Transgenic Production Of Human Proteins For Therapeutic Use

8 January, 1999

Transgenic Production Of Human Proteins For Therapeutic Use

Human proteins for therapeutic use have been produced by extraction from tissues and plasma and by recombinant technology from mammalian and microbial cells that oftentimes sacrificed cost effectiveness for a large scale production of pure, native and stable proteins. As transgenic technology makes considerable progress, so called non-scientefically "animal factory" has drawn much attention for the production of native human proteins in a large and economically feasible scale. Success is now coming in.
Take antithrombin III for example. It was produced at 8-10 g/L in transgenic goat milk (Genzyme Transgenics) that was similar to that in transgenic mice for research purpose. Approximate productivity comparison with CHO (Chinese hamster ovary) cells is as follows for 10 kg of ATIII: goat milk 2100 liters (7 goats, lactation 150 days, 16 g/2 L/day, 60 % recovery); CHO cells 17000 liters (batch, 10-day cycle, 1 g/L, 60% recovery). Purification of the protein was much easier from goat milk with only a few steps than from cell culture. The production of similar level was also achieved for albumin and monoclonal antibodies. Economically feasible cost for human albumin production is ca $1/g so far by extraction from plasma and recombinant technology from yeast. This is now achievable by transgenic technology.

Most advanced in "animal factory" are Genzyme Transgenics (USA; goat and cow for ATIII, human serum albumin, tissue plasminogen activator, monoclonal antibodies), PPL Therapeutics (England; sheep and cow for alpha 1 protease inhibitor/cystic fibrosis, alpha-lactoalbunin, factor IX) and Pharming (Holland; cow and rabbit for alpha-glucosidase/glycogen storage disease, type II). Typically and Technically, a strong milk promoter (bovine alpha casein: 10 mg/ml, goat beta casein: 16 mg/ml, sheep lactoglobulin: 3 mg/ml) is selected for transgene expression and the expression vector is microinjected into fertilized eggs that are transferred into recipient female. Offsprings are tested for the transgene. Transgenic animals mate. Then milk transgenic female. In the farm for "animal factories", GAP (Good Agricultural Practice) is observed according to FDA's "Points to Consider in the Manufacture and Testing of Therapeutic Products for Human Use Derived from Transgenic Animals " <www.fda.gov/cger/points.htm> thus, for example, virus and scrapie validation is carried out for the transgenic products.

SMI (Sumitomo Metal Industries) Genzyme now plans to carry out a clinical trial in Japan of recombinant antithrombin III produced from goat milk as it demonstrated safety and efficacy of the treatment of 30 patient of artery bypass surgery in the USA. Plasma-derived ATIII (now $75 million in Japan per year for disseminated intravascular coagulation) may be replaced by transgenic counterpart if the trials are successful.

Similarly, transgenic monoclonal antibodies are quite promising as they may replace humanized mAbs for therapeutic use. The possibility of immune reaction to humanized antibodies depends on the extent of humanization and it has to wait till clinical trials of such mAbs to assess immunogenicity. Humanization, however, has made several mAbs real therapeutic possibilities for breast cancer (HER2/neu/c-erbB-2: Herceptin, Genentech), Crohn's disease (Avakine, Centocor), non-Hodgkins lymphoma (Rituxan, Genentech, approved 11/97), and several others for leukemia, head and neck cancer, heart disease, asthma and transplant rejection. So mAbs are coming back after a long spell of disappointment. It is now most likely that transgenic technology gradually replaces hybridization technique for mAb production. This is especially useful for the production of native human mABs with least immeunogenicity and better characteristics of stability and permeability.

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