AFFINITY OF ANTIBODIES FOR LJP 394 INFLUENCES PHARMACODYNAMIC RESPONSE TO LJP 394 IN SLE PATIENTS

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

Introduction: LJP 394 consists of 4 dsDNA epitopes (394 epitope) coupled to an inert platform. It binds antibodies to dsDNA in blood and on B cells and is designed to induce B cell tolerance.

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 double-blind, placebo (PBO)-controlled trial (90-05 trial) of LJP 394 in SLE patients with positive dsDNA antibody titers were analyzed for affinity to the 394 epitope. Surface plasmon resonance was used to measure the apparent equilibrium binding constant (Kd') between total IgG and the 394 epitope.

Results: Affinity of patient antibodies for the 394 epitope was measured prior to first administration of study drug and following 4 months of weekly treatment with 100 mg LJP 394. Pretreatment affinity was determined in 104/114 LJP 394 patients and 106/116 PBO patients and was similar between groups. Antibody affinity in drug patients (n=70) was reduced following 4 months treatment (p<0.001) while affinity of PBO patients (n=75) was stable. Over 89% of the patients in the 90-05 trial had an initial Kd' < 0.8 mg/ml and a treatment effect toward reduction in affinity was observed in this group (p<0.001).

Conclusion: Patients with high-affinity antibodies to LJP 394 showed a reduction in affinity during 4 month weekly exposure to LJP 394. This pharmacogenomic assay predicted patients most likely to respond to treatment with LJP 394.

Presented at
The 6th International Lupus Conference
Barcelona, Spain
March 24-28, 2001