Biologics and the emergence of biosimilars: innovation driving global opportunity (2011)

Biologics are recombinant DNA-derived therapeutic proteins and oligonucleotides. They include such entities as growth factors, cytokines, hormones and monoclonal antibodies, for the treatment of the major disease indications cancer, inflammatory disease (rheumatoid arthritis, Crohns disease etc) and infectious disease. The present growth in the biologics industry is due to the unrelenting demand for new biologic entities and the expiry of a number of key patents, the latter driving the rapid emergence of biosimilars. Indeed Walsh1 points out that in the four and a half years prior to late 2010, there were 58 approvals within the European Union and/or the United States, of which about 40% (25) were new biologics; and around 50% of the remaining approvals (28) were biosimilars and reformulated existing products. Monoclonal antibodies are the most rapidly growing class of biologic medicine, with over 40 per year entering clinical trials since 2007.2 There is considerable biologics R&D and commercial activity not just in markets of the developed countries, but in the emerging markets of the BRIC countries (Brazil, Russia, India and China) and the Asian Pacific Rim region. Growth in biologics is outstripping that of conventional pharmaceuticals, and this is reflected in the global dynamic of mergers and acquisitions within the biotechnology and pharmaceutical industries. There is also a growing imperative for organisations such as the World Health Organisation and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), to foster a more even and consistent global regulatory landscape, particularly for biosimilars. In this In Focus issue on biologics, we present three review and three research articles, dealing with some of the issues confronting the biologics industry. Two review articles examine cell line engineering from different perspectives; the first review article highlights that manufacturers have in the past been focussed on achieving high titre in the bioreactor for maximising yield, with product quality being a secondary consideration.3 Hou et alcontend that by using innovative strategies in cell engineering such as site specific integration, ubiquitous chromatin opening elements (UCOETM) or scaffold/matrix attachment regions (S/MARs) and zinc finger mediated host cell engineering, more stable cell lines can be generated compared to traditional amplified cell lines, and with more of a focus on product quality, an issue which regulatory bodies are addressing with increasing scrutiny. In the second review article, Dietmair et al4 discuss efforts to date in the engineering of cell lines with superior productivity characteristics (e.g., improved robustness, enhanced protein processing, and metabolic efficiency). Although a number of such strategies have proven successful, the majority have resulted in mixed outcomes. The authors surmise that a fuller understanding of cellular complexity through the application of systems biology approaches, will give clues as to how cells might be manipulated to generate a “mammalian super producer”. Global activity in biosimilar development and the concomitant requirement to demonstrate comparability with the innovator biologic has placed a new emphasis on analytical techniques and methodologies, and has revealed the limitations of analytical methodologies as well as the need for new, more sophisticated techniques. The review by Falconer et al5 explores the analytical techniques and methodologies that are available for testing biologics and assessing comparability, and highlights the concept of an orthogonal approach for determining various physicochemical properties to build a better picture of comparability. Currently 60–70% of biologics are now produced in mammalian cells, with Chinese hamster ovary (CHO) and NS0 myeloma the preferred mammalian hosts. However preclinical assessment of a candidate biologic medicine requires an initial availability of adequate quantities of material, prior to creation of stable production cell lines. There is a need for high yielding, transient expression systems to facilitate rapid pre-clinical assessment; utilising the same host for transient and stable production has advantages from a product consistency and quality perspective, as the candidate biologic progresses from preclinical to clinical testing. Codamo et al6 have developed a transient gene expression (TGE) system based on CHO cells (Epi-CHO system), utilising episomal replication of the gene of interest. Using this system, they have achieved very high product titre, through a combination of high specific productivity and the ability to expand biomass six fold without the need for any extra transfection reagents. HEK cells are commonly used for transient expression, however there may be instances where a stable cell line may be advantageous. Generation of stable, high producing HEK cell lines is described in the second research article by Song et al,7 where a combination of FACS and Clonpix has facilitated the development of a clonal selection method for isolating HEK293 cell lines with high specific productivity. Lastly, there is a consensus in the industry that lowering cost of goods for biologics will be driven principally through innovation in downstream processing. The third research article by Falconer et al8 demonstrates that addition of basic amino acids to Protein A elution buffers improved antibody yield in this case study. Most authors of the articles published in this In Focus issue are researchers from the Australian Institute for Bioengineering and Nanotechnology (AIBN), located at the University of Queensland, Brisbane Australia. The National Biologics Facility (NBF), housed within the AIBN, has extensive bioprocessing and protein characterisation capability, with a mission to develop new biologics (particularly monoclonal antibodies) in conjunction with industry and collaborators, engineer new host cell lines for biologics production, and importantly to translate these research and development activities to the clinic. An exciting development is the new DSM biologics production facility in Brisbane, due for commissioning in 2013. The NBF will work closely with DSM, enabling production of biologics for preclinical testing and early stage clinical trial, and servicing principally both the Australian and Asia Pacific region. The future for biologics is bright, with new biologics entering the pipelines of big pharma, and biosimilars coming to the fore in recent times. The editors of JCTB encourage new submissions of high quality papers associated with the many facets of biologics R&D and manufacture.