cells are removed by separators. The reactors support Roche Pharma projects by culturing many cell lines and applying different process techniques, allowing for batch and fed-batch processes with up to three nutrient feeds. To provide proteins for early project phases, mammalian cell lines are transfected with DNA plasmids, or insect cells are infected with baculoviruses. Murine hybridoma lines can also be cultivated in SUBs. During late project phases, stably-expressing CHO lines are used for producing material for preclinical toxicological studies, as is the case with the CrossMAb . Bioprocesses with stable CHO lines are transferred to the GMP area, equipped with identical 250L SUBs and meet the demand for the early clinical phases. Implementing SUB technology at Roche’s site in Penzberg established a fermentation platform producing enough material to cover demand from early project phases up through clinical studies. Outlook The CrossMAb proves that these new antibody formats can be manufactured for therapeutic applications. Further development of these formats will lead to proteins that are designed for specific indications and that clearly differ from naturally occurring antibodies. SUB technology allows it to shorten development timelines and to use identical processes for supply of GLP-tox and early clinical phases. Fermenters on a scale of about 10 m³ are needed for late clinical phases and market supply. Stainless steel reactors will continue to be used for these applications, as these dimensions are still difficult to achieve with SUBs.
References Eisenkrätzer D, Herrmann A, Lipok G , Caudill U, Guilmaille O, Paul W, Traverse M , Reithmeier R, De Roo E (2010) Roche’s platform for early process development & transfer based on single use bioreactors. GVC/DECHEMA Tagung Bioprozessorientiertes Anlagendesign, 2010, Nürnberg. Herrmann A, Eisenkrätzer D, Paul W, Lipok G, Kuske S (2011) Implementation of single-use technology into existing facilities. 4th European Biotechnology Day 2011, Neuss. Klein C & Schaefer W (2009) Bivalent, bispecific anibodies. WO 2009080253 A1. Kohnert (2011) Expression of bispecific antibodies in CHO Cells. IBC's 7th Annual Cell Line Development & Engineering, 2011, Boston. Paul W, Hauser F, Schwald C, Reithmeier R, Herrmann A, Eisenkrätzer D (2011) Single-use sensors in the environment of disposable bioreactors with application in fermentation processes. BioTech 2011, Wädenswil. Ridgway JB, Presta LG, Carter P (1996) “Knobs-into-holes” engineering of antibody CH3 domains for heavy chain hetreodimerisation. Protein Eng 9: 617-621. Schaefer W, Regula JT, Bähner M, Schanzer J, Croasdale R, Dürr H, Gassner C, Georges G, Kettenberger H, Imhof-Jung S, Schwaiger M, Stubenrauch KG, Sustmann C, Thomas M, Scheuer W, Klein C (2011) Immunoglobulin domain crossover as a generic approach fort the production of bispecific IgG antibodies. Proc Natl Acad Sci USA 108(27): 11187-11191
Contact Stefan Koch, Ingo Gorr und Wolfgang Paul Roche Diagnostics GmbH, Biologics Research Pharma Research and Early Development (pRED) Stefan Koch@roche.com
European dealmaking numbers went up in 2011, but what will 2012 look like? It’s still early days, but the year has already seen some major agreements and takeovers. With the exception of Roche, which has issued a US$5.7bn hostile bid for Illumina Inc., most of the activity is dominated by US companies like Amgen, Bristol-Myers-Squibb and Celgene. Because many antibody patents run out this year, however, the biosimilars sector in particular is expected to see a lot more action.
By 2017, biologics revenues of US$60bn are in danger due to patent expiry, according to an analysis by Burrill & Co. Despite its special requirements, biosimilar development has become a very popular area. None of the currently approved biosimilars comes even close to antibodies in terms of complexity, but financial incentives make the idea of biosimilar antibodies tempting. Remicade (US$4bn in annual sales) goes off-patent in Europe in 2014. Herceptin (US$5.7bn) and Rituxan (US$5.5bn) follow in the same year and 2015, respectively. One of the most active players in the market is Merck & Co. The US pharma is aiming to have five biosimilars in late-stage testing by 2011. To do so, it has formed various alliances. Merck’s new friends include the CRO Parexel and South Korean manufacturer Hanwha Chemical. The partners are currently trying to bring to market a generic version of the fusion protein Enbrel (sales of US$6.2bn in 2010). And there are new players in the sector, including Samsung. The South Korean electronics conglomerate known for mobile phones and flat-screen TVs has identified biologics as a promising target. Over the next 10 years, it’s investing US$1.9bn in the area. Even Amgen, not long ago one of the strongest opponents of biosimilars, has teamed up with Watson Pharmaceuticals to develop and commercialise biosimilar oncology drugs, among them many antibodies.
