Eric M. Smith, Michael J. Branks, Todd H. Davis, Mary-Ann Campbell, David S. Jones, Keith A. Cockerill, Matthew D. Linnik

La Jolla Pharmaceutical Company
6455 Nancy Ridge Drive, San Diego, CA. USA

Anti-b2glycoprotein1 (b2GP1) autoantibodies are strongly associated with thrombotic events in Antiphospholipid Syndrome. Induction of tolerance to b2GP1 presents a novel approach for these patients. We have shown that the majority of APS patients have antibodies specific for the first protein domain of b2GP1 (D1). In this study we examine the plasma clearance and toleragenic potency of several potential therapeutic compounds.

Multiple copies of purified recombinant D1 were conjugated to synthetic platforms to produce Toleragens of specific sizes and configurations. To screen potential candidates, radiolabeled Toleragens were injected into catheterized rats to determine their clearance rates from plasma.

An in vivo immunized rodent model was used to investigate the efficacy of these conjugates as Toleragens. Rats immunized with D1 coupled to KLH were treated with Toleragens or placebo, then boosted with D1-KLH. Tolerance was defined as a reduction in anti-D1 antibody titers and a reduction in D1-specific antibody forming cells. Our results show that multivalent D1 conjugates effectively reduce anti-D1 antibody titers and numbers of antibody forming cells.

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