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Laupheim to become an international forum for biomanufacturing

The 2nd Laupheimer Zelltage conference organized by Rentschler Biotechnologie GmbH in Laupheim on 11th and 12th June 2012 focused on “Bioprocess light”. Twelve experts from applied research institutions and biotech companies from Germany and abroad provided the 200 or so guests with information on how modern bioproduction methods can be made simpler, more robust, cheaper, more reliable and hence more competitive.

Initially conceived as a stimulus for regional academic and industrial research, the Laupheimer Zelltage conference, now in its second year, has already become an international forum for industrial bioprocessing. The organizers say that in future the conference will become a platform for the international exchange of ideas and will take place every two years, alternating with the ESACT (European Society for Animal Cell Technology) meeting, which focuses specifically on animal cell culture, combining basic science and the application of basic science in industrial biotechnology. The 3rd Laupheimer Zelltage conference will be held on 2nd and 3rd June 2014.

A legend to give keynote lecture

A “legend in the field of cell culturing”, was how organizer Roland Wagner from Rentschler introduced Manuel Carrondo from iBET (Instituto de Biologia Experimental e Tecnológia) in Oeiras (Portugal) and long-term president of the European Society of Animal Cell Technology. Carrondo opened the symposium with a speech on the state of animal cell culture technologies. He is seen as a key pioneer in the further development of bioprocess technology and pharmaceutical biotechnology in Europe. Carrondo pointed out that at present around 70 percent of all biopharmaceuticals are produced using CHO (Chinese hamster ovary) cell lines, which are one of the most popular tools in pharmaceutical biotechnology. However, due to their restricted susceptibility to viruses, hamster ovary cell lines are unsuitable for use in vaccine production.

Market of the future: virus-based biologics

The 2nd Laupheimer Zelltage conference was held in Großlaupheim castle and provided a unique venue for the international exchange of knowledge. © Rentschler

Rentschler Biotechnologie GmbH’s Markus Hörer spoke about virus-based biologics and the potential of cell culturing for the new class of ATMPs (advanced therapy medicine products, which include products for cell and gene therapy, viral therapies, regenerative medicine and cancer vaccines). Virus-based biologics use custom-made viruses or parts of viruses to transport a specific freight into human cells where they exert their effect. Industry believes that virotherapies have great market potential in the treatment of cancer. Virotherapies are treatments that use biotechnology to reprogramme viruses to attack cancerous cells, leaving healthy cells undamaged. These oncolytical viruses selectively target and lyse cancer cells as they arise. In principle, therapies involving oncolytic viruses work, but a breakthrough cannot be expected in the near future as the level of efficiency is still too low.

Rentschler is involved in the development of these new technologies, both in its own research centres in Laupheim and in cooperation with universities such as the Hanover Medical School and the Gene Therapy division at the University of Ulm.

Copper does cells good

Martin Gawlitzek from the San Francisco-based company Genentech reported on a development in the upstream area that was new even to experts. Genentech, which is the biotechnology industry pioneer, succeeded in considerably increasing protein yield by adding copper to the nutrient medium. Copper, which is added in the form of copper(II) salt (2+ ions), activates a specific enzyme of the electron transport chain (also known as respiratory chain). The cell transports the copper ions to the correct destination within the electron transport chain. At lower concentrations, copper ions play an important biological role (essential trace element, electron/oxygen transportation), whereas large amounts are toxic. The use of specific copper concentrations in the nutrient medium led to a doubling of the protein yield and was also associated with a better metabolism profile, reported Gawlitzek at the Laupheim conference.

Niall Burron from Dublin City University gave a presentation on how the control of genes and the genome enables researchers to predict cell productivity. Until now, the development of cell lines has frequently been associated with clones becoming instable and either abruptly or gradually losing their transgene expressivity. Bioinformatic methods can now be used to identify genes as suitable biomarkers and increase the productivity of cells.

