RESEARCH TRIANGLE PARK, N.C. -- You can still count on thefingers of one hand (not including thumb) the number ofcompanies dedicated to producing high-value, high-volumeproteins in transgenic animals. All four of these major playerscommercializing pharmaceuticals, respectively, in the milk ofcows, sheep and goats, and the blood of pigs, updated the statusof their programs here Monday at a workshop on "TransgenicAnimal Technology and Food Production" at the SeventhInternational Biotechnology Meeting and Exhibition.
This annual event is being sponsored for the last time by theAssociation of Biotechnology Companies (ABC), which votedTuesday evening to ratify its merger with the IndustrialBiotechnology Association (IBA) to form BIO, the BiotechnologyIndustry Organization. However, BIO will not officially comeinto existence until July 1, and ABC's present officers will retaintheir positions until June 30.
By Tuesday's count, 1,368 registrants are attending themeeting here, nearly double the 700 attendees at last year'smeeting in San Diego. They come from some 300 companiesand institutions in the U.S. and 20 other countries.
Jonathan MacQuitty, founder and chief executive officer ofGenPharm International Inc. of Mountain View, Calif., andchairman of the transgenic animals workshop, told participantsthat his company in recent weeks set a new world record forhuman protein production in the milk of a murine transgenichost.
A GenPharm mouse expressed 28 micrograms per milliliter oflactoferrin. From mouse prototype to bovine producer, thisextrapolates to a potential yield of 28 grams per liter in cows.MacQuitty pointed out that small animals, such as mice andrabbits, can also be milked for proteins to be used in researchor even early clinical trials, as well as drug discovery.
GenPharm's founder animal is a 2-year-old Holstein bull namedHerman, who is expecting offspring in a few months. With newpromoter constructs, MacQuitty expects the lactoferrin yield ofthe transgenic females to approach that of the prototypemouse. A cow that typically gives 10,000 liters of milk a yearshould net some 300 kilograms of human protein.
A herd of such cattle could churn out enough human lactoferrin(trademarked NuLactin) to satisfy a sizable share of the world's$4 billion infant-formula market. GenPharm aims to humanizethe product, now mainly extracted from cow's milk, byfortifying it with NuLactin, and also NuLysin (humanlysozyme). These two proteins, salient ingredients of mother'smilk, confer anti-infective and iron-transport properties on thefemale.
MacQuitty noted that with more mothers working, only one infour babies over the age of 6 months is still breast-fed; theother 75 percent are on reconstituted infant formula. He addedthat adults suffering from bacterial infections, notably AIDSvictims and septicemia patients, will benefit from oralprophylactic drugs based on the human milk proteins.
GenPharm, a free-standing spinoff of Genencor (a one-timejoint venture of Genentech Inc. and Corning Glass) has raised$27 million, with $14 million still banked. It will go public,MacQuitty vouchsafed, "once the public market returns to itsnormal vigor."
After four years of development, MacQuitty told BioWorld,"transgenic pharming is definitely coming of age. Any proteinlooking for a production technology would be making a mistakeif it didn't evaluate a transgenic animal system." He commendsthree categories of human proteins in particular for mammarygland expression:
-- orally active, to avoid most purification processing;
-- those requiring a lot of post-translational modification;
-- proteins needed in very large quantities.
Sheep in Scotland were the bellwethers of animal transgenesisfor producing drugs. Pharmaceutical Proteins Ltd. (PPL) ofEdinburgh now has its second generation of ewes expressinghuman alpha-1-antitrypsin in their milk. The company'smanager of new business development, Erica Whittaker, toldthe workshop that PPL's seven current producers derive from asingle in vitro fertilized founder ram transformed with thegene for human alpha-1-antitrypsin.
This protein is aimed at a valuable market in treatingemphysema, marked by dysfunction of pulmonary elastin. Asingle sheep, Whittaker said, can produce 500 to 600 liters ayear of milk containing high-quality, high-quantity protein.
In their first-generation mini-production flock, seven of ninetransformed females yielded 15 to 20 grams per liter ofprotein, and the same gene copy number has been stablytransmitted to the next generation.
PPL, she said, expects to go public in two years. Meanwhile,Whittaker plans to visit the U.S. once a month to drum up newbusiness for PPL. The Scottish company also announcedTuesday its merger with a low-profile startup namedTransPharm Inc., which has begun experiments with pig milk(see sidebar).
Whittaker emphasized that the sheep-expressed alpha-1-antitrypsin is 100 percent identical to the human molecule, andthat it is fully glycosylated in the mammary gland.
"Well over a dozen different human enzymes have beenexpressed in animals," said James Geraghty, president andgeneral manager of Genzyme Transgenics, spun off fromGenzyme Corp. of Cambridge, Mass., in February. "Over 10 ofthese," he told BioWorld, have been expressed by Genzyme,notably long-lasting tissue plasminogen activator (in rabbitsand goats) and anti-thrombin III, a clot inhibitor in thecoagulation cascade.
"We are about to disclose in the next couple of weeks," headded, "having expressed this factor in mice and goats."
Geraghty also said that his company has recently synthesizedin animals "the most complex protein ever expressed" -- CFTR,the cystic fibrosis transmembrane regulator. "But not yet incommercial quantities," he added.
Geraghty stressed cost benefits to the workshop. "You can haveresearch quantities of protein in mice in six months afterinserting DNA: in rabbits in eight; in goats in 18 months moresignificant quantities." He declared, "Once past one to twograms per liter, the cost in dollars per gram is so low thatfurther lowering production costs doesn't matter.
"In the near future," he added, "how would anyone developingan important protein not consider transgenesis as a significantalternative?"
Raising human proteins in pig blood "raises an entirelydifferent set of issues than in milk," observed MacQuitty. DNXCorp. (NASDAQ:DNXX) of Princeton, N.J., produces humanhemoglobin in transgenic swine, and Gerald Messerschmidt, thecompany's medical and regulatory vice president, dwelt onissues other than the expression technology. He took up thelooming regulatory problems of consuming or disposing ofperfectly healthy swine carcasses conceptually contaminatedby the foreign gene.
Two other regulatory experts rounded out the workshopagenda. Pat Basu of the U.S. Department of Agriculture andattorney Charles Morin, managing partner of Burditt andRadzius' San Francisco office, affirmed and reaffirmed thatgovernment regulation should target products rather than(genetically engineered) process.
In the audience sat Leonard Ruiz Jr., senior vice president andchief scientific officer of GalaGen Inc. of Arden Hills, Minn. Henoted that "gala" is Greek for "milk," and told BioWorld that hiscompany is gearing up to express human proteins -- startingwith lactoferrin -- in the milk of cows and pigs. Meanwhile, thecompany is developing an oral therapeutic for intestinalbacterial infections -- including travelers diarrhea and the gutproblems of immunoincompetent patients -- from bovineantibodies to such pathogens as cryptosporidium and shigella.Clinical trials are under way and in the offing, with the U.S.Army and NIH.
Dairy-products giant Land O Lakes founded GalaGen, initially asProCor. It retains a 30 percent equity in the new company, butbrought in private investors to fund it.
MacQuitty foresees that in the near future, GalaGen will convertthe Big Four major players of animal transgenics into the BigFive.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.