Pharming (biotechnology)

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Pharming (crossword from pharm aceutical engineer ing - pharmaceutical development and farming - agriculture), also called molecular pharming , gene pharming or bio-pharming , describes in biotechnology the production of drugs with the help of genetically modified organisms (GMO). With the help of pharming, recombinant proteins in particular are produced as biopharmaceuticals ( biologicals ) in plants and animals. Pharming is doing a in comparison with conventional cell culture in fermenters or microorganism culture may cost effective method of production of biological drugs. With the recombinantly produced clotting inhibitor antithrombin alfa was 2006, the first pharming product approved from genetically modified goats to therapy.

history

The field cultivation of plants for the production of medicinal substances can be traced back over several millennia. In the last few centuries in particular, animals have also been used as active ingredient producers , for example for passive vaccines , insulins and conjugated estrogens .

The possibility of producing recombinant proteins in animals was first created in the early 1980s with the first transgenic mouse. In 1990 the production of the first recombinant human protein from agricultural plants, human albumin from tobacco and potato plants , was presented. It took another 16 years until the first recombinant protein from pharming, antithrombin III from genetically modified goats, was approved under pharmaceutical law . In 2012, the first recombinant drug produced in plant cells, taliglucerase alfa , was approved in the USA .

technology

Animals

Recombinant proteins are usually isolated from easily accessible animal body fluids such as blood, milk and urine. Isolation from eggs is also possible. In particular, the selective production of recombinant proteins in the mammary glands and their release into the milk offers the advantage of less stress on the production organism. Standard transgenic techniques are used to generate the production organisms. The protein-coding genes required for this are introduced into the embryonic stem cells of the production animals and implanted in blastocysts in pregnant mother animals.

plants

Moss bioreactor with Physcomitrella patens

Tobacco , maize , rice , potatoes , safflower and duckweed in particular were tested as production organisms. For safety reasons, plants that are not used for the production of food will gain in importance in practice. Some plants (duckweed, the moss Physcomitrella patens ), like plant cell cultures, can be cultivated in closed systems ( photobioreactors ) and thus enable manufacturing conditions according to GMP guidelines . In the optimal case, the protein can be purified directly from the culture medium, which simplifies the downstream process and lowers production costs. For the production of pharming plants , gene transfer techniques such as transformation with the help of Agrobacterium tumefaciens , biolistic transformation with a gene gun and protoplast transformation are used.

Advantages and disadvantages

Product features

The production of recombinant drugs in animals or plants can have a decisive impact on the properties of the pharmaceutical product ultimately manufactured. In contrast to proteins produced biotechnologically with the aid of bacterial strains such as E. coli , recombinant proteins from plants and animals can be equipped with characteristic eukaryotic post-translational protein modifications such as glycosylations . However, the pattern of glycosylation differs from production organism to production organism and can differ considerably from the human glycosylation pattern, especially in the case of proteins from plants.

In the case of pharming products, contamination by bacterial endotoxins is not to be expected. These pose a problem in conventional fermenter production using E. coli and have to be separated in a laborious manner. The risk of the transmission of prions as the causative agent of spongiform encephalopathy can also be excluded in the production of recombinant medicinal substances in plants. In the manufacture of vaccines in plants, research is conducted into whether oral administration in the form of an edible product can avoid injection . However, problems with the characterization of the antigen stability in the plant material, with the bioavailability and with the reproducibility have been described.

costs

Pharming is seen as an inexpensive method of obtaining recombinant drugs. Possible savings compared to conventional and financially expensive production in fermenters do not only depend on the protein to be produced and its production quantity, but also on possible additional costs due to approval procedures and requirements. A possible cost advantage would be minimized in the case of a possible requirement to cultivate pharming plants or to keep pharming herds in a closed system, for example in greenhouses or closed stables.

Individual evidence

  1. ^ Molecular Farming
  2. ^ Gordon JW, Ruddle FH : Integration and stable germ line transmission of genes injected into mouse pronuclei . In: Science . 214, No. 4526, December 1981, pp. 1244-6. PMID 6272397 .
  3. ↑ Sijmons PC, Dekker BM, Schrammeijer B, Verwoerd TC, van den Elzen PJ, Hoekema A: Production of correctly processed human serum albumin in transgenic plants . In: Nat. Biotechnol . 8, No. 3, March 1990, pp. 217-221. doi : 10.1038 / nbt0390-217 . PMID 1366404 .
  4. ↑ Schmidt C: Belated approval of first recombinant protein from animal . In: Nat. Biotechnol . 24, No. 8, August 2006, p. 877. doi : 10.1038 / nbt0806-877 . PMID 16900113 .
  5. ↑ Maxmen A: Drug-making plans blooms . In: Nature . 485, No. 7397, May 2012, p. 160. doi : 10.1038 / 485160a . PMID 22575938 .
  6. ↑ JR Gasdaska, Spencer D and L Dickey: Advantages of Therapeutic Protein Production in the Aquatic Plant Lemna . In: BioProcessing Journal . , Pp. 49-56.
  7. ↑ Büttner Mainik, A., J. Parsons, H. Jerome, A. Hartmann, S. Lamer, A. Schaaf, A. Schlosser, PF Zipfel, R. Reski , EL Decker (2011): Production of biologically active recombinant human factor H in Physcomitrella. Plant Biotechnology Journal 9, 373-383. doi: 10.1111 / j.1467-7652.2010.00552.x
  8. ↑ Baur, A., R. Reski , G. Gorr (2005): Enhanced recovery of a secreted recombinant human growth factor using stabilizing additives and by co-expression of human serum albumin in the moss Physcomitrella patens. Plant biotech. J. 3, 331-340 doi: 10.1111 / j.1467-7652.2005.00127.x
  9. ↑ a b S. Rosales-Mendoza, VA Márquez-Escobar, O. González-Ortega, R. Nieto-Gómez, JI Arévalo-Villalobos: What Does Plant-Based Vaccine Technology Offer to the Fight against COVID-19? In: Vaccines. Volume 8, Number 2, April 2020, p., Doi : 10.3390 / vaccines8020183 , PMID 32295153 .

literature

Web links