By David N. Leff
People sometimes perceive gnats or mosquitoes flitting slowly past their field of vision. In fact, what they're noticing are little bugs that aren't there - what eye doctors call "floaters."
These optical illusions (literally) usually are benign and passing, but some floaters signal trouble. They are symptoms of a common sight-threatening eye disease called noninfectious inflammatory uveitis.
"The symptoms of uveitis," research ophthalmologist Robert Nussenblatt pointed out, "are of course brought forward by the patient. If the inflammation is in the back of the eye - a posterior uveitis - they will probably not have pain, but may experience a drop in visual acuity that's sometimes very dramatic. And initially they're likely to see floaters in front of their eyes.
"Floaters are frequently intraocular debris," he continued. "In the inflammatory situation, they are clumps of inflammatory cells. But the inflammation itself alters the structure of the eye's vitreous gel, which it can cause to congeal and form these little pockets of debris." Nussenblatt is scientific director of the NIH's National Eye Institute (NEI) in Bethesda, Md.
"Inflammation of the eye is a very common problem that is faced almost daily by an ophthalmologist," he observed. "Patients who have changes and inflammation in the front of the eye," he continued, "may complain of pain or photosensitivity, but less of a drop in visual acuity.
"The signs of the disease are what the ophthalmologist sees when he or she looks into the interior of the eye, and determines where the inflammation is. They can look in and see evidence of inflammation, whether it be in the retina or cells floating in front of the eye. This is readily observable, unlike other autoimmune diseases, such as multiple sclerosis and arthritis.
"Uveitis is a disease that affects young people and young adults," Nussenblatt went on, "so it has a pretty significant impact on the family. And its sequellae can cause cataracts, glaucomas, retinal degeneration. So in fact, patients with any of those disorders have them because they have had uveitis first."
Uveitis tends to be self-limiting, but that spontaneous recovery may be delayed 15 to 20 years, by which time the patient likely will be blind. "So," Nussenblatt observed, "it invariably requires a marriage between the eye doctor and the patient, going on for years."
From the viewpoint of the body's immune system, autoimmune uveitis is akin to a foreign, unmatched donor-organ transplant. And the defenses' autoaggressive cells react accordingly. Which is why the same immunosuppressive agents that transplant recipients must take to fight off graft rejection are the lifelong drugs that treat uveitis.
This immunity-clobbering regimen of corticosteroids, cyclosporine, cytotoxic methotrexate and their ilk have the same horrendous side-effects - the threat of opportunistic infections to damaged kidney function. "In autoimmune diseases," Nussenblatt said, "it's presumed that the drugs are targeting actively dividing immune cells. Hence, those are the targets when one uses these cytotoxic agents against autoimmune disease. Thus, in the eye we presume that therapy is really aimed against the immune cells that are directing the inflammatory response."
Late in 1997, the FDA approved a monoclonal antibody dubbed daclizumab (Zenapax) to prevent acute graft rejection in kidney transplant patients - but sans the adverse events of immunosuppression. Protein Design Labs Inc., of Fremont, Calif., created and commercialized the 90 percent humanized antibody.
"The initial work was done here at NEI," Nussenblatt recounted, "together with Thomas Waldmann, of the National Cancer Institute's clinical sciences division. He developed a theory that this antibody could be used in transplants, and also for treating certain neoplasms in which the cancerous cells express interleukin-2 receptors (IL-2 R's) in large numbers on their surface.
"He began developing this," Nussenblatt went on, "and ultimately Protein Design Labs became partners" with Hoffmann-La Roche Inc., of Nutley, N.J., which brought it forward to be commercialized." (See BioWorld Today, Dec. 12, 1997, p. 1.)
Nussenblatt is first author, and Waldmann a co-author, of a paper in today's Proceedings of the National Academy of Sciences, dated June 22, 1999. Its title is: "Treatment of noninfectious intermediate and posterior uveitis with the humanized anti-Tac mab: A phase I/II clinical trial."
"When T cells are activated," Nussenblatt told BioWorld Today, "an additional portion of the IL-2 R is placed on to the already-present receptor, making it extremely receptive to interleukin-2. It is that T-cell-activated portion of the receptor that the antibody is directed against."
To test the monoclonal's therapeutic effect, if any, on patients with uveitis, NEI mounted an uncontrolled, non-randomized open clinical trial, in which it enrolled 10 patients. They had been staving off blindness by long-term heroic immunosuppressive treatment. The first step in the study was to wean them off of these distressing drugs, and replace them with staged intravenous infusions of the antibody over 12 months.
"We really embarked on a very small pilot study," Nussenblatt recalled, "and we were quite heartened to see that nine of the 10 patients were able to come off all of their immunosuppressive agents, and simply be maintained on monthly IV therapy of the HAT - humanized anti-Tac antibody. These nine had minimal side effects, no recurrence of their eye disease, and no loss of vision."
Sight Improved - Unexpectedly
"As that trial ended its first year," he added, "we see evidence that they have had pretty good maintenance of their visual acuity because of the immunosuppression they came in on. It turned out that their vision actually improved a bit with the antibody, which was an extra benefit of the study."
Next, Nussenblatt continued, "we will be doing a clinical trial in Behget's disease. Its most common major complication is uveitis.
"We didn't know what the effect of the antibody would be," he explained, "but now that we've gained some experience we have a protocol just about ready to get started on Behget's disease, here at NEI. And we've also had discussions about considering a multi-center study of the HAT antibody.
"Uveitis is an excellent way to evaluate therapies," Nussenblatt concluded, "because we can get responses very quickly. So potentially these can be applied to other putative autoimmune diseases, such as multiple sclerosis and arthritis."