Germany launches EUR200 million biotechnology research programme
Berlin – Germany is to invest EUR200 million over the coming 15 years to develop the next generation of biotechnology processes. “The full potential of biotechnology isn’t yet fully exploited”, said BMBF State Secretary Helge Braun during the presentation of the new Biotechnology 2020 Plus programme in Berlin. “We can change this by applying engineering principles to biotechnology.” A long-term goal of the ambitious programme is to separate biological functions from cells, and to create robust reaction modules that can mimic biological processes even under harsh reaction conditions. This would enable engineers to integrate the water-soluble biological processes into existing industrial value chains, for example using cell-free photosynthesis modules for energy production, or artificial enzymes or cell modules to produce chemicals in a solvent-free environment. Because most of these goals are currently more vision than reality, the Ministry for Research has kicked off a so-called strategy process that brings together experts from a variety of fields to discuss the kinds of projects required to realise the biologisation of industrial processes. Four major research organisations have signed a memorandum of understanding to contribute to the process. Synthetic biology is expected to play an important role in the programme.
Martinsried – SuppreMol GmbH has enrolled the first patient in a Phase Ib/IIa clinical trial with SM101, a treatment for Idiopathic Thrombocytopenic Purpura (ITP). Up to 36 patients will receive 4 weekly doses of the recombinant,...
Martinsried – SuppreMol GmbH has enrolled the first patient in a Phase Ib/IIa clinical trial with SM101, a treatment for Idiopathic Thrombocytopenic Purpura (ITP). Up to 36 patients will receive 4 weekly doses of the recombinant, soluble, non-glycosylated version of the Fcg receptor IIb, or matching placebo intravenously. Subsequently, SuppreMol plans to enroll an additional 15 patients to expand the study to a Phase IIa parallel-group clinical trial. Primary endpoint is the incidence of adverse events. The main efficacy endpoint is the proportion of subjects with a substantial platelet response. Secondary endpoints comprise number of bleeding events, time to reach platelet response, duration of platelet response, proportion of subjects with rescue medication, and dose reduction of concomitant ITP medication.
Life Technologies PD-Direct® has partnered with Cytovance Biologics to demonstrate rapid process transfer and scale-up using new media developed for fed batch processes and DASGIP Bioreactors. The new media were developed by...
Life Technologies PD-Direct® has partnered with Cytovance Biologics to demonstrate rapid process transfer and scale-up using new media developed for fed batch processes and DASGIP Bioreactors. The new media were developed by Life Technologies as cGMP-compliant for a broad variety of cells, and investigations included the optimisation for bioreactor operations and scale-up. A variety of minor adjustments were also made to maximise product yield and cell density and minimise nutrient depletion between feeds.
Life Technologies PD-Direct® developed a fed-batch bioreactor process for a recombinant CHO cell line producing an IgG antibody at 0.6L bioreactor scale. The process description and cell line were transferred to Cytovance Biologics for scale-up to 5L Process Development Bioreactors and to the 100L production bioreactor in the GMP Manufacturing Facility. The feed medium (GIBCO® CHO CD Efficient Feed™ A) was provided as a prototype of the medium being prepared for commercial launch.
Preparation and procedure
To the extent that scale-up considerations and design differences among the bioreactors would allow, the original bioreactor operating conditions used with Life Technologies’ DASGIP 0.6L bioreactors were used in the Cytovance 5L and 100L bioreactors. No specialised engineering or operating procedures were required to implement the fed batch process. A volume of “Efficient Feed A” equal to 10% (vol feed/initial culture vol) of the initial culture volume on Day 0 was added on each of the days indicated in the feed schedule for each experiment. No adjustments were made to the feed volume to compensate for changes in culture volume due to sampling and feed additions. Efficient Feed A was added at a rate of 2 mL/minute to the bioreactor to avoid oxygen depletion. Glucose was added to maintain glucose at 2-4 g/L before addition of the feed medium. The Cytovance contract manufacturing facility uses a 100L stirred tank bioreactor system designed for GMP production. The bioreactor is designed for automated CIP and SIP, and has been fully qualified and validated. The 5L fed batch process was transferred from Cytovance Process Development Laboratories, with parameters scaled as necessary for the production bioreactor. The scaled-up process was incorporated into the Cytovance platform for GMP manufacturing, including development of approved master batch records, and formal quarantine and release of raw materials against approved specifications by Cytovance Quality Assurance. The Wave Bioreactor cell suspension was used to seed the 100L bioreactor at a working volume of 70L and a cell density of 0.62 x 106 cells/mL. The seeding density was higher than the 5L reference bioreactor run, but was believed to be within the range of acceptable variation for the process. On Days 2, 4, 6, and 8 after inoculation, Efficient Feed A at 10% (v/v) of the initial culture volume was added. The feed medium was added over a period of 3-4 hours to avoid oxygen depletion. The culture was terminated when viability decreased below 50%.
