IN VIVO CHARACTERIZATION OF BIOCONJUGATE B CELL TOLERAGENS WITH SPECIFICITY FOR AUTOANTIBODIES IN ANTIPHOSPHOLIPID SYNDROME

Cockerill KA, Smith E, Jones DS, Branks MJ, Hayag M, Victoria EJ, Linnik MD, Campbell MA

La Jolla Pharmaceutical Company, 6455 Nancy Ridge Drive, San Diego, CA 92121, USA.
keith.cockerill@ljpc.com

This study investigated the use of well-defined bioconjugate molecules to suppress antigen-specific B cell responses to domain I (DI) of human beta(2)-glycoprotein I (beta(2)GPI) in rats. DI is the dominant target of pathogenic autoimmune antibodies in patients with antiphospholipid syndrome (APS), a disease characterized by antibody-mediated thromboembolic events. Rats primed with DI conjugated to keyhole limpet hemocyanin (DI-KLH) were rendered tolerant to subsequent antigen challenge by treatment with multivalent conjugates of DI. Antibodies to DI were suppressed 89-96% with intravenous doses of 500 micro g, and reductions were paralleled by decreases in splenic antigen-specific antibody-forming cells (AFC). Suppression was achieved with a variety of conjugates having two to four copies of DI and circulating half-lives of 2.6-8.7 h. Antibodies to KLH were not suppressed, indicating the specificity of the approach. These results establish the basis for further development of therapeutic B cell toleragens to suppress pathogenic antibodies in APS and other autoimmune diseases.

Published in
International Immunopharmacology, 2003
Volume 3, Issue 12: pp 1667-1675