In December 1996, following nearly three decades of research, the multiple sclerosis drug copolymer-1 (Copaxone®) became one of the first Israeli medications to receive the approval of the U.S. Food and Drug Administration. Prof. Ruth Arnon, the Institute's Vice President for International Scientific Relations, who, along with Weizmann Institute colleagues Prof. Michael Sela and Dr. Dvora Teitelbaum, originally synthesized and developed copolymer-1, recently documented the drug's dramatic history in the scientific journal Immunology Letters. Interface presents a chronology of the drug's development, along with excerpts from Prof. Arnon's personal account.
1968. Profs. Ruth Arnon and Michael Sela and Dr. Dvora Teitelbaum synthesize several molecules, known as copolymers, that mimic a component of myelin, the protective coating of nerves. Because this component is believed to trigger multiple sclerosis, the scientists hope that their molecules can help create an animal model for the study of MS. However, the copolymers fail to produce an MS-like disease in laboratory animals.
"Disappointment. Was our hypothesis wrong? Did the synthetic approach fail us in this case? Should we give up?"
1971. Despite the initial failure, the scientists persist in their study of the molecules' properties and stumble on a surprising finding: rather than causing MS symptoms, the copolymers actually block an MS-like disease.
"The results ... were overwhelming -- not one, but several of the synthetic copolymers showed high efficacy in suppressing the MS-like disease in animals! Already at that early stage, we realized that this might eventually lead to a therapeutic agent."
1972-74. Patent applications for copolymer-1, dubbed Cop 1, are submitted in Israel and several other countries. Meanwhile, the scientists show that while suppressing the symptoms of the MS-like animal disease, called EAE, Cop 1 does not depress the entire immune system indiscriminately. They also show that it works in several species of laboratory animals.
"The next logical step was to investigate whether Cop 1 was of any benefit to MS patients."
1977. The first clinical trial is conducted at the Hadassah-Hebrew University Medical Center in Jerusalem, in collaboration with Dr. Oded Abramsky, a former Ph.D. student of Arnon's, who at the time was Head of Neurology and then served as Dean of the Medical School at Hadassah. Four MS patients in the terminal stages of the disease receive Cop 1 and show no major side effects.
"This information paves the way for further clinical trials in less severely affected patients."
1978-81. The Weizmann Institute scientists embark on the formidable task of convincing clinicians to perform larger-scale clinical trials. Two physicians respond to their call: Dr. Helmut J. Bauer of the University of Gottingen, Germany, and Dr. Murray B. Bornstein of the Albert Einstein College of Medicine in New York.
"I recall this time as the 'peddling period': I participated in almost any conference, large or small, that dealt with MS. I presented our experimental data ... and talked to anyone who was prepared to listen."
1980-85. Preliminary results both in Gottingen and in New York are encouraging, and Bornstein decided to extend the evaluation of Cop 1 to a rigorous double-blind study. Fifty patients are recruited for the study, a complicated process involving the interviewing of several hundred people.
"This trial lasted more than three years, and in the beginning the suspense was nervewracking. I used to call Dr. Bornstein at least once a month, to find out how it was going."
1987. The results of the double-blind trial are published in the New England Journal of Medicine. Cop 1 is found to reduce the number of attacks in patients with relapsing-remitting MS while having minimal side effects.
"The results of the pilot trial justified all the efforts of everyone involved in it."
1987. Cop 1 is licensed to Teva Pharmaceutical Industries Ltd., Israel. Commercial development of the drug is launched.
"A new era has begun."
1987. Meanwhile, the scientists continue to pursue research aimed at clarifying Cop 1's mechanism of action.
"Our studies provided a plausible theoretical basis for the drug's therapeutic effect."
1994. Weizmann Institute scientists are invited to the presentation of the results of an extensive trial conducted by Teva at 11 medical centers throughout the United States.
"It is difficult to describe in words the wonderful sensation of satisfaction and accomplishment which arises from the realization that our research has brought relief to somebody, be it only to a single individual."
June 14, 1995. The file on Cop 1 is submitted by Teva to the U.S. Food and Drug Administration.
"For Prof. Michael Sela and myself, together with our colleague Dr. Dvora Teitelbaum, this was a high point after over 27 years of persistent research effort, perseverance and tenacity of purpose... The promise is there and the hopes for success, and the desire to be able to help alleviate the suffering of MS patients worldwide, many of whom I learned to know, love and respect during our long years of research."
