Firms boost prospects for transgenic drugs Biopharmaceuticals tend to be based on large, fragile human protein mole­cules. Nature makes such molecules best, but they can be produced in mi­crobial or mammalian cell cultures by using recombinant DNA methods. An­other approach being explored is the production of selected proteins in the milk of genetically engineered animals. Soon, transgenic proteins produced by these animals are expected to enter clinical trials, the first step toward be­coming commercial products.

Only a few major companies com­pete in the development of transgenic drug production. These companies have been carving out the technological countryside, especially as patents begin to issue, largely in terms of the type of animals that they use. Genzyme Trans­genics, Framingham, Mass., is develop­ing transgenic goats; Pharming B.V.,

Genzyme Transgenics' goat produces

monoclonal antibodies at Charlton, Mass., "plant."

Leiden, the Netherlands, is developing transgen­ic cows; and PPL Ther­apeutics, Edinburgh, Scotland, is focusing most of its projects on transgenic sheep.

Other companies, not known specifi­cally for focusing on transgenics, in­clude Boulder, Colo.-based Somatogen, which uses pigs to produce human he­moglobin, and Holland Labs, part of the American Red Cross, which is working to produce blood plasma products in pigs' milk.

Although work is also being conduct­ed with botanical systems, milk-produc­ing animals probably are the closest to being used commercially. Pharming re­cently received European patents on transgenic cattle and on gene constructs for high-level protein production in the

milk of transgenic animals. According to Pharming, these are the first two patents granted by the European Patent Office in this field. The company holds related patents and has applications pending in other countries.

The transgenic dairy cattle patent covers "a fundamental technology cru­cial for the cost-effective production of high-volume health care proteins," ac­cording to Pharming. For example, the company is working to produce hu­man lactoferrin, for the treatment of gastrointestinal infections, and human serum albumin, for the treatment of

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trauma after severe blood loss. Pharm-ing's transgenic bull, Herman, has sired many female calves that carry the lactoferrin gene (C&EN, Feb. 14, 1994, page 30).

A cow, by far the largest milk pro­ducer, can produce as much as 10,000 L of milk per year containing 30 to 35 g of endogenous protein per L. Even if the yield of a target protein were sig­nificantly less, tens of kilograms of a drug—large quantities on the scale of biopharmaceutical drug production—

still could be produced. Protein purifi­cation is not expected to be any more difficult than it is from cell cultures, says the company.

In April, Genzyme Transgenics an­nounced the birth of Grace, a transgen­ic goat. The goat carries a gene to pro­duce BR-96, a monoclonal antibody (MAb) developed and being tested by Bristol-Myers Squibb to deliver conju­gated anticancer drugs.

Transgenic production is expected to yield larger quantities of drugs less ex-

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pensively—as much as 75% less, ac­cording to PPL—particularly when capital costs are factored in. Genzyme Transgenics says it has developed transgenic goats that produce certain MAbs at levels of more than 4 g per L—10 to 100 times greater than those achieved in cell culture. In addition, as the market for a product expands, pro­duction can be "brought on-line" by creating or breeding more animals.

Many of the proteins or MAbs select­ed for transgenic production are not eco­nomically feasible to produce in large quantities or may be difficult to produce in cell culture. Furthermore, as patents expire on biopharmaceuticals—already a $7 billion market—transgenics may be­come the cheap production alternative for "generics."

Genzyme Transgenics expects soon to receive a European patent and calls it the 'broadest patent covering transgenic production technologies ever issued." The company says the patent creates a strong proprietary position applicable to all transgenic proteins produced in milk. Using even stronger language, company President and Chief Executive Officer James A. Geraghty contends, "Any com­pany seeking to use transgenic technolo­gy to produce proteins in milk will be required to have access to these patent rights." Similar patents are pending in the U.S. and Japan.

If transgenic firms prove the useful­ness of their technologies, they could compete for drug industry partners looking for different production meth­ods. PPL Therapeutics has collabora­tions with two drug firms, and Gen­zyme Transgenics has convinced five major drug producers to look at trans­genics. Genzyme Transgenics has near­ly a dozen projects with partners or on its own. Its lead project is with Cam­bridge, Mass.-based Genzyme, which owns 48% of the company.

Genzyme Transgenics is expected to file an application to begin the first clinical trials of a transgenically pro­duced drug, antithrombin III, this year. The anticlotting protein isolated from blood plasma already is an approved product, but its market has been limit­ed by its high cost. The Food & Drug Administration has been preparing for the first application for transgenic drug clinical trials and last year published guidelines on the use of transgenic ani­mals in drug production.

Ann Thayer

24 AUGUST 26,1996 C&EN CIRCLE 11 ON READER SERVICE CARD