Greater productivity, smaller manufacturing plants

Gerben Zijlstra from DSM Biologics based in Groningen in the Netherlands provided information about a highly efficient product enrichment process during which the cells are left in the bioreactor for longer than normal. The Dutch contract manufacturing company achieved yields of 25 to 40 grammes of protein (monoclonal antibodies) per litre, and was also able to switch the production process from 50-l reactors to smaller disposable bioreactors. This high-performance process will help to reduce the size of future production plants.

Andreas Popp from the Munich-based biotech company Morphosys, which has a well-filled antibody pipeline, reported on the future production of three proprietary products. The company has established a versatile production platform that addresses a broad range of different requirements associated with the development of therapeutic antibodies, from discovery to preclinical and clinical development.

Process monitoring with light

Anurag Khetan from Boehringer Ingelheim gave the audience an overview of Boehringer’s activities. Khetan, a specialist in process technologies who also worked for several years for the big biotech company Biogen Idec in Boston, pointed out that Boehringer’s activities will be expanded to smaller (single-use) bioreactors in the near future, rather than just using fermenters ten cubic metres in size. The company envisages that smaller fermenters will give greater production flexibility.

Khetan also reported on how cell culture processes can be improved through online monitoring, which is another step towards automating the biopharmaceutical production process. The different production processes were previously monitored by determining physical parameters such as temperature and by removing samples for checking a cell’s vitality parameters or nutrient content. Digital, spectral methods enable the minimally invasive monitoring of the reactor broth as the light-induced collection of information from the nutrient medium can be converted into mathematical data and enable safe monitoring of the production processes.

Turbo cell: a cell ready for production

What turns a bioprocess light? Laupheim was a platform for discussing the latest developments in industrial biomanufacturing. © Rentschler

Dethardt Müller from Rentschler Biotechnologie GmbH reported on turbo cells, which are specifically prepared cells containing a marker gene that can be quickly exchanged with a gene needed by the company’s clients. The new method is the result of the targeted integration of genes into the genome of cells and also enables Rentschler to minimize the time required for cell line development at the same time as increasing process reliability. The traditional development of cell lines harbouring a gene at a desired location was a time-consuming process that required a lot of material. The new development is much less costly and saves a great deal of time, taking the process from 5 months to 7 weeks.

Ana Teixeira from the Instituto de Biologia Experimental e Tecnológica (iBET) in Portugal spoke about multivariate analysis in the cell culture process. Multivariate analysis combines all variables into a uniform system, thereby becoming a useful tool for data search and the data-driven modelling of complex systems where complete mechanistic information is still lacking. Teixeira also provided examples that show where this biopharmaceutical process can be used, including the analysis of multi-dimensional fluorescence data in CHO cells for monitoring cell density and antibody yield or the high-throughput screening of cell cultures. The method is specifically suited for late development stages and market production. 

Specialist for sugar residues

Lars Stöckl from Berlin-based Glycotope GmbH which also owns a production plant in Heidelberg, reported on a technology used to produce glyco-optimized biopharmaceuticals. CHO cells are almost as efficient as human cells in post-translational glycosylation. Glycotope is trying to close the gap and achieve fully identical human glycosylation. Glycotope owns cells and methods with which it can carry out fully human glycosylations that reduce the likelihood of being seen as foreign by the human immune system. The company can also modify glycosylation in line with the requirements of a particular drug. Glycotope has around 150 employees and is a leading company in glycomics and immunotherapeutics and popular partner for the biopharmaceutical industry.

The two doctoral students Verena Thies and Julia Suerth from the research group led by Christopher Baum at the Institute of Experimental Haematology at the Hanover Medical School (Germany) talked about alpha retroviruses, their safety and their potential use in gene therapy.

Marc Bisschops from Tarpon Biosystems based in Leiden in the Netherlands spoke about methods for the continuous purification of monoclonal antibodies. These new methods are more efficient, require less space and process more material than previous downstream methods. This technology could thus be a solution for achieving much greater productivity in large bioreactors.

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