December 23, 1996. Copaxone® is approved by the FDA for use in patients with MS.
 and Prof. Ben-Nun..jpg "Kerlero de Rosbo and Ben-Nun. reverse effect")
Like a Forest Fire
Why autoimmune diseases occur is still a mystery, but they appear to stem from the immune system's failure to distinguish between foreign, disease-causing agents and the body's own proteins. Juvenile diabetes, for instance, is caused when a protein essential for the proper functioning of insulin-producing cells is mistakenly attacked, while multiple sclerosis develops when the immune system erroneously attacks the myelin sheath around nerve fibers in the central nervous system.
One approach in the struggle against autoimmune diseases has been to weaken the entire immune system. However, this leaves the body extremely vulnerable, which is why scientists are anxious to find means to selectively target the immune system's faulty attacks against the body's proteins without affecting its ability to combat foreign invaders. To this end, Prof. Avraham Ben-Nun of the Weizmann Institute's Immunology Department has developed a new strategy for treating autoimmune diseases, particularly multiple sclerosis.
For years, scientists studying multiple sclerosis assumed that the immune system's attack on myelin focused on one of myelin's most abundant proteins, called myelin basic protein, or MBP. Further studies, showed, however, that the attack can also be directed against another myelin protein, called proteolipid protein, or PLP. And the list continued to grow. Several years ago, Ben-Nun and Dr. Nicole Kerlero de Rosbo showed that a third protein, myelin oligodendrocyte glycoprotein, or MOG, is also targeted; and recently Ben-Nun and his colleagues discovered two additional myelin proteins that draw the immune system's "fire" in multiple sclerosis.
These findings drove home the complexity of uncovering autoimmune disease processes. Further studies revealed that not only can a mistaken immune attack against any of these five proteins trigger multiple sclerosis, but the major proteins targeted can vary from patient to patient, and in a given patient at different stages of the disease. Just like a forest fire, the immune attack may initially target one protein but then spread to any or several of the other five proteins, sequentially or simultaneously, while often abandoning the original target.
It became clear that to selectively suppress harmful autoimmune responses without shutting down the entire immune system one would have to identify the specific proteins targeted in each patient at any given stage - a process requiring complex, expensive, and time-consuming tests. Ben-Nun set out to devise a therapy theoretically suitable for most patients - one that would selectively neutralize an autoimmune attack against any of the five proteins, regardless of which protein is attacked. For this purpose his team identified the main "draw-fire" regions on each of the five target proteins, using biological testing methods and computer modeling in collaboration with Dr. Miriam Eisenstein of the Weizmann Institute's Chemical Services Unit. Then, using genetic engineering, Ben-Nun with the assistance of Dr. Lydia Cohen, generated a synthetic gene in which all of these regions are encoded in a sequential molecular chain. This synthetic gene was subsequently introduced into bacteria, which then produced the novel "draw-fire regions" protein - a protein that does not exist in nature.
When administered under certain conditions, this genetically engineered protein was found to protect mice against multiple sclerosis-like disease whereas injection under other conditions led to disease onset. Ben-Nun and his colleagues also demonstrated that it is possible to vaccinate mice against the disease using the gene itself. When incorporated into mouse cells, this gene serves as a "data bank," allowing the cells to manufacture the "draw-fire regions" protein, thus eliminating the need for continuous protein administration. This strategy was employed by the Institute scientists to design synthetic genes coding for "draw-fire regions" proteins pertinent to immune-specific therapies for several autoimmune diseases: a protein called Y-MSP for potential treatment of multiple sclerosis, Y-DMP for juvenile diabetes, and Y-RAP for rheumatoid arthritis. Yeda Research & Development Co. has filed a patent application for this approach.
In current studies Ben-Nun and his colleagues are further developing their approach to produce genetically engineered "draw-fire regions" proteins modified to effectively suppress these autoimmune diseases without triggering other disease processes.
Other scientists participating in this study were Dr. Gregor Sappler and research students Itzhack Mendel, Ming-Chao Zhong, and Joel Kay, all of the Weizmann Institute's Immunology Department; Dr. Roni Milo, Neurology, Assaf Harofeh Medical Center; Prof. Oded Abramsky, Neurology, Hadassah University Hospital; and Dr. Michael Hoffman and Prof. Israel Yust, Internal Medicine, Ichilov Medical Center.