Marian L. Plunkett, Scott A. Mendler, Wendy C. Blackwood and Stephen M. Coutts.

La Jolla Pharmaceutical Company, San Diego, CA 92121

Systemic lupus erythematosus (SLE) is characterized by the production of antibodies against ds DNA and other nuclear antigens. Immune complexes with these antibodies deposit in tissues, such as the kidney, and may activate complement to cause pathology. The molecule LJP 249 was designed to tolerize (or anergize) DNA-specific B cells. Male BXSB mice, which spontaneously develop SLE-like symptoms at an early age, were used to determine whether or not treatment with LJP 249 could delay the appearance of anti-ds DNA antibodies and prolong life. We find that LJP 249 caused significant, dose-dependent reductions in anti-ds DNA antibodies in male BXSB mice, compared to mice treated with formulation buffer, at biweekly doses as low as 0.15mg/kg, iv. No mortality was observed in the high dose group (15mg/kg, iv, biweekly) up to ages of 8.5 months, while all members of the control group (N = 5) died at 5.5 months (± 0.5 sd). The suppressive effect of LJP 249 was specific: the drug did not affect levels of auto-antibodies spontaneously produced against histone 2B in the same model. These data indicate that LJP 249 significantly reduces production of anti-ds DNA antibodies and protects against SLE-like disease in male BXSB mice.

Presented at 207th meeting of the American Chemical Society, Spring, 1994, San Diego, CA.