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Jan 1, 2010 (Vol. 30, No. 1)

Innovating Protein-Expression Systems

As Companies Diversify Portfolios, Production Processes Need to Be Retooled

  • Mind the Gap

    “In the course of stable bacterial cell-line development, we need to consider process formulation and regulatory requirements at the earliest time possible,” says Annette Hillebrand, Ph.D., senior scientist at Dynavax Technologies. Her company currently has several products in clinical trials, including a hepatitis B vaccine, and two additional therapeutic agents for hepatitis B and hepatitis C. Dynavax’ research strategy also encompasses products for asthma, autoimune diseases, and flu.

    Hillebrand sees a gap, especially in larger biotech firms, between the research division and the production division, with the result that frequently the two phases of a drug-development program fail to mesh effectively. The result is that protocols mapped out by research teams may fail in the production phase because R&D units are primarily concerned with proof of principle, and industrial-scale expansion of production may not figure into the equation. This means that time and resources are wasted, and clinical programs are delayed.

    “There is a huge gap between researchers and process developers with the result that the two groups frequently do not communicate and work at cross purposes to one another,” believes Dr. Hillebrand. “So it is critical in microbial cell-line development that all regulatory requirements be accounted for at an early stage.”

    She cites her experience with different expression plasmids—while there is a huge variety of commercial options from which to chose, there is only a limited choice of ones that will function in the production phase.

    Dr. Hillebrand also details the development of a stable expression strain for Dynavax’ universal flu vaccine. At Rhein Biotech, the company’s European subsidiary, she tested various strains to evaluate the long-term expression stability of the same genetic construct in different host strains. “This testing in an early stage of development helped avoid possible issues that could arise at the upscaling phase when clinical quantities are required.”

  • From A to Zera Fusions

    “We are working on multiple applications of our assembler peptide, one being a versatile bioprocess for protein manufacture,” states Stefan Schmidt, Ph.D., vp of technology at ERA Biotech. The company’s technology is based on the use of the g-zein protein in maize. This storage protein takes part in protein body formation, notably in the endosperm of the corn plant.

    ERA’s technology involves the construction of a fusion protein between the Zera assembly peptide and a target recombinant protein gene. As the protein bodies are formed in the course of cellular biosynthesis, the Zera fusion protein is sequestered inside the storage organelle where it is well-folded and protected from proteolysis. These StorPro Organelles can be engineered into mammalian cells or other eukaryotic hosts without affecting the host cell’s viability.

    This technology is of particular value in protecting unstable or difficult to express recombinant proteins, such as peptides, and antimicrobials from normal host-cell metabolism. Purification and removal of contaminants is particularly easy, Dr. Schmidt says. Major advantages of the system include compatibility with existing vector and expression enhancing systems, protection of both cell and protein by encapsulation, simplifying the downstream process, thus leading to a shorter time frame and lower costs of goods, he adds.

    “We are currently pushing product applications,” Dr. Schmidt says. The expanding platform technology of the company will embrace cleavage systems and affinity binder options, a tool box of vectors and enhancers, and a multihost, high-throughput system.

    “The Zera format is especially versatile, in that it could allow various administrations of the fusion proteins in the StorPro bodies, as well as traditional application of the highly purified recombinant protein.”

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