Matthew D Linnik, Patricia A McNeeley and G Michael Iverson. La Jolla Pharmaceutical Co., San Diego, CA 92121.

Introduction: LJP 394 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 relative affinity of antibodies from SLE patients for the dsDNA epitope on LJP 394 may influence a patient's pharmacodynamic response to drug.

Objective: To determine if pretreatment affinity of patient antibodies for LJP 394 correlates with the pharmacodynamic response to drug treatment.

Methods: Serum samples from a multicenter, double-blind, placebo (PBO)-controlled trial of LJP 394 in patients with SLE (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.

Results: 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. Pretreatment affinity was determined in 104/105 LJP 394 patients and 106/106 PBO patients and was similar between groups (Kd' = 0.41 + 0.03 and 0.39 + 0.03 mg IgG/ml serum, respectively, mean + SEM). Affinity of LJP 394 patients (n = 70) was reduced at the end of 4 months treatment while affinity of PBO patients (n = 75) was stable (Kd' = 0.84 + 0.03 and 0.46 + 0.03 mg IgG/ml serum, respectively, mean + SEM). Patients with the highest initial affinity for LJP 394 exhibited the greatest reduction in affinity over the initial 4 month treatment. A treatment effect toward reduction in affinity was noted in patients with initial Kd' < 0.8 mg/ml. Over 85% of the patients in the 90-05 trial had an initial Kd' < 0.8 mg/ml.

Conclusion: Patients with high-affinity antibodies to LJP 394 showed a reduction in affinity during 4 month weekly exposure to LJP 394. This affinity assay identified patients most likely to exhibit the intended pharmacodynamic response to treatment with LJP 394.

Presented at The 64th Annual Scientific Meeting of the American College of Rheumatology, Philadelphia, PA., Oct. 29 - Nov. 2, 2000.