Pharmacokinetics of LJP 993, a tetrameric conjugate of domain 1 of β2-glycoprotein I for antiphospholipid syndrome

Abstract

β2-glycoprotein I is the best-characterized antigenic target for antiphospholipid autoantibodies. We synthesized a tetrameric conjugate of the domain 1 of β2-glycoprotein I (LJP 993) aimed at developing the conjugate as a Toleragen to suppress antiphospholipid syndrome. The present studies focused on determining the stability, tissue distribution, plasma concentration-time profile and excretion of the LJP 993 in mice. The stability of LJP 993 in mouse plasma was quantitatively evaluated using strong cation-exchange high performance liquid chromatography. 125I-labeled LJP 993 was intravenously injected to mice, and levels of 125I-labeled LJP 993 in plasma, tissues, urine and feces were determined at known intervals. Incubation of LJP 993 with mouse serum at 37°C for 8 h resulted in a decrease by 34% of LJP 993 concentration. No degradation fragment was observed during the incubation. After a single intravenous administration of 125I-LJP 993 (0.5 and 5 mg/kg) to mice, both Cmax and area-under-curve values increased in a dose-proportional manner, and blood radioactivity disappeared in a bi-exponential manner with the distribution half-lives equal to 1.7 min, and the elimination half-lives 188 and 281 min, respectively. The 125I-LJP 993 was moderately distributed into organs and tissues with the exception that brain level of 125I-LJP 993 was negligible. The major sites of 125I-LJP 993 uptake were the kidney (at 30 min post dosing), and kidney, lung, liver, heart, spleen, skin, muscle and fat tissues (at 4 h post dosing). Cumulative urinary and fecal radioactivity for 0—48 h post dosing accounted for 44.7% and 4.2% of the administered dose, respectively, with the fast rate of urinal excretion occurring within the first 8 h. In summary, LJP 993 was fairly stable in mouse plasma. After administration to mice, 125I-LJP 993 was taken up mainly by kidney and then distributed extensively to tissues except brain. Both Cmax and area-under-curve values increased in a dose-proportional manner. It was predominantly excreted in the urine with an elimination half-life longer than 3 h. Kidney is a major route to excrete the tetrameric conjugate. Lupus (2010) 19, 130—137.