La Jolla Pharmaceutical Company, San Diego CA, USA.
Lupus. 2010 Feb;19(2):130-7. doi: 10.1177/0961203309348982. Epub 2009 Nov 17.
beta2-glycoprotein I is the best-characterized antigenic target for antiphospholipid autoantibodies. We synthesized a tetrameric conjugate of the domain