The process of creating monoclonals was discovered in 1975 by biologists Cesar Milstein, a British- Argentinian, and Georges Koehler, a German, for which they shared a Nobel Prize in 1984. Monoclonals have been used in research virtually since that time.
Making use of monoclonals` ability to seek out specific substances in the body, researchers can now study basic biology in greater detail.
``One can now look at small areas on large molecules and essentially map those molecules with monoclonals,`` said University of Illinois microbiologist Stephen Kaufman. ``This has really been a revolutionary change.``
Monoclonals also allow investigators to precisely reproduce reagents, substances used in chemical reactions to measure and produce other substances. More recently, monoclonals have become a standard tool in diagnostics, improving the accuracy and specificity of tests to detect infections, pregnancies and other conditions. Nearly 170 monoclonal-based tests are now in use, and Wall Street analysts predict that the market for such tests may approach $1.5 billion or more worldwide by 1990.
It is in the transplant field, however, that monoclonals are first fulfilling their therapeutic promise. They offer a novel means of controlling rejection, in which the immune system attacks and tries to destroy a transplanted organ.
Transplant specialists have searched for years for ways to control rejection without seriously compromising the body`s infection-fighting ability or causing unacceptable side effects.
Three decades of research yielded a series of drugs, steroid hormones and others, that remain part of standard rejection therapy today.
One such drug, a serum against the human white blood cells that cause rejection, was developed 20 years ago. This was the forerunner of monoclonal antibodies like OKT-3, only not as potent or precise.
At present, the most heralded antirejection drug is cyclosporine, a slime mold derivative that cripples the immune system`s crucial T-cells.
Although cyclosporine sharply boosted transplant success rates, it has drawbacks. Most notably, when given in doses high enough to stop rejection, it has serious side effects, including kidney damage.
OKT-3, developed by Ortho Phrmaceutical Corp. in 1979, blocks rejection without such side effects. It has drawbacks, including that it can only be used for a short time before the body`s immune system renders it ineffective. But OKT-3`s ability to fight rejection makes it exceptionally attractive. It successfully reversed initial rejection episodes in 94 percent of 123 kidney transplant patients studied in a national study last year, versus 75 percent for standard antirejection drugs.
It even salvaged grafts in 65 percent of patients where rejection defied all other therapy.
``It`s been very gratifying to see how the thing has worked,`` said Russell of Massachusetts General, head of the first research group to test OKT-3 in patients. ``It`s an application of scientific knowledge, which has been gradually accumulating, to clinical medicine.``
``These are the kinds of things we`ve been waiting for for 20 years,``
said Dr. Frank Stuart, chief of the kidney transplant program at the University of Chicago Medical Center and an early monoclonal investigator.
``We sat there basically with little change in the drugs we could use to control immune system response between the middle 1960s and the early 1980s,`` Stuart said. ``Now, in the last two or three years, we have cyclosporine plus an effective monoclonal antibody. It`s just a new ball game.``
As with cyclosporene, OKT-3`s target is the T-cell. Shaped like a ``Y,``
OKT-3 latches onto the appendage of the T-cell that recognizes the transplanted kidney as something to be attacked. Under normal circumstances, T-cells use these appendages to lock onto cells in the new organ, triggering rejection.
With OKT-3 stuck to it, a T-cell cannot fit onto the kidney cell. And in an ironic immune system manipulation, the monoclonal may also mark the T-cell itself as a target for destruction by the body`s defense mechanisms, as some scientists believe.
OKT-3 is so effective that a few milligrams clear the blood of T-cells in as little at 15 minutes, said Russell, who admits to being ``really amazed``
by the process. Rejection eases in days, and T-cells return within 48 hours after the drug is stopped.
Like any immuno-suppressant, OKT-3 has drawbacks, since the same mechanism that fights rejection saps the body`s ability to fight infection. In addition, half or more of those treated with OKT-3 in the tests developed an immune response that eventually rendered the drug useless.
Doctors try to get around the problem through additional drug therapy and by administering the antibody only for a short time. And researchers are confident that this complication can be resolved significantly.
``There`s no doubt that we have a useful agent,`` Russell said. ``There are problems and further progress needs to be made. But the indications are that the progress is there to be made.``