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DOMAIN SPECIFICITY OF AUTOANTIBODIES TO BETA2-GLYCOPROTEIN
I IN PATIENTS WITH ANTIPHOSPHOLIPID SYNDROME ENROLLED IN A PHASE
1/2 TRIAL WITH LJP 1082
Matthew D. Linnik, Luisa Salter-Cid, Andrew C. Miller, Richard
A. Furie, Arash Horizon, Michael H. Weisman, Daniel J Wallace,
Joan T. Merrill, Keith Cockerill
A serum depletion study evaluated the epitope specificity of antibodies
to beta-2-glycoprotein I (beta2GPI) in patients enrolled in a
phase 1/2 clinical trial with LJP 1082, an investigational drug
for antiphospholipid syndrome. LJP 1082 is a tetravalent conjugate
of recombinant domain 1 of human beta2GPI, and is intended to
specifically target and tolerize B cells producing pathogenic
antibodies. Antibodies to beta2GPI have been associated with an
increased risk for thrombotic events and recurrent fetal loss
and have been shown to cause coagulation defects in vitro.
Methods:
Sera from 15 patients were selected based on an anti-beta2GPI
activity greater than 20 standard IgG units as determined by the
INOVA QUANTA Lite™ anti-beta2GPI ELISA kit. Sera from baseline
and 1 hour after drug administration were analyzed. Sera were
depleted 3 times, 30 minutes each, by incubating with His-tagged
recombinant human beta2GPI domain 1 (D1) or domains 2-5 (D2-5)
coupled to nickel agarose beads. Mock-depleted samples were incubated
in a similar fashion with nickel beads coupled with a control
protein.
Results and conclusions:
Anti-beta2GPI reactivity was completely depleted from 14 of
15 samples by adsorption on D1. With the remaining serum, reactivity
to beta2GPI could not be depleted on D1 or on D2-5. The ability
to deplete antibodies was not affected by treatment with LJP 1082.
Three of the 14 sera that were completely depleted on D1 were
also partially depleted (14-28%) on D2-5, suggesting that some
patients have autoantibodies that cross-react with D1 and an epitope
on D2-5. Taken together, the data support the notion that D1 contains
the dominant epitopes recognized by autoantibodies to beta2GPI.
Cross-reactivity with epitopes on other domains may arise from
similarities in the consensus repeats that form the structure
of beta2GPI.
Presented at the
67th Annual Meeting of the American College of Rheumatology
Orlando, FL
October 23-28, 2003
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