Monoclonal antibodies manufacturing

Hood, E.E., Woodard, S.L., and Hon, M.E. (2002). Monoclonal antibody manufacturing in transgenic plants myths and realities. Curr. Opin. Biotechnol. 13(6) 630-635. 

Projected Intensified Large-Scale Monoclonal Antibody Manufacturing Process... 

Drug Class monoclonal antibody Manufacturers Pfizer Pharmaceuticals, 235 East 42 Street, New York, NY 10017 PanGenetics BV, Heath House, Princes Mews, Royston, SG8 9RT, UK Johnson and Johnson, One Johnson Johnson Plaza, New Brunswick, NJ 08933... 

Figure 1.18 Upstream process flow diagram of a design proposal for a 3x lOm (working volume) monoclonal antibody manufacturing facility. The tanks and bag(s) at the right...

Huang, P. Y., and Peterson, J. (2001). Scale up and vims clearance studies on vims filtration in monoclonal antibody manufacture. In W. K. Wang (Ed.), Membrane Separations in Biotechnology. Marcel Dekker, New York, p. 327. 

Rituximab is a recombinant mouse/human chimeric monoclonal antibody whose in vitro activity varies with the number of terminal galactose moieties glycosylated to the peptide backbone at residue asparagine 301 [8]. The ability to monitor the levels of each discrete species present would allow the manufacturing process to... 

Mammalian cell culture is more technically complex and more expensive than microbial cell fermentation. Therefore, it is usually only used in the manufacture of therapeutic proteins that show extensive and essential post-translational modifications. In practice, this usually refers to glycosylation, and the use of animal cell culture would be appropriate where the carbohydrate content and pattern are essential to the protein s biological activity, its stability or serum half-life. Therapeutic proteins falling into this category include EPO (Chapter 10), the gonadotrophins (Chapter 11), some cytokines (Chapters 8-10) and intact monoclonal antibodies (Chapter 13). 

Anon. (1997h). Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use. http //www.fda.gov/cber/cberftp.html... 

The ratio of primary antibodies to Fab fragments required for the formation of complexes that produce optimal immunolabeling of specific antigen does not appear to vary dramatically with primary antibody specificity or species. Primary antibody to Fab fragment ratios of 1 2 1 4 (weight for weight, based on concentration data supplied by manufacturers) typically produces optimal results with primary mouse monoclonal antibodies. 

In addition to the above extracellular parameters, cell concentration and cell activity are two important cell-associated parameters that determine how well a fermentation process is performing. The manufacturing of biological products (antibiotics, amino acids, monoclonal antibodies, and other protein products) at large scales requires that cells be cultured at high cell densities and stay metabolically active. Consequently, much effort has been expended to develop techniques that can allow the estimation of cell concentration and cell activity in real time during a fermentation. 

Immunoglobulins in the form of monoclonal antibodies are manufactured commercially for therapeutic and diagnostic uses. Major areas of consideration in these applications are quality control and bioactivity. Separation of immunoglobulins has proven to be a challenge even for well-established techniques such as HPLC. Difficulties arise due to the large size of antibodies and their surface properties, which increase their tendency to interact with proteins and matrix. 

The development and commercial success of the first monoclonal antibody used to treat tumors in the United States have had broad consequences. Companies have pushed ahead with the development of a variety of additional monoclonal antibodies. Six years after rituximab was approved, more than one third of the 38 approved recombinant proteins manufactured in mammalian cells were antibodies (some of the most notable are listed in Table 32.1). Many of these antibodies are used at large doses that were not thought to be economically practical 10 years ago. Today, the pharmaceutical industry is facing a projected shortage of manufacturing plants for recombinant proteins synthesized by mammalian cells, and there are still more than 400 monoclonal antibodies reported to be in clinical trials. 

Is the discovery and development of another blockbuster monoclonal antibody like rituximab a feasible research and development model today Many of the special events that contributed to its success are probably not replicable. As with several other successful drugs, the market turned out to be much larger than anticipated, so competition from other drugs being simultaneously developed was not so intense. Similarly, the ability to manufacture the drug in a cost-effective manner did not exist when the project was initiated, but there were other advantages unique to rituximab. Its toxicity is minimal, a... 

Center for Biologies Evaluation and Research. Guidance for Industry Monoclonal Antibodies Used as Reagents in Drug Manufacturing, FDA, RockviUe, MD, 2001. 

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