February 1, 2013 (Vol. 33, No. 3)

The optimal development of cell lines to provide protein-based medicines for applications targeting diseases in humans is essential for increased efficiency and lowering final cost of goods. Biotechnology companies require their outsourcing partners to take concepts from the laboratory and produce stable cell lines, yielding a high-protein titer at the fastest speed and at a minimum cost. Cell-line development is a fundamental growth area for contract manufacturing organizations such as Cobra Biologics, providing new business and facilitating strong growth in European and North American markets.

Cobra Biologics optimizes cell-line development using a unique technology that infuses ubiquitous chromatin-opening element (UCOE) technology with cell-line development expertise to yield increased recombinant protein and antibody production. UCOE expression vectors contain the DNA sequences of housekeeping genes that increase transgene expression in eukaryotic cells by remodeling the surrounding chromatin, inducing a decondensed state—a prerequisite for efficient gene expression. Importantly, UCOE technology enables rapid isolation of high-expressing clones—a key obstacle to cell-line development.

Utilising an automated plate-handling robotic system (Cello™, from TAP Biosystems) for cell-line development enables large-scale, rapid clone selection based on factors such as number of clones per well, clone size, and shape. In addition to screening, it has expansion capabilities from 96- to 6-well plates and employs a high-resolution microscope permitting visual clone detection. The robotic system is coupled with software, allowing complete management of the process and traceability of all liquid handling for each clone.

The company uses microbioreactor technology (Ambr, from TAP Biosystems) for evaluation of process parameters. The better monitoring and process control capability, compared to the shake flask culture, is a significant advantage and allows data on the cells’ behaviour and product characteristics to be collected before larger bioreactor studies. This ensures superior product similarity to that achieved in a large scale bioreactor. Twenty four differing bioreactor conditions can be evaluated in tandem, and additions/sampling is automated making optimization highly efficient. Clones can be selected from expression studies in batch or fed-batch mode and expression stability can be evaluated. There is also scope for evaluating temperature shift and information regarding pH changes.

Alligator Bioscience, Algeta, and KAHR Medical are all leveraging aspects of some or all of these technologies for cell-line development.

Ulrica Skoging-Nyberg, Ph.D. ([email protected]), is service delivery manager, cell culture at Cobra Biologics.

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