Advantages Of Recombinant Protein Synthesis In Transgenic Animals

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Several different organisms have been harnessed to produce recombinant proteins. Bacteria, yeast, fungi, plants, and cultured mammalian cells can all be reprogrammed and, if properly managed, yield relatively large amounts of recombinant proteins. Problems begin to arise, however, when one examines the ability of these organisms to posttranslationally modify and even release recombinant proteins. Bacteria, for example, are often unable to package and secrete recombinant proteins. In these instances, the recombinant protein must be physi cally extracted from the bacteria, a process that can be difficult and costly. Whereas yeast can secrete recombinant proteins that are glycosylated, the enzymatic pathway(s) that they utilize to accomplish protein glycosylation differs from that employed in higher plants and animals. As a result, many of the recombinant proteins produced by yeast exhibit inadequate glycosylation. Posttrans-lational modification of recombinant proteins produced in fungi appears to be aberrant in many instances as well. Mammalian cell lines, in contrast, typically perform posttranslational modifications of recombinant proteins that are quite similar to those observed in indigenous proteins. Primary drawbacks to the synthesis of recombinant proteins in animal cell lines include cost and the logistical challenge associated with developing and managing cell cultures for large-scale protein production.

In contrast, transgenic animals, as Louis-Marie Hou-debine describes,[1] share most of the properties of animal cells in culture, exhibit appropriate posttransla-tional modifications of recombinant proteins, and synthesize and secrete proteins extremely efficiently. Indeed, mammary gland epithelia typically have a cell density that is 100- to 1000-fold greater than that used in mammalian cell culture bioreactors. In one recent example, 35 transgenic goats that produced a human monoclonal antibody at a concentration of 8 g/L in their milk were equivalent to an 8500-liter batch cell culture running 200 days/year with a 1 g/l final production level.[2] Thus, from a production standpoint, the amount of antibody synthesized in 170,000-liter cell culture yield was equivalent to that generated in 21,000 liters of milk from transgenic goats. Assuming a process yield of 60%, both systems would generate 100 kg of purified monoclonal antibody, yet the transgenic bioreactor was significantly more efficient.

Another obvious incentive for the production of biopharmaceuticals in transgenic livestock is their potential economic value (Table 1). The cost of human proteins obtained from donated plasma and used in replacement therapy has ranged from $4/g for serum albumin and $5000/g for antithrombin III to $150,000/g for human blood clotting factor VIII (FVIII).[4] Although the individual values of these seem dramatic, they pale in

Table 1 Molecular pharming projects: Potential biomedical and commercial products from transgenic farm animals

Products

Use

Commercializing firm(s)

a 1 antitrypsin

Hereditary emphysema/cystic fibrosis

(Bayer/PPL)

a 1 proteinase inhibitor

Hereditary emphysema/cystic fibrosis

(Bayer/PPL)

a fetoprotein (rhAFP)

Myasthenia gravis, multiple sclerosis,

(Merrimack/GTC)

and rheumatoid arthritis

Antithrombin III (rhATIII)

Emboli/thromboses

(GTC)

b glucosidase

Glycogen storage disease

(Pharming)

Collagen

Rheumatoid arthritis

(Pharming)

CFTR

Ion transport/cystic fibrosis

(GTC)

Factor VIII

Hemophilia A

(ARC)

Factor IX

Blood coagulation/hemophilia

(GTC, PPL)

Fibrin, fibrinogen

Tissue sealant development

(ARC, PPL, Pharming)

Hemoglobin

Blood substitute development

(Baxter)

Lactalbumin

Food additive

(Univ. Illinois)

Lactoferrin

Immunomodulatory, antiinflammatory

(Pharming)

MSP 1 (Merozoite Surface Protein 1)

Malarial vaccine

(GTC)

Phytase (Enviropig™)

Bioremediation, pollution control

(Univ. Guelph)

Human antibodies

Biotherapeutics, biodefense

(Abgenix, Hematech, Medarex)

Human C1 inhibitor

Hereditary angioedema

(Pharming)

Human lysozyme

Antimicrobial, immune modulator

(UC Davis)

Human protein C

Blood coagulation

(ARC, PPL)

Human serum albumin

Blood pressure, trauma/burn treatment

(Pharming; GTC)

Spider silk (Biosteel®)

Materials development

(Nexia)

tPA

Dissolve fibrin clots/heart attacks

(Genzyme)

Tissues/organs

Engineered for xenotransplantation

(Alexion, Bresagen, Novartis)

Monoclonal antibodies and immunoglobulin fusion proteins:

5Gl.l

Rheumatoid arthritis, nephritis

(Alexion/GTC)

AntegrenTM

Neurological disorders

(Elan/GTC)

CTLA4Ig

Rheumatoid arthritis

(Bristol Myers Squibb/GTC)

D2E7

Rheumatoid arthritis

(Abbott/GTC)

huN90l

Small cell lung cancer

(ImmunoGen/GTC)

MM 093

Myasthenia gravis, multiple sclerosis,

(Merrimack/GTC)

and rheumatoid arthritis

PRO 542

HIV/AIDS

(Progenics/GTC)

Remicade®

Crohn's disease, rheumatoid arthritis

(Centocor/GTC)

(Adapted from Ref. 3.)

comparison to the projected worth of a number of recombinant structural products. Biomedical applications of Biosteel™ (Nexia Inc.), a recombinant form of dragline spider silk, produced in the milk of transgenic goats, is projected to represent $150 to $450 million in annual earnings (exclusive of military and other industrial applications).

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