A CHEMICALLY DEFINED, TOLERAGEN-BASED APPROACH FOR TARGETING ANTI-b2-GLYCOPROTEIN I ANTIBODIES.

GM Iverson, DS Jones, D Marquis, MD Linnik and EJ Victoria.

La Jolla Pharmaceutical Company, San Diego, CA 92121

Antiphospholipid syndrome is characterized by a prothrombotic state and the presence of b2-Glycoprotein I (b2-GPI)-dependent antiphospholipid antibodies. The feasibility of a B cell tolerance-based approach for specific reduction of anti-b2-GPI antibodies was investigated. Anti-b2-GPI antibodies isolated from a patient with antiphospholipid syndrome were used to screen peptide libraries expressed in phage, resulting in the identification of a phage that specifically bound anti-b2-GPI antibodies. The phage-displayed peptide was identified and chemically optimized to generate a synthetic 14-mer peptide with an internal thioether linkage (LJP 685) that retained the binding profile of the original phage. LJP 685 was conjugated to a defined, non-immunogenic organic platform to generate a tetravalent presentation of LJP 685 for use as a toleragen. Tetravalent LJP 685 induced a dose-dependent reduction in antibody levels in mice previously immunized and boosted with LJP 685 coupled to the carrier keyhole limpet hemocyanin. These experiments support the technical feasibility of a tolerance-based approach for reducing anti-b2-GPI in vivo.

Published in Lupus (1998) 7, Suppl 2, S166-S169.