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The Skaggs Institute for Chemical Biology
Scientific Report 1998-1999


Expression of Antibodies in Microalgae


S.P. Mayfield, E. Efuet, C. Fong, M. Gonzalez, D. Hogan, H.-C. Hung, B. Ngo, A. Somanchi

We express antibodies in algae for several reasons. First, because of the emergence of bacteria resistant to antibiotics, alternative treatments are essential to maintain the present standards of health care. Treatment of bacterial infections with antibodies is quite effective, but the cost of producing antibodies makes such treatment prohibitively expensive. In addition, antibodies have the potential to block viral infection, something that antibiotics, in general, cannot do.

Currently, a number of recombinant protein expression systems are available for the production of antibody proteins. Each system has distinct advantages in terms of protein yield, ease of manipulation, and cost of production. Microalgae are one group of organisms that have received little attention concerning their use as bioreactors for the production of recombinant proteins. Yet, use of microalgae in such an endeavor has several advantages. These include relatively fast growth rates; high cell densities; extremely large culture volumes, in excess of 500,000 L; low risk of contamination by viruses, prions, or endotoxin; low media costs; the ability to transform chloroplast, nuclear, or mitochondrial genomes in a variety of genetic backgrounds; and rapid progression from initial transformants to the large-scale production of proteins.

For many recombinant antibodies, currently available methods of production are inefficient or are simply too costly, a situation that has severely limited the wider use of these proteins in a variety of applications. Functional antibodies, for example, are hard to produce in prokaryotic expression systems, because these complex proteins tend not to fold correctly in these systems. Although some antibodies produced from mouse cell cultures are used as therapeutic agents in oncology, antibodies produced in this manner are simply too expensive to be of practical use in fields such as biocatalysis or bioseparation (purification of stereoisomers) or as therapeutics for a number of non­life-threatening human diseases. The use of antibodies in these endeavors could be quite effective if the high cost of production could be reduced.

We are engineering strains of the green alga Chlamydomonas reinhardtii to express antibody genes in both the chloroplast and the cytoplasmic compartments (Fig. 1). We have expressed several truncated versions of antibodies, known as single-chain antibodies, in the chloroplast. These antibodies include ones that recognize herpes simplex virus proteins and tetanus toxin and an antibody that is a catalytic aldolase. We have also constructed vectors for the expression of larger antibodies composed of both a light-chain protein and a heavy-chain protein that will export these antibodies from the cell. The vectors designed for the export of antibodies should direct the accumulation of functional antibodies to the culture medium, allowing easy purification of the protein.

In general, antibodies expressed in algae have properties similar to those of the original antibodies, which were expressed in either mouse or human cells. Some of the single-chain antibodies we have expressed accumulate to relatively high levels in transgenic strains and appear to be stable within the cells. These studies indicate that pharmacologically important antibodies can be produced in algae at high levels and that these antibodies act exactly as do antibodies produced in more traditional and expensive systems. Antibodies expressed in algae should allow easy purification and should lack many of the undesirable toxins or mammalian viruses that can potentially contaminate antibodies expressed in bacterial or eukaryotic cell cultures.

Publications

Bruick, R., Mayfield, S.P. Light-activated translation of chloroplast mRNAs. Trends Plant Sci. 4:190, 1999.

Bruick, R., Mayfield, S.P. Processing of the psbA 5´ untranslated region in Chlamydomonas reinhardtii depends upon factors mediating ribosome association. J. Cell Biol. 143:1145, 1998.

 

 







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