Enzymes and Endogenous Biologically-Active Proteins
Much of the body's complex biochemistry is made possible and regulated by special proteins called enzymes. Each is coded for by a specific gene and each acts as a catalyst to speed up (as much as 100,000,000,000,000,000,000 times) specific biochemical reactions. Enzymes often take the name of their substrate plus the ending "-ase," as in "lactase," which speeds up the conversion of the sugar lactose to glucose. Hormones are any of a variety of natural chemicals that act as the body's long-distance chemical messengers. Israeli investigators have been quite adept at developing new therapeutical approaches and products based on both types of active biochemicals, often using biotechnological methods to produce the large quantities needed for research, testing and commercialization.
For example, Weizmann Institute scientists were among the first to produce tissue plasminogen activator (tPA) in tissue culture, and to develop a commercially-viable process for producing this potent enzyme, which can quickly dissolve blood clots blocking the arteries of stroke and heart attack victims.
Weizmann Institute scientists have used recombinant genetic engineering techniques to make commercial amounts of human superoxide dismutase (SOD), an enzyme that can prevent free-radical damage. Israel's Biotechnology General (BTG, see below) acquired the U.S. patents for the plasmid vectors for making human recombinant Cu/Zn-SOD in 1992, and for broad therapeutic claims for Cu/Zn-SOD in 1993. Both were obtained under license from Yeda, the Weizmann Institute's commercialization unit. BTG's SOD-product, Oxsodrol, is now under clinical trials for use in preventing bronchopulmonary dysplasia, a severe lung disease in premature newborn infants. Other potential targets, such as treating arthritis and limiting the damage that can follow a heart attack, have yet to pan out. Recently the SOD-gene was shown to be linked to familial amyotrophic lateral sclerosis (Lou Gehrig's disease).
The United States produces huge amounts of organophosphate (OP) pesticides, such as methyl parathion, a year. These are important mainstays of modern agriculture, but cause an estimated 500,000-1,000,000 cases of pesticide poisoning, and 19,000 pesticide-related deaths, each year. The main culprit is the ability of such organophosphates (OP) to block the action of cholinesterases (ChE), enzymes essential to the proper transmission of signals between nerve cells, and between nerve cells and muscle. OP have also been implicated in cases of fetal malformation and death and in an increased risk of leukemia in occupationally-exposed farmers. Hebrew University scientists have recently determined the primary amino acid sequence of acetyl-cholinesterase (AChE) and butyl-cholinesterase (BChE), using molecular cloning techniques. They have also developed ways to produce large amounts of human recombinant AChE, which could be used prophylactically or therapeutically to treat OP-intoxication. Recent animal and human studies suggest the feasibility of such an approach. Organophosphates are also well-known chemical warfare agents, a point brought poignantly home by the U.S. experience in Iraq during the Gulf War. Although the sources of Gulf War Syndrome remain unknown, U.N. inspectors found 5,000 tons of chemical warfare agents and more than 46,000 filled munitions in subsequent inspections. AChE purified from fetal calf serum has been shown to protect rats from lethal doses of Soman, a well-known OP chemical warfare agent.
Some 25 million Americans are afflicted with osteoporosis, a brittle-bone syndrome common in the elderly, particularly women. Sufferers sustain some 250,000 hip fractures a year (12-20 percent fatal) at a cost of billions of dollars to the U.S. health-care system. Hebrew University investigators have discovered a small naturally-occurring peptide, osteogenic growth peptide (OGP), which promotes bone growth. Not only is it unlikely to produce side-effects, but it can probably be modified (e.g., be shortened from 14 to 7 amino acids) to allow oral or nasal administration. The investigators have successfully characterized OGP and used it to promote bone formation and increase bone density in laboratory animals at low doses. Using their polyclonal anti-OGP antibodies, the investigators have also been developing a sensitive (0.5 ng/ml) ELISA assay for OGP, to diagnose osteoporosis and to monitor the course of OGP-therapy. If successful, the eventual market for OGP-based drugs could easily be in the billion-dollar range, since small peptides are rapidly degraded and have to be administered daily.
Two other YISSUM projects, still under development, include Bowman-Birk inhibitors (BBI), which have been shown to have anticancer and other useful properties in U.S. tests, and clodine-displacing substance (CDS), an Israeli-discovered endogenous chemical apparently involved in regulating essential hypertension.
