By David N. Leff

Some autoimmune diseases look like the work of individual hit men, assigned to assassinate specific organs in the body. Others look more like the victims of cytocidal serial killers, which attack multiple organ systems.

Among the best known of the single-organ targets are rheumatoid arthritis, in which autoimmune antibodies inflame membranes of the joints; multiple sclerosis, where the target is the myelin sheath that insulates nerve cells, and myasthenia gravis, in which the hit aims at receptors that convey nerve impulses to muscles.

Besides those sharp-shooting forms of friendly fire, there's systemic lupus erythematosus (SLE), which wastes organs ranging from skin, joints, membranes and blood to brain, heart, lung and kidney.

Especially kidney.

While most of SLE's wide-ranging symptoms can be horrendous, the lethal one is glomerular nephritis — inflammation, and eventual destruction, of the kidney's waste-filtering apparatus. And that is the target of a novel, potentially therapeutic, approach outlined in the current Proceedings of the National Academy of Sciences (PNAS), dated March 4, 1997. Its title tips its hand: "Peptide inhibition of glomerular deposition of an anti-DNA antibody."

The autoimmune antibodies that do the dirty work in SLE don't attack organ-specific tissues, such as myelin or membrane. Rather, they zero in on the double-stranded DNA in the nuclei of its target kidney cells. Of course, that genetic material is shielded from antibody attack by the nuclear membrane, but the SLE antibodies catch up with their prey by going after the DNA spilled out of dead cells. Then they infect the victim's bloodstream with large immune complexes programmed against the kidney glomeruli.

Rheumatologist and immunologist Betty Diamond, at the Albert Einstein College of Medicine in Bronx, N.Y. — the PNAS paper's principal author — noticed a possible loophole in that kidney-antibody complicity.

"A significant proportion of anti-DNA antibodies," she wrote, "may cross-react with renal antigens and [thus] be sequestered in the kidney . . . ." By seeding that kidney tissue with decoy antigenic peptides, she reasoned, "antigenic competition for pathogenic antibodies might prevent their deposition in kidneys, and the ensuing tissue damage."

Outsmarting, Not Suppressing, Autoantibodies

She described this approach as "outsmarting the immune response, rather than suppressing it, as SLE chemotherapy does."

She and her co-authors screened a random peptide library with normal and mutated versions of a mouse monoclonal antibody that causes glomerulonephritis in nonimmune mice. "The mutant," she told BioWorld Today, "with three amino-acid substitutions, displayed a 10-fold greater increase in its binding of double-strand DNA. And it shifted deposition of the antibody-antigen complex from the blood-filtering renal glomeruli to the urine-excreting kidney tubules."

Each of these antibodies binds separate but related peptides in vitro. A small, soluble synthetic peptide derived from these blocked the parent antibody in vivo, in the mice. "So," she pointed out, "such peptides — which fit snugly into an antibody's binding site — could have therapeutic utility to protect kidneys from antibody-mediated injury."

She observed that the role of DNA, "whether target for the SLE autoantibody, or innocent bystander, is still controversial."

Since submitting their paper to PNAS, Diamond and her colleagues have moved into developing such potentially therapeutic peptides against antibodies from human SLE patients. "We found eight monoclonal antibodies from as many genetically unrelated patients," she said. "They bind to human glomeruli in vitro, and are being tested in mouse kidneys in vivo." This time, the mice they use are specific SLE-prone models.

"In this SLE mouse," she observed, "the response to SLE antibodies is polyclonal, indicative of several peptides. Right now we can block 50 percent of them, and DNA with a single peptide."

She foresees initial clinical application of the DNA-mimicking peptides as emergency rescue of kidneys from life-threatening SLE flare-ups. "We often encounter patients with fulminant kidney inflammation," she observed. "By the time immunosuppressant drugs can take hold, the acute process could totally destroy the kidneys, so the patient would have to go on dialysis — a poor alternative. The peptides would protect the kidneys in such an acute setting."

"A chronic clinical setting," she added, "is still a question."

Peptides Face Broader Future Beyond SLE

But Diamond foresees "very broad applications" for the surrogate peptides, beyond SLE therapy. "Any autoantibody attack on any organ," she observed, "could be met by providing peptides to protect the organ from tissue injury."

Her research has now reached a point where it can distinguish between levo-rotary L-peptides and dextro-rotary D peptides. "The fact that the antibodies bind the D-form," she pointed out, "enhances the potential of peptides therapeutically, because they will have a longer in vivo half-life."

Next on her agenda is "to construct such a D-peptide."

LaJolla Pharmaceuticals Co., of San Diego, has a different anti-SLE molecule, now in Phase II clinical trials. (See BioWorld Today, Dec. 27, 1997, p. 1.) Diamond commented: "La Jolla is trying to use a small molecule, in this case a DNA molecule, to tolerize B cells making pathogenic antibodies. We would also like to use these peptides of ours to tolerize B cells, and I think that it remains to be determined whether DNA or a peptide is going to work better."

She concluded: "If a small panel of peptides could be identified that inhibits the binding of the anti-dsDNA antibodies in the serum of lupus-prone mice, or patients, then it is possible that such peptides can provide a significant therapeutic option."

A recent survey for the Lupus Foundation of America Inc., Rockville, Md., "showed that in 1994, between 1.4 million and 2 million Americans had been diagnosed with some form of lupus. The Foundation's health educator, Mary Anne Hardy, told BioWorld Today that "90 percent of them are women." *