REDUCTION OF ANTI-DS DNA ANTIBODIES USING LJP 394 IN PATIENTS WITH LUPUS.

Bonnie Hepburn, La Jolla Pharmaceutical Company, San Diego, CA; Richard Furie, North Shore University Hospital, Manhasset, NY; Joseph Cash, The Cleveland Clinic, Cleveland, OH; Mary Cronin, Medical College of Wisconsin, Milwaukee, WI; Robert Katz, Rheumatology Associates, SC, Chicago, IL; Michael Weisman, UCSD, San Diego, CA; Cynthia Aranow, SUNY, Brooklyn, NY; Michael Liebling, UCLA, Torrance, CA; N. Paul Hudson, The Ohio State University, Columbus, OH; Stephen Coutts and Marian Plunkett, La Jolla Pharmaceutical Company, San Diego, CA; and Vibeke Strand, San Francisco, CA.

LJP 394 is a molecule designed to act as an antigen-specific B cell toleragen by binding anti-dsDNA on the B cell surface. It is composed of 4 oligonucleotides attached to ends of triethylene-glycol platform. Injections of LJP 394 in oligonucleotide-immunized mice and in the BXSB murine lupus model reduced anti-dsDNA forming cells (as much as 80% and 59% respectively) and suppressed serum levels of anti-dsDNA (by approximately 80% and 77% respectively). In the BXSB model, treatment also decreased proteinuria, reduced glomerulonephritis (as determined by biopsy), and prolonged survival by approximately 130.

LJP 394 has been administered intravenously to 56 patients with systemic lupus erythematosus (SLE). Each of 4 patients receiving single 100 mg doses had reductions in anti-dsDNA of 29% to 83% as measured one hour after dosing by Farr assay. The rapid reduction of antibody in these patients may reflect immunoabsorption of circulating anti-dsDNA.

In a blinded placebo-controlled trial, 49 patients with SLE and anti-dsDNA received LJP 394 at doses of 1, 10 or 50 mg weekly, biweekly or monthly. Following 17 consecutive weekly doses, reductions in anti-dsDNA persisted for as long as eight weeks after the last dose, suggesting sustained modulation of B cell function. Median anti-dsDNA were reduced from baseline by approximately 3% (n=4), 36% (n=6) and 48% (n=5) in the 1, 10 and 50 mg groups, respectively, compared to 5% increase in the placebo group (n=9). Those patients treated with cyclophosphamide or > 20 mg/day of prednisone were excluded. LJP 394 was well tolerated with no suggestion of drug-related toxicity.

LJP 394 has not been shown to be immunogenic in mice or humans and drug-related reduction of anti-dsDNA has not been associated with changes in C3 or C4 levels below the normal range. Further trials are planned in patients with SLE to evaluate the clinical benefit of LJP 394.

This study was sponsored by La Jolla Pharmaceutical Co. Vibeke Strand is a consultant to LJP.

Presented at The American College of Rheumatology's 60th National Meeting, Oct. 21, 1996, Orlando, FL.