Scientists at US biotechnology firm Cell Genesys have developed a gene expression technology that could improve the commercial production of monoclonal antibodies and other complex therapeutic proteins, reports Phil Taylor.
The system enables the production of full-length monoclonal antibodies at commercially relevant levels from a single production cell line, and cuts the time required to develop cell lines that can be used for commercial production can be significantly shortened from months to weeks, according to the researchers.
The discovery relies on the use of a peptide called 2A, derived from the virus that causes foot and mouth disease, alongside viral vectors used to deliver genetic material into cells. Making cell lines for producing complex proteins such as MAbs generally involves transfecting a mammalian cells line - often Chinese hamster ovary (CHO) cells - with plasmid or viral DNA. But stable expression of recombinant proteins in CHO and other mammalian cells is tedious and time consuming since only a small percentage of stable clones express large quantities of protein.
The Cell Genesys researchers' solution is to transfect the sequences coding for the two portions of the antibody - known as the light and heavy chains - alongside a sequence that codes for the 2A peptide. The latter acts as a bridging sequence, allowing both the heavy and light chains to be read form a single frame. The researchers, led by Drs. Jianmin Fang and Karin Jooss, reported the work in the April 17 on-line issue of the journal Nature Biotechnology.
Dr Peter Working, senior vice president of research and development at the US company, said: "While this exciting scientific accomplishment lies outside of our current business focus, we plan to generate value from our research and intellectual property through strategic licensing arrangements with other biotechnology and pharmaceutical companies."
Monoclonal antibodies have become important therapeutic agents for the treatment of cancer, arthritis, infection, and other serious diseases. The gene expression technology reported here may be of particular value for the production of stable antibody-producing cell lines which could result in expedited and lower cost development, potentially saving as much as a year in overall development time, according to the researchers.
Moreover, recent experimental results indicate that the production levels achieved with the technology may be more than double those achieved with conventional technologies. Importantly, this gene expression technology can potentially provide the same advantages to the production of therapeutic protein products, including those comprised of multiple subunits or polypeptide chains, such as Factor VIII, a blood clotting factor, as well as chimeric proteins such as TNF-alpha IgG, the active principle in Johnson & Johnson and Schering-Plough's rheumatoid arthritis treatment Remicade (infliximab).
Drug delivery application?
Meanwhile, in addition to the manufacturing application, the new gene expression technology has the potential benefit in the long-term delivery of therapeutic antibodies, which are currently administered by repeated injection into patients.
It could be used to express the antibodies in the body as a form of gene therapy. Cell Genesys scientists demonstrate in the Nature Biotechnology publication that this approach resulted in continuous expression of biologically active monoclonal antibodies at high concentrations in vivo for over four months and that such treatment has significant anti-tumour activity in animal models.
The company has several pending worldwide patent applications directed to this gene expression technology.