Process transfer and optimisation
At the time the process was transferred, the optimisation of the feed schedule was not complete. The reference 0.6L run in DASGIP bioreactors used a feed schedule of 10% (v/v) CHO CD Efficient Feed™ A feeds on Days 3, 6, and 8. However, glucose was exhausted by Day 5, and glucose, lactate and glutamine were exhausted by Day 9. The Cytovance 5L bioreactor process transfer run used a feed schedule of 10% (v/v) CHO CD Efficient Feed™ A on Days 3, 5, and 7. In addition, glucose supplementation was used as required to prevent the glucose concentration from falling below 1 g/L (Fig. 1). This schedule increased the culture life to 14 days, prevented nutrient exhaustion, and limited waste metabolite accumulation. However, the maximum cell density and product yield were low. The product concentration increased less than 7% after Day 10.
The feed schedule was changed to 10% (v/v) feeds of CHO CD Efficient Feed™ A on Days 2, 4, 6, and 8 without glucose supplementation for the 5L reference bioreactor run. The new feed schedule achieved the desired result of increasing production and cell density, and of preventing exhaustion, or excessive accumulation, of nutrients and metabolites (Fig. 2). Consequently, the conditions for 5L were used to design operating parameters for the 100L bioreactor run. Although there are differences in the growth profile, by the measures of final product yield, specific productivity, and the general metabolic properties of the cultures, the results in the 5L and 100L bioreactors are very similar. In addition, Life Technologies PD-Direct® obtained very similar results with this feed schedule in their 0.6L DASGIP and 5L bioreactors.
A critical issue in process transfer and scale-up is that any significant differences in results among groups and scale of operation can be used to better understand the process. This proved to be true in this project, as shown when Life Technologies PD-Direct™ used the final feed schedule in their 0.6L DASGIP and 5L bioreactors and obtained productivity very similar to the Cytovance bioreactors (Fig. 3). In spite of cell density distinctions, the impact on nutrient and metabolite concentrations is minimal. The extent to which these differences are a consequence of the high seeding density in the 100L bioreactor is not clear. Although the feed schedule should be linked to the time course of cell density, this process is sufficiently robust that the terminal product yield was stable in spite of the variations between runs. In both the 5L and the 100L bioreactors, the metabolic properties of the cells made maintenance of a stable culture environment an easily managed process. Control at the acid side of the pH control dead band required only limited additions of base. pH was regulated by the CO2 stripping action of the fixed air sparge. Oxygen demand was satisfied without difficulty. The feed schedule maintained the major nutrients and metabolites in acceptable ranges until exhaustion of the Day 8 feed. Although there are differences in the cell density profiles between the bioreactors, the final product concentration is remarkably consistent at 900 mg/L and 950 mg/L. Consistent yields were obtained across an approximately 200-fold range of bioreactor volumes (0.6 - 100L) in two unrelated companies, and in three different facilities.D
Literature  Source: Jonathan Mitschelen, Christa Short, Pete VanStraten, Jay Peterson, Ricardo
Graniello, John Conner, Steven Perry, and
John Lightholder, 2010, www.cytovance.com/resources.html, Successful Transfer and 200-fold Scale-Up of a r-CHO Cell Fed-Batch Process Using a New cGMP Compliant Basal and Feed Medium Combination
Acknowledgements Thanks to the co-authors and other people from Life Technologies and Cytovance Biologics for their support.
Tübingen — German mRNA vaccine specialist CureVac GmbH has secured a 27.6 million euro financing round with Dievini Hopp BioTech Holding. The company has announced that it will use the proceeds to drive forward its programmes for...
Tübingen — German mRNA vaccine specialist CureVac GmbH has secured a 27.6 million euro financing round with Dievini Hopp BioTech Holding. The company has announced that it will use the proceeds to drive forward its programmes for RNActive therapeutic vaccines against solid tumours, and to accelerate the development of prophylactic vaccines against infectious diseases. CureVac’s lead compound for prostate cancer, CV9103, is in a Phase IIa trial, with results expected in the second half of 2010. The company is developing CV9201, an mRNA vaccine compound to treat non-small cell lung cancer (NSCLC), in a separate Phase I study.
