Periodic Reporting for period 2 - IcoCell (Cell line development platform for SMEs to reduce the length and cost of biologic drug development) Reporting period: 2017-05-01 to 2018-08-31 Summary of the context and overall objectives of the project Due to high development and production costs, biologic drugs are expensive for patients and reimbursement agencies ($45 per day vs. $2 per day in case of chemical drugs, on average), limiting the access to these therapies and burdening healthcare systems. To a great extent, this is because traditionally flexible and creative biotech SMEs currently lack rational engineering tools for mammalian cell line development, meaning that large initial investment in terms of capital and time is required to engineer a production cell line.Icosagen Cell Factory (ICF) develops a platform for more rational, efficient and cost-effective development of mammalian cell lines for high-yield protein production. This platform utilizes cell lines with predefined integration sites at the most transcriptionally active genomic loci. By predefining the integration sites, more than 10x less clones have to be analysed to find cell line with high levels of recombinant protein production compared to the current random screening. In addition, initialization of the specific recombination-dependent integration of the expression unit and amplification of the recombinant DNA reduce additionally the need for the screening of large number of clones. The platform reduces the need for robotic systems and high-throughput screening facilities, while reducing also the time required for cell line development from 6-12 months to less than 3 months.Advances in cell line development technologies are crucial to support the rapid development of biologics, where improvements in the timeline and the ease of generating high producing cell lines can contribute to the faster development of biosimilars and innovator products alike. Market introduction of the IcoCell technology is expected to result in better health outcomes through better availability of biologics, and cost reduction for healthcare systems.The objective of the IcoCell project was to optimize and validate the IcoCell technology for market introduction. Successful implementation of the project was expected to allow ICF to significantly increase the coverage of the needs of the customers who are developing therapeutic proteins. In addition to assisting them in pre-clinical phase, ICF would be able to help the customers to enter into the clinical phase of the drug development, and start serving more attractive and profitable client segments. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The project has been implemented according to the initial work plan. The Work Package 1 (WP1) aimed to generate necessary tools and know-how for cell line development in later stages of the project. The development work resulted in the method for IcoCell cell line generation, which was used in WP2 to generate suitable IcoCell cell lines. Also, standard Operating Procedures (SOPs) useful for generation and characterization of IcoCell cell lines were developed and validated by using these to test the cell lines. Characterization and comparison of all cell lines allowed selecting the one that showed the best growth characteristics and stable high-yield reporter protein expression, thus having the most potential for industrial application. The analyses conducted by subcontractor confirmed that the cell line does not contain microorganisms such as bacteria (including mycoplasma) and fungi. Furthermore, transmission electron microscopy (TEM) analysis did not detect virus-like particles nor other contaminants in the cell line. In WP3, we came to a conclusion that the majority of clones behave similarly to the landing-pad cell line in terms of growth and stability, and thus, could be used in large-scale protein production. The results suggest that targeted integration through recombination mediated cassette exchange is a beneficial approach to generate stable recombinant cell lines for industrial manufacturing of recombinant proteins, of which stability is an important characteristic. However, recent results suggest that the cell line might not be suitable for cGMP production, and thus we have shifted our initial commercialization focus to the IVD segment, which uses large amounts of proteins for diagnostics and research. In WP4, many new customer prospects have been directly contacted in international events and major conferences, current and potentially new customers have been approached with a proposals for cell line development, and the project and its results have been disseminated from a public interest perspective. ICF started the more intensive sales process in August 2018 and has approached several of its current and potentially new customers with concrete proposals and price quotes for cell line development. By now we have signed the first contract for cell line development. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Compared to the current state-of-the-art, cell line development with IcoCell will be up to 50% less expensive and requires lower investment but still provides an improved combination of benefits in terms of speed, quality, quantity and usability. IcoCell technology will support the introduction of new biosimilars and lower manufacturing costs, providing an ever-increasing opportunity for biologics to penetrate more cost-sensitive indications, markets and target groups. This translates into better population health: quicker recovery times, fewer additional treatments, and improved quality of life.According to our best knowledge, a few biotechnology companies have started developing technologies to address the same market gap, indicating the relevancy of the challenge and existence of the business opportunity. However, all these alternative technologies are still in a very early stage of development, meaning that market introduction of the IcoCell technology in the near future as planned has still the same socio-economic impacts as expected. So far, the main societal implication of the project is the increase of awareness about the IcoCell technology and the addressed challenge among relevant stakeholders and the general public. The expected wider socio-economic impacts of the IcoCell technology are already arising as we have signed the first contract for cell line development. icosagen-002.jpg
