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Recent Advances and Trends in the Biotechnology Industry - Development and Manufacturing of Recombinant Proteins and Antibodies


Michael Pohlscheidt and Robert Kiss Genentech, Inc.


Since the early 1980s, biotechnology products have shaped the pharmaceutical industry. A large number of monoclonal antibodies and therapeutic proteins have been approved, delivering meaningful contributions to patients’ lives, and are anticipated to be the major growth driver for the industry in the upcoming years [1-5]. In 2012, the list of the top 20 best-selling drugs included 8 biologics [6] (see Table 1).


Mammalian cells are the expression systems of choice [7-10] due to their ability to properly fold and modify these complex proteins and antibodies. Tremendous process development efforts throughout the last decade have resulted in significantly increased manufacturing scales, product titers (up to 8g/L in fed batch processes), and recovery yields, thereby satisfying heightened market demand for existing and new products. Cell culture manufacturing scales up to 25 m3


operated


in a batch, repeated batch, or fed batch mode, followed by a sequence of chromatography, filtration, and concentration steps delivering API batch sizes of up to 50 to 100 kg of protein/antibody, represent state of the art technology – a typical antibody production process is shown in Shukla and Thömmes 2010 [11-13]. Perfusion processes have been reported as an alternative manufacturing strategy to traditional large-scale fed-batch processes. Perfusion processes typically utilize smaller bioreactors in scales up to 1000 L, with high perfusion rates and process durations up to 200 days. [12, 14-23]


Since the generation of murine monoclonal antibodies via hybridoma technology by Kohler and Milstein [24], numerous milestones in the industry have been achieved, and advances in research, development, and manufacturing have been described.


These include fully


humanized recombinant monoclonal antibodies and the exploitation of antibody fragments for favorable characteristics, as well as the introduction of novel scaffolds based on antibody technology. Recently, the glyco-engineering of antibodies and fusion proteins are exploiting favorable modifications of antibody binding sites, as well as the antibody Fc sequence for enhanced effector function. The first non-radioactive antibody drug conjugates (e.g. Adcetris®, Kadcyla®, Mylotarg®) have received approval and will enable more targeted therapies and – in conjunction with companion diagnostics – open the gate to personalized healthcare. The version “2.0” of future


48 | | September/October 2013 - 15TH ANNIVERSARY ISSUE


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