TREATMENT OF ANTIBODY-MEDIATED SLE-LIKE DISEASE IN MALE BXSB MICE WITH A B-CELL TOLERAGEN SPECIFIC FOR ANTI-dsDNA ANTIBODIES

Douglas C. Saffran, Marion L. Plunkett, Larry Quisenberry, G. Michael Iverson, Richard M. Jack, and Matthew D. Linnik

La Jolla Pharmaceutical Company, 6455 Nancy Ridge Drive, San Diego, CA 92121.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies against numerous nuclear antigens, including double stranded DNA (dsDNA), that are thought to be causative agents in lupus nephritis. We have developed a specific toleragen approach that is directed against dsDNA-specific B-cells. The lead compound (LJP 394) presents B-cell epitopes in the absence of T-cell epitopes. LJP 394 consists of four 20-mer synthetic, double stranded oligonucleotide (dsDNA) B-cell epitopes on a non-immunogenic organic platform. To study the efficacy of LJP 394 in vivo, we developed an immunized mouse model using C57Bl/6 mice primed with dsDNA-KLH then boosted three to four weeks later to elicit an anti-dsDNA antibody (Ab) response. Administration of LJP 394 five days prior to boosting suppressed circulating anti-dsDNA IgG levels by > 80% as measured by a Farr assay, while not affecting anti-KLH Ab levels. This decrease in Ab levels correlated with a similar reduction (> 80%) in anti-dsDNA specific plaque-forming cells as determined by an ELISPOT assay. We next tested the efficacy of LJP 394 in BXSB male mice, which have clinical features consistent with human SLE, including spontaneous production of anti-dsDNA Ab. Administration of LJP 394 to male BXSB mice twice weekly from two to five and a half months of age significantly lowered anti-dsDNA Ab levels (> 60%), with no observed non-specific effects. Diminished anti-dsDNA Ab levels also correlated with decreased anti-dsDNA specific plaque-forming cells, a reduction in proteinuria, and increased survival (p<0.05) in these mice. In summary, LJP 394 treatment resulted in decreased production of anti-dsDNA Ab by autoimmune B-cells, consistent with the hypothesis that tolerance induction leads to amelioration of pathogenesis and mortality caused by these antibodies. LJP 394 is currently being tested in a Phase III clinical trial as a prophylactic therapy to prevent renal flares in lupus patients with a previous history of renal disease.

Presented at the
Keystone Symposium: Mechanisms & Applications of Immune Tolerance
Steamboat Springs, CO.
April 3-9, 2002.