Monoclonal antibody products form one of the main pillars supporting R&D efforts as well as the very structure of the global biotechnology industry. Market research company Visiongain has reported that the therapeutic monoclonal antibody market alone (not including diagnostics) led to total revenues of over $35 billion in 2009. Datamonitor forecasts a six-year compound annual growth rate of 9.5% from 2009–2015. This issue’s article commemorating GEN’s 30th anniversary is reprinted from May/June 1983. It discusses the issuance of the first patents to a commercial organization, whereas all previous patents were awarded to universities and academic centers. Also covered are the initial applications for monoclonal antibodies in the diagnostic and therapeutic market segments.
The monoclonal story is the latest example of our decision to reprint an article from one of GEN’s early issues in each issue in 2011. All these stories demonstrate a particular importance and relevance to the bioindustry, so be on the lookout for them!
—John Sterling, Editor in Chief
“As Seen in GEN” Volume 3, Number 3, May/June 1983
First Commercial Patents on Monoclonals Awarded to Ortho for Nine New Antibodies
By Ginna Sulcer
Companies large and small are quietly conducting clinical research to claim territory in the burgeoning business of monoclonal antibodies. The stakes are high—an estimated $728 million world market by 1985 for monoclonal products and procedures. As the competition heats up, Ortho Pharmaceutical Corp. has established a major new beachhead.
In October , the Johnson & Johnson subsidiary of Raritan, N.J., won the first patents issued to a commercial enterprise for monoclonal antibodies. Previous patents on monoclonal antibodies were held by universities.
A panel of nine monoclonal antibodies patented by Ortho Pharmaceutical is being sold for research purposes by Ortho Diagnostic Systems, Inc., also a J&J affiliate, under the trademark Ortho-Mune. The patent that protects Ortho-Mune covers monoclonal antibodies which identify subclasses of lymph cells in the human immune system by their biological function and stage of maturation. These antibodies enable clinicians to measure the proportion of various types of lymphocytes in the blood to indicate quickly and precisely the state of a patient’s immune system.
Monoclonal antibodies which can identify T cells by pedigree are not only invaluable tools in basic immunological research, but they have a broad array of potential diagnostic and therapeutic applications. Their initial impact in the diagnostics business will be seen as they replace polyclonal antibody preparations, which are produced from the blood of animals or human donors and contain many antibodies irrelevant to the diagnosis. Immunodiagnostics now comprises 20 percent, or $250 million, of the U.S. medical diagnostics industry.
Because the diagnostic testing business is well-defined, test kits using monoclonal antibodies should move rapidly from the research laboratories to the marketplace, improving or replacing existing tests. Monoclonal antibodies already are used to identify the level of maturation of immune system cells to classify malignancies such as leukemias and lymphomas for effective therapy.
In its patent application, Ortho successfully claimed that monoclonal antibodies which specifically identify characteristic sites on the surface of T cells are a novelty.
Because of the potential for profit, the broadly-descriptive patents granted to Ortho eventually may be challenged in court. Competitors also selling monoclonal antibodies targeted to the components of the immune system may have to license the process for producing T cell markers from Ortho Pharmaceutical Corp.
Some monoclonal antibodies are currently being used in clinical studies to monitor patients undergoing immunosuppressive therapy, such as cancer patients, patients who suffer from immunodeficiency states, such as rheumatoid arthritis, and most recently, the newly-discovered disease AIDS (acquired immune deficiency syndrome).
Only 13 monoclonal products now have FDA clearance for in vitro, or out-of-the-body diagnostic tests, but the market is expected to explode to nearly $4 billion within a decade. In the meantime, there is a basic research market for monoclonal antibodies which includes major research institutions, medical schools and clinicians studying autoimmune diseases, cancer and renal transplantation. The market for precision reagents in research alone is projected to be $40 million by 1992.
Market growth will depend upon clinical utility. The extent to which physicians accept the monoclonals as useful in measuring the size of various lymphocyte populations for specific disease states will determine how much the market will grow.
