LJP 394: A NOVEL CLINICAL CANDIDATE FOR THE TREATMENT OF LUPUS NEPHRITIS.

Marian L. Plunkett, G. Michael Iverson, Jacqueline Crisologo, Carrie Fu, Yin Gu, Mingsheng Qin, Larry Quisenberry, Antoinette Reyes, Marissa Skari and Stephen M. Coutts.

La Jolla Pharmaceutical Company, San Diego, CA USA

LJP 394 tolerizes anti-dsDNA-specific B cells in both immunized and spontaneous, lupus-like mouse models. C57B1/6 mice were immunized with oligonucleotide (ON)-KLH conjugate to elicit an anti-ON response. LJP 394 suppressed serum levels of anti-ON by >80%, with a mean ED50 of 21 mg/mouse, when administered ip 3 weeks after priming and 1 week before boosting. Anti-KLH levels were not affected. LJP 394 also reduced anti-ON-specific plaque-forming cells by > 80%, with a mean ED50 of 34 mg/mouse.

LJP 394 was administered to BXSB male mice starting at 9 weeks of age. Once to thrice weekly iv injections, at doses of 30, 100 and 300 mg/mouse, lowered anti-dsDNA ELISA slopes by 60, 74 and 77%, respectively (p<0.05). The drug had no effect on anti-histone levels. LJP 394 (300 mg, iv, twice weekly) decreased anti-dsDNA antibody-forming cells by 59% (p<0.05). LJP 394 also reduced proteinuria and increased survival (p<0.05) in these mice.

LJP 394 was neither immunogenic nor antigenic in 4 strains of mice, nor was it antigenic in vitro with PBL from normal and lupus donors. LJP 394 is a specific B cell toleragen for down-regulating anti-dsDNA antibodies, and is in early clinical trials for treatment of lupus nephritis.

Presented at the 4th International Conference on Systemic Lupus Erythematosus ­ SLE, March 26-31, 1995, Jerusalem, Israel.