Heidelberg – Individualised cancer immunotherapy holds great promise, but clinical results have been disappointing because the tumour antigens used to date have not been able to induce sufficiently strong immune responses. Now,...
Heidelberg – Individualised cancer immunotherapy holds great promise, but clinical results have been disappointing because the tumour antigens used to date have not been able to induce sufficiently strong immune responses. Now, German researchers at the University of Heidelberg have presented a novel automated method that is capable of comprehensively identifying candidate tumour proteins that spontaneously trigger strong immune responses (JCI, doi: 10.1172/JCI37646). The team headed by Christel Herold-Mende applied two-dimensional chromatography to fractionate the tumour proteome, and subsequently verified that these protein fractions activate tumour-specific memory immune cells. Applying this method to human cell lysates, the authors identified two previously unknown tumour proteins (transthyretin and calgranulin B/S100A9) that were targeted by the immune system in a patient with a malignant brain tumour. Herold-Mende et al. found that the immune system in 4 out of 10 other brain tumour patients also targeted these proteins. The method is reproducible, fast and inexpensive, and the authors hope that it will be suitable for identifying candidate tumour proteins for the development of individualised cancer immunotherapies.
Ingelheim/Bethesda -Boehringer Ingelheim (BI) and Micromet Inc. will jointly develop a BITE (bi-specific T-cell engager) antibody for the treatment of multiple myeloma. According to the collaboration agreement for the research,...
Ingelheim/Bethesda -Boehringer Ingelheim (BI) and Micromet Inc. will jointly develop a BITE (bi-specific T-cell engager) antibody for the treatment of multiple myeloma. According to the collaboration agreement for the research, development and commercialisation of the bifunctional antibody announced on Wednesday, Micromet will be responsible for the discovery, and will jointly conduct pre-clinical studies of the drug candidate with BI. Micromet’s pharma partner will be responsible for all manufacturing activities, clinical development and worldwide commercialisation, subject to Micromet’s co-promotion right in the US. Micromet will receive an upfront payment of 5 million euros from its partner, and milestones of up to 50 million euros plus low double-digit royalties on product sales outside the US. While Micromet will reimburse a defined amount of preclinical and other costs for its US sales, BI will be responsible for all other payments. BITEs target tumor cells by binding to tumour-specific antigens. They activate T killer cells against the tumour cells by binding to the CD3/CD19 moiety on the surface of the cytotoxic cells.
Berlin - On Monday, German NOXXON Pharma AG announced the successful completion of a Phase I trial with the 1st "Spiegelmer" NOX-A12, an antagonist of stromal cell-derived factor-1 (SDF-1). Final data analysis demonstrated an...
Berlin - On Monday, German NOXXON Pharma AG announced the successful completion of a Phase I trial with the 1st "Spiegelmer" NOX-A12, an antagonist of stromal cell-derived factor-1 (SDF-1). Final data analysis demonstrated an excellent safety and tolerability up to the highest tested dose of 10.8 mg/kg. In addition, analysis by flow cytometry revealed a long-lasting and dose dependent mobilization of WBC and CD34 positive cells. The protocol also allowed that an additional group of volunteers received leukapheresis, should certain thresholds of circulating CD34 positive cells were reached, to further characterize the mobilized cells and this was undertaken. Noxxon intends to develop its intravenously administered drug candidate in haematological malignancies and/or solid tumours. NOX-A12 is scheduled to enter a multiple dose Phase I clinical trial by mid 2010, and phase II clinical testing soon thereafter. NOX-A12 has been evaluated in models of stem cell mobilization, angiogenesis, inflammation and lung and kidney injury. In all of these models, NOX-A12 reduced pathological angiogenesis and tissue remodelling. In preclinical safety and two weeks toxicology studies, NOX-A12 was established as safe with no organ toxicity. In particular, NOX-A12 did not exert any immunotoxicity effects, such as Toll-like receptor activation or changes in cytokine levels.
Berlin/Chicago – Despite the financial crisis, the German biotechnology sector grew in the last year. According to a brand-new biotech-report commissioned by the German Research Ministry and published just a couple of days...