Panel of Specificities
The monoclonal antibodies for which Ortho received the patents were developed by Dr. Gideon Goldstein. An M.D. and Ph.D.,. Goldstein is well known for the isolation of thymopoietin, a thymic hormone which restores balance to the immune system. He joined Ortho Pharmaceutical Corp. in 1977 and is now vice president of the Immunobiology Division.
The nine monoclonals work as a panel; each identifies a specific type of lymphocyte. One labeled OKT3, for example, reacts with all mature lymphocytes, while OKT4 is targeted to the suppressors. Thus monoclonal antibodies, themselves a product of the immune system, are being used to locate and study the component cells of the immune system itself.
Sequential testing with the panel of monoclonal antibodies can reveal patterns of preservation and change in the state of the immune system. The helpers and suppressors they identify interact as partners to keep the immune system in balance, or homeostasis. Normally there are about twice as many helpers as suppressors. In disease states, however, this 2:1 ratio may change dramatically. Monoclonal antibodies which seek out the different types of T cells enable researchers to count the number of T cells of a certain class, like helpers or suppressors, in the body. Changes in the relative size of these cell populations may indicate a certain disease state, much as a fingerprint helps identify a person.
In rheumatoid arthritis, for example, the ratio of helper to suppressor cells may increase to as much as 5:1. So many helper T cells are stimulating antibody production by B cells that antibodies begin to attack the body’s own tissues.
In the case of AIDS, however, the ratio is reversed. The number of suppressors increases, inhibiting the body’s resistance to infection.
Another diagnostic application for which various monoclonal antibodies are being clinically tested is in immunodeficiency disease states such as leukemia and lymphoma. By enabling physicians to monitor changes in the body’s immune system more precisely, monoclonals may help minimize the use of conventional chemotherapy and radiation treatments, which kill some healthy tissues and can have undesirable side effects, such as loss of hair or nausea.
Monoclonals in Therapy
Some researchers have had limited success using monoclonal antibodies in the experimental treatment of cancer patients. In 1981, Drs. Richard A. Miller and Ronald Levy reported partial remission of a lymphoma patient treated at the Stanford University Medical Center. In cancer therapy, monoclonals seek out and kill cancer cells exclusively or deliver drugs to tumor cells. But over the course of treatment, cancer cells seem to lose their sensitivity to the antibodies.
For example, in cases studied at Harvard’s Dana-Farber Cancer Institute, the targets for antibodies on cancer cells vanish when the antibodies are preset, and then reappear again when the antibodies have gone. It is not known exactly why this happens. Furthermore, no one has found characteristic target sites unique to cancer cells, although antigens not normally found in a patient’s tissues have been discovered.
Preliminary results of studies by a group at Dana-Farber and the Children’s Hospital in Boston suggest that monoclonal antibodies can be used to purify bone marrow samples taken from leukemia patients. After the remaining leukemic bone marrow is destroyed by radiation and drugs, the purified marrow can be reinfused into the patients.
The monoclonal antibodies sold by Ortho are being tested for therapeutic applications in bone marrow and organ transplantation. Clinical trials supervised by Otho and elsewhere by competing companies are under way to use monoclonal antibodies for suppressing the immunity of a patient’s system to prevent graft-versus-host rejection in renal transplants.
The monoclonal antibodies are being tested for therapeutic applications in bone marrow and organ transplantation. Clinical trials are under way to use monoclonal antibodies for suppressing the immunity of a patient’s system to prevent graft-versus-host rejection in renal transplants. There were nearly 5000 kidney transplants performed in 1981, the most recent statistic available.
In many organ transplants, it is necessary to suppress the rejection response in the person receiving the transplant. But such general suppression of the immune function leaves the patient susceptible to many other diseases. The precise specificity of monoclonal antibodies shows promise in preventing graft rejection by suppressing only those T cells active in rejecting the graft, leaving the body’s immune system otherwise intact.