Sweden’s Karo Bio AB has been hit hard by toxicity issues with its lead compound eprotirome. The anti-cholesterol drug – which was in Phase III clinical development – proved unsafe in a long-term animal tests. The drug lead to...
Sweden’s Karo Bio AB has been hit hard by toxicity issues with its lead compound eprotirome. The anti-cholesterol drug – which was in Phase III clinical development – proved unsafe in a long-term animal tests. The drug lead to cartilage damage in dogs after 12 months of exposure. “These unexpected findings mean that it cannot be excluded that humans could suffer from similar cartilage damage,” said Karo Bio in a statement, which indicated it had spent around €11m (SEK 100m) on the eprotirome programme to date, with another €6.2m (SEK 55m) still to come in wind-up costs. “Eprotirome has been a project with great potential, but also a project with risks,” commented Karo Bio CEO Per Bengtsson. “Unfortunately, the risks associated with long-term use do not outweigh the benefits, which is why we are forced to make this difficult decision.” In the wake of that news, the Huddinge-based company announced it was also giving up its plan to spin off its preclinical development business. Karo Bio had intended to sell it to new owners in order to strengthen its financial position. But with the termination of the eprotirome program, the developer is now faced with having to interest investors in the prospects of the company’s other projects and its collaboration with Pfizer. The US drug giant agreed last December to fund research of the biotech’s drugs that target the RORgamma pathway to fight autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. At the end of February, Karo Bio announced it was laying off 17 employees – a quarter of its workforce. Together with other measures, this should save cash and keep the company afloat until at least 2013.
Brussels – With three new Innovation Partnerships, the European Commission (EC) intends to eliminate weaknesses, bottlenecks and obstacles in the European research and innovation system. The key challenges to be met are the...
Brussels – With three new Innovation Partnerships, the European Commission (EC) intends to eliminate weaknesses, bottlenecks and obstacles in the European research and innovation system. The key challenges to be met are the supply of raw materials, sustainable agriculture, and active and healthy ageing. It’s the Commission’s view that all three require a more concerted innovation effort across the public and private sector, in order to improve quality of life and position Europe as a global leader. The agricultural productivity and sustainability partnership aims at the reversal of the recent trend of diminishing productivity gains and targets to improve soil quality to a satisfactory level by 2020. In order to increase innovation supporting exploration, extraction and processing of raw materials, the Commission launched the raw materials partnership. The project is set to improve recycling of electronic equipment and other waste and calls for the development of substitutes for critical raw materials. Finally, the European Innovation Partnership on active and healthy ageing seeks solutions for the demographic change in Europe. The number of European citizens aged 65 and over will double over the next 50 years. This poses the European care and social systems to a challenge and calls for redesigning these systems in the interest of patients, healthcare systems and the innovative industry.
Inspiration Biopharmaceuticals Inc. reported on 22 February that its lead candidate drug proved successful in a clinical trial involving 12 patients who suffer from hemophilia B. The results were presented at the 5th Annual EAHAD...
Inspiration Biopharmaceuticals Inc. reported on 22 February that its lead candidate drug proved successful in a clinical trial involving 12 patients who suffer from hemophilia B. The results were presented at the 5th Annual EAHAD Congress in Rome, where Inspiration is also headquartered. The drug, an intravenous recombinant Factor IX product, safeguarded major surgical measures by guaranteeing effective hemostasis. It has now completed pivotal Phase III clinical testing in the US, Europe, Israel and India.
7th Berlin Conference on IP in Life Sciences: Big Data, Big Drugs
The health care industry faces significant transformation, driven by a boom in knowledge within biomedical sciences and breakthrough technologies such as gene sequencing. The management of "big data“ will change the understanding of diseases, development of drugs and treatment of patients. more