Berlin/Chicago – Despite the financial crisis, the German biotechnology sector grew in the last year. According to a brand-new biotech-report commissioned by the German Research Ministry and published just a couple of days before BIO (Chicago, 3-6 June), Germany’s biotech firms increased employment by 5% to a total of 31.600 jobs (more...). Additionally, the number of biotech companies grew by 6% while revenues remained stable at EUR2.2bn, as in 2008. The report, conducted by biotechnologie.de (with a response rate of over 80% from the companies) provides an excellent source of internationally comparable figures, at it covers all biotech companies active in Germany and is compliant to the OECD biotechnology guidelines. In 2009, there were 531 dedicated biotechnology companies, an increase of 12 firms compared to 2008 and employing 14,950 staff (2008: 14,450). Additionally, the number of companies, in which biotech was only one aspect of business activity, grew from 92 to 114 enterprises, with 16,650 staff (2008: 15,520). The dedicated biotechnology firms had 8 drugs on the market and 102 under clinical development, had invested EUR1bn into R&D and received funding of EUR51m, the same amount as in the year before the financial crisis. However, while public companies increased their capital by EUR122m (+32% as compared to 2008), VC money was difficult to obtain for the most biotech SMEs. VC investments decreased by 30% compared to 2008 and achieved only EUR142m. "German biotech companies have shown tremendous robustness in the economic crisis. Many companies have adapted to the difficult financial environment and reduced their loss, mainly by establishing a profitable service business," said Boris Mannhardt, PhD, Director of Studies of biotechnologie.de and responsible for the annual survey.
Munster – Germany’s federal state North-Rhine Westfalia is to channel EUR 80million into the medical applications of stem cell research. On Friday, the country’s minister Juergen Ruettgers announced that the money will be used...
Munster – Germany’s federal state North-Rhine Westfalia is to channel EUR 80million into the medical applications of stem cell research. On Friday, the country’s minister Juergen Ruettgers announced that the money will be used to create a new Center for Advanced Regenerative Engineering (CARE), at Munster, in which top researchers will focus on applications of stem cell research such as drug screening with cells derived from induced pluripotent stem cells. Such individual human cells provide a new source of disease models that better mimick the processes in the human body than animal cells or models, particularly in drug toxicity screening or medelling of disease mechanisms. Several life science firms including Roche, GE Healthcare and Pfizer are already active in the field. North-Rhine-Westfalia will contribute with 75% of the funding and the rest will come from by the German Research Ministy. The Centre will be located at the Max-Planck-Insitute for Molecular Biomedicine, headed by Germany’s top-stem cell researcher Prof. Hans Schoeler. Schoeler announced that 4 research groups for young investigators will kick-off in the summer of 2010 as part of the funding.
Wuppertal – Bayer’s anti-infectives spin-out AiCuris has raised EUR 55 million in this year’s largest financing round of a German biotech company lead by the existing shareholders. The money will be used to push Aicuris clinical...
Wuppertal – Bayer’s anti-infectives spin-out AiCuris has raised EUR 55 million in this year’s largest financing round of a German biotech company lead by the existing shareholders. The money will be used to push Aicuris clinical development, with particular focus on phase IIa drug candidate AIC246 against infections with the human cytomegalie virus. It will also support other projects, such as against Herpes simplex, HIV, Hepatitis B and C or multi-resistant bacteria. The main investor is the Santo Holding, the financing vehicle of Andreas and Thomas Strüngmann, former owners of the generics company Hexal. AiCuris announced that is also in talks with strategic partners interested in the in-license of Aicuris’ HCMV programme, comprising three further compounds beyond AIC246.
Berlin - On March 30th, Berlin-based biomarker specialist Epigenomics, successfully raised EUR 33,1 million at the public market through the placement of 14,697,361 new shares. The offering started on March 15 at a subscription...
Berlin - On March 30th, Berlin-based biomarker specialist Epigenomics, successfully raised EUR 33,1 million at the public market through the placement of 14,697,361 new shares. The offering started on March 15 at a subscription price of EUR 2.25 per new share and all existing shareholders could buy one new share for every two shares they owned. 46.2% equalling 6,789,613 new shares were sold this way. The remaining 7,907,748 unsubscribed new shares were sold at the subscription price to retail investors as part of a public offering in Germany and Austria, as well as to selected institutional investors in Germany and abroad. London based Abingworth LLP utilised this to become the biggest shareholder of Epigenomics after the capital increase. Epigenomics AG intends to use a significant portion of the net proceeds from the offering to commercialise the septin9-biomarker for the diagnosis of colorectal cancer and develop it further for the use as a diagnostic tool for lung cancer.
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