Patricia A. McNeeley, the LJP 394-90-05 Clinical Trial Consortium and Mattherw D. Linnik, La Jolla Pharmaceutical Company, San Diego, CA 92121

LJP 394 is a proprietary compound currently in Phase III clinical trial for the treatment of lupus nephritis. The compound consists of 4 dsDNA oligonucleotide epitopes coupled to an inert platform. It binds antibodies to dsDNA in the blood and on the B cell surface and is designed to induce B cell tolerance. The current study was designed to determine if pre-treatment affinity of patient antibodies for LJP 394 correlates with the pharmacodynamic response to drug treatment.

Serum samples from a multicenter, double-blind, placebo (PBO)-controlled trial of LJP 394 in patients with lupus (90-05) trial) were analyzed for affinity to the LJP 394 oligonucleotide epitope. Patients were required to have dsDNA antibody titers > 15 IU/ml by Farr assay and a history of renal disease for inclusion in the trial. Surface plasmon resonance was used to measure the apparent equilibrium binding constant (kd') between the total IgG fraction isolated from serum and a trace amount immobilized LJP 394 dsDNA epitope.

The affinity of patient antibodies for the LJP 394 dsDNA epitope was measured at 2 points in the trial, prior to first administration of study drug and following 4 months of weekly treatment with 100 mg LJP 394 or PBO. Pretreatment affinity was determined in the North American trial population, 104/105 (99%) of patients treated with LJP 394 and 106/106 (100%) of patients treated with PBO, as was similar between groups (Kd' = 0.41 + 0.03 and 0.39 + 0.03 mg IgG/ml serum, respectively, mean + SEM). 89% of the patients in the 90-05 trial had high initial affinity (Kd' < 0.8 mg/ml). Affinity of LJP 394 treated patients (n = 92) was reduced at the end of 4 months treatment while affinity of PBO patients (n = 95) was stable (Kd' = 0.84 + 0.03 and 0.46 + 0.04 mg IgG/ml serum, respectively, mean + SEM). Patients with the highest initial affinity for LJP 394 exhibited the greatest reduction in affinity over the 4-month treatment. There was an associated decrease in anti-dsDNA antibody titers.

These results indicate that the initial affinity for LJP 394 can be used to select patients that are likely to have a pharmacodynamic response to the drug. It may be possible to use this to select patients that also would have a positive clinical response to treatment with LJP 394.

Presented at
The 26th Annual Conference of the La Jolla Immunologists
La Jolla, California
October 24-25, 2000