Using goats to solve autoimmune diseases

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Using goats to solve autoimmune diseases

Monday, July 25, 2005

By Katharina Schoebi, Checkbiotech

People suffering from autoimmune disorders, such as rheumatoid

arthritis, psoriasis or multiple sclerosis, may be aided in the future:

Merrimack Pharmaceuticals, Inc. is developing MM-093, a recombinant

version of human á-Fetoprotein (hAFP), which is believed to have a

beneficial impact on many autoimmune disorders. The twist is that

Merrimack’s strategic manufacturing partner, GTC BIOTHERAPEUTICS, INC,

is producing MM-093 in the milk of transgenic goats.

The glycoprotein called human á-Fetoprotein (AFP) is constitutively

produced at low levels throughout life. In the fetus’ blood, there are

about five microgram AFP per milliliter. Since fetal AFP enters the

maternal bloodstream, pregnant women have a maximal concentration of

300 – 500 nanogram per milliliter during the third trimester of

pregnancy. It is known that during pregnancy, especially during the

last three months, several autoimmune disorders, such as multiple

sclerosis, rheumatoid arthritis and psoriasis, go into remission.

Therefore, researchers have examined AFP for its immunomodulatory

properties. The effect of AFP on rheumatoid arthritis, multiple

sclerosis, myasthenia gravis and thyroiditis has been well documented

in animal experiments and provides a rationale for testing MM-093 in

humans. However, human clinical testing requires a great deal of

properly constructed and biologically active protein. Therefore, there

is need for a production system that can cost-effectively generate

large amounts of MM-093.

Several experiments have shown, that recombinant AFP produced in

systems such as Escherichia coli, baculovirus and yeast, has

immunomodulatory properties. However, the molecule is quite large and

complicated and recovery of a sufficient yield of properly folded

protein can be problematic in certain systems – for example, E. coli.

Thus, there was a need to investigate a novel production system and

Merrimack chose to investigate the transgenic goat system with GTC

Biotherapeutics (previously Genzyme Transgenics) of Framingham,

Massachusetts.

GTC Biotherapeutics has developed the transgenic goat technology as a

cost-effective alternative for the production of complex proteins on a

large scale. The goats produce the protein of interest in their milk –

the goats are maintained on a high-tech farm using state-of-the-art

animal husbandry techniques and procedures and milked using standard

processes that would be employed on a dairy farm.

Merrimack then developed a process to purify MM-093 out of the goat

milk and performed a battery of tests to demonstrate that it was highly

comparable to human AFP (M. H. et al,. 2004. Purification and

characterization of recombinant human alpha-fetoprotein expressed in

the milk of genetically modified goats. Protein Expression and

Purification. 38:177-183.)

Once the goat milk is filtered to remove milk fat and milk proteins –

essentially creating “extreme” skim milk – the purification process is

very similar to purification of proteins from any other production

system. The process involves standard chromatography-based purification

steps that remove contaminants. The development team demonstrated that

MM-093 and hAFP were virtually identical using several analytical

techniques to evaluate primary, secondary and tertiary structure. In

addition, the biological activity of MM-093 produced in transgenic

goats was tested using cell binding assays and in animal models of

disease and MM093 was determined to be biological active.

Merrimack has tested MM-093 produced in transgenic goats in Phase 1

human clinical trials and is currently testing MM-093 in a large

clinical trial of rheumatoid arthritis patients who do not receive

adequate relief from current therapies. Like most other therapeutic

proteins, MM-093 is administered to these patients by a subcutaneous

injection.

While sometimes joked about, it is important to note that it is not

possible to use goat milk or goat cheese therapeutically, as the

management of the goats, and the goat products, are strictly regulated

by multiple government agencies. The goats are handled with the utmost

care and neither the goats nor their milk will ever end up in the food

chain.

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