Another YISSUM opportunity involves the recent Israeli discovery that c-Abl, a protein-tyrosine kinase (PTK) enzyme, forms a complex with other chemicals to regulate the transcription of hepatitis-B genes into messenger-RNA (the first step in making viral proteins). The same complex performs a similar task in CMV and polyoma virus. If c-Abl contributes to transcription-regulation by phosphorylating itself and/or other proteins in the complex, it may be possible to block it with known PTK-inhibitors. This could prove useful in regulating cell growth, cell differentiation and viral replication. Although this approach seems speculative, a patent has already been filed.
Two Israeli firms specialize in health-related hormone and peptide/protein biotechnology products: Biotechnology General and Peptor.
Founded in 1980, Biotechnology General (BTG) was one of Israel's first biotechnology companies. BTG is probably best known for its pioneering recombinant human (HGH) and bovine (BGH) growth hormones, which were developed in 1981. American Cyanamide licensed BGH in 1986, but FDA approval is still stalled, and there is some public resistance to using recombinant hormone products in food animals. American Cyanamide has also recently completed field trials of BTG's porcine growth hormone (PGH). BGH and PGH each have a potential market of over $300 million once approved. Biotechnology General's HGH is widely marketed abroad: the Ferring Group is now selling it in Europe (replacing SmithKline Beecham) and JCR Pharmaceuticals has licensed it in Japan. Israeli (short-stature and Turner syndrome indications) and Korean HGH sales continue apace. The lucrative U.S. market for HGH is closed pending resolution of current litigation with Genentech. U.S.-based Eli Lilly and Co. is already litigating a similar HGH claim with Genentech. In 1993, BTG's HGH was designated by the FDA as an "orphan drug" for the treatment of cachexia (general ill health) in AIDS patients. Pilot clinical trials indicate it promotes protein synthesis and reverses severe weight loss. It is also being evaluated clinically for preventing cachexia in pancreatic cancer patients. This frenetic activity explains why much of the action in Israel hormone-related biotechnology has moved from the campus to Israel's biotechnology industries.
Traded on the NASDAQ, BTG now has its formal headquarters in New Jersey, although most basic R&D and production are still done in Israel (Rehovot). In August 1993, BTG merged with the American firm, Gynex Pharmaceuticals. Also in 1993, a new American corporation, Bio-Cardia, was formed to develop cardiovascular and Ophthalmic drugs based on BTG technology. Its $37.5 million of capital was raised by a private placement of stocks and warrants. BTG's $30 million agreement to develop products for Bio-Cardia should bring in $10 million in 1994.
Finally, after 13 straight years of losses, while its products inched their way through the R&D/regulatory pipeline, BTG turned its first profit in the first half of 1994. Sales were $8.5 million, compared to $2.9 million for the first half of the previous year, and profits were $1.2 million, compared to a $5.7 million loss. This should increase BTG's credibility, though the modest nature of its returns may test the patience of investors who are still waiting for large future profits.
BTG has wide R&D interests, with many different products under simultaneous development. It has already filed over 300 patents and been granted 177. Four of its products have completed Phase III clinical trials and are already being marketed:
New indications for Bio-tropin (cancer cachexia) and Oxandrin (HIV cachexia, Turner Syndrome) are already in Phase II or III clinical trials, as are a new oral contraceptive and three new drugs:
Peptor, a recent startup, specializes in therapeutic peptides and proteins for asthma, cancer, bone disease and AIDS. It already has sales of about $3 million. Potential topics for more basic R&D collaboration include peptide chemistry and the molecular biology and biochemistry of hormone receptors.
Although it was not possible to identify North Carolina firms with R&D directly related to the Israeli medical applications in this chapter, several have considerable capability and interest in proteins and protein chemistry. For example, Protein Delivery, Inc. (RTP) is developing innovative protein drug delivery systems, such as insulin and growth hormone polymers, and Apex Bioscience, Inc. (Durham) has been doing research on variants of hemoglobin, the oxygen-carrying protein of the blood. Macronex (Morrisville) shares Peptor's interest in asthma, although it is specifically interested in new drugs that regulate macrophages.