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Chapter 15 - Immunoactive Agents and Immunotherapy

The human body protects itself from invading viruses, bacteria and other pathogens by a complex, interacting arsenal of detection, recognition, activation/inactivation and destruction mechanisms, collectively known as the immune system. Some of these involve the production of freely-circulating antibodies by B lymphocytes (humoral immunity), while others involve the local action of a variety of T lymphocytes (cellular immunity). Some T lymphocytes secrete signalling chemicals (cytokines), such as interleukins and interferons, which can stimulate and regulate a more effective immune response.

Israel's international reputation in this field, and indeed her first major financially successful biotechnology product, began in 1978, with the formation of Interpharm Laboratories (see below). Interpharm developed and marketed the world's first commercial, recombinantly-derived human beta-interferon. Interpharm's 60-person R&D staff has gone on to produce a variety of other cytokines, such as recombinant human interleukin-6. The company uses large-scale, commercial cultures of mammalian cells, often genetically-engineered Chinese hamster cells, rather than bacteria. Although more difficult to grow, the final processing steps in these mammalian cells produce an "authentic" final product that is almost indistinguishable from the natural human agent. In particular, all glycoproteins are fully glycosilated and active.


Many important new approaches to preventing or treating disease involve activating, strengthening or tricking the immune system. For example, Israeli scientists at the Weizmann Institute have developed a cure for juvenile-onset diabetes shown to be 90 percent effective in mice. In juvenile-onset diabetes, which afflicts millions of Americans, T lymphocytes (T-cells), part of the body's own immune defense system, attack the highly-specialized insulin-producing beta cells of the pancreas. The destruction continues unnoticed until almost 90 percent of the body's beta cells are destroyed. The remainder can no longer keep up with insulin demand, and regular insulin injections become necessary. The Israeli scientists inject diabetic mice with a peptide protein fragment that is also targeted by the pancreas-destroying T-cells. The T-cells attack and bind harmlessly to the "decoys," sparing the real pancreas cells. Although the treatment cannot restore damaged cells, it may prevent further damage. The peptide can also be used as the basis of a diagnostic blood test to unmask harmful T-cells long before serious damage begins. Clinical trials are underway.

Other Weizmann scientists have developed a revolutionary new procedure that enables doctors to successfully transplant bone marrow from noncompatible donors. The new Israeli technique has already been used to save the lives of "bubble" children, whose immune systems were so deficient they had to be kept within sterile plastic enclosures 24 hours a day.

In Industry

In comparison to the wide variety of Israeli companies in biotechnology-related diagnostics (Chapter 12), and their overlapping interests and products (e.g., chlamydia and HIV test kits), Interpharm is virtually unopposed in its field. Although interferon did not live up to its initial overexpectations in the late 1970's and early 1980's as a "cure all" for cancer, viral diseases, etc., Interpharm's interferon products for the treatment of genital herpes, and more recently breast cancer, have done increasingly well. Beta-interferon has fewer side-effects than -interferon, and it slashes recurrence rates in genital herpes to a fourth or fifth their normal values. Interpharm now sells some $50 million worth of recombinant interferon a year, accounting for about half of all Israel's health-related biotechnology sales. This easily makes Interpharm Israel's largest (specifically) biotechnology company in terms of current industrial activity.

Interpharm is a subsidiary of the Swiss Ares-Serono Group and is traded publicly on the NASDAQ exchange. It largely targets European markets. These factors limit its need for, or interest in, additional U.S. capital or relationships. Its Rehovot facilities are located near the Weizmann Institute, although it also cooperates with researchers at Bar-Ilan University, Tel Aviv University and several major Israeli hospitals. Interpharm's recent R&D interests include interleukin-6, which was discovered at the Weizmann Institute (and independently elsewhere). When Interpharm researchers remove lung cancer cells from mice, kill them (to produce nontumorigenic cancer antigens) and reinject them into the same mice along with interleukin-6, the treatment prevents metastases and kills tumor cells in the mouse donors. The hope is that interleukin-6 will eventually lead to a useful human cancer vaccine.

Xenograft has exclusive rights to Prof. Yair Reisner's xenographic technology and associated Weizmann Institute patents, one of Israel's most amazing and versatile breakthroughs in immunology-related biotechnology. Severe combined immunodeficient mice (SCID), mice whose bone marrow is unable to produce functional lymphocytes (white blood cells that mount the immune response), have been available for some time, although they are somewhat fragile. Prof. Reisner took hearty normal mice, irradiated them to destroy all their bone marrow cells, and then gave them SCID bone marrow transplants. The mice survive, but are immunologically a "blank page." He then added human peripheral blood lymphocytes (PBL), which the mice are unable to reject, and challenged the animals with antigens.

The mouse's human PBL mount a human immune response, and the mouse's spleen accumulates "human" B-cells. These are harvested and hybridized to cancer cells so they will grow well in culture (Appendix A). The cultures can then be used to churn out large amounts of true human monoclonal antibodies to human cancers, infectious disease agents, etc. Unlike animal or part-animal (chimeric) antibodies, these human antibodies are well-tolerated, and can be taken therapeutically daily and indefinitely without major side-effects. The mice themselves are valuable as model "human systems" for drug-screening tests and other experiments that, for ethical or economic reasons, cannot be carried out in humans.

Xenograft is now pioneering an even newer technique in which irradiated SCID-marrow transplanted mice are given human liver-fragment transplants which, again, they are unable to reject. The goal is to create mice models for human hepatitis B and hepatitis C (liver diseases), which can be used to test human antiviral drugs and vaccines. The advantages of using mice for such preliminary "human" clinical trials are obvious, and numerous additional refinements, extensions and applications of this approach can be expected.

Xenograft was founded in 1992 by the Castle Group (venture capitalists) and Yeda, the Weizmann Institute's commercialization unit. They raised additional funds by private placements in 1993, mostly from Israeli investors. Since December 1994, Xenograft's CEO has been the former Vice President for Technology and Business Development of Syntex, a large American pharmaceutical company (now part of Hoffman-LaRoche).

Only one North Carolina company, Burroughs Wellcome Company actively develops new therapeutic immunological products of the Interpharm variety, as distinct from immunological agents for antibody diagnostic test kits or vaccines. Interestingly, Burroughs Wellcome, like Interpharm is a subsidiary of a European entity, in this case the Wellcome Foundation (U.K.). They have been active in clinical research on alpha-interferons, marketed as Wellferon. Alpha-interferons are produced by white blood cells, while beta-interferons are produced by connective tissue cells (fibroblasts), in Interpharm's case human foreskin fibroblasts.

Several other North Carolina drug firms seem involved in potentially-related issues. Macronex (Morrisville), for example, is developing drugs that regulate macrophages, large cells that can ingest and destroy bacteria. Macrophages are involved in several inflammatory and immune disorders, including arthritis, asthma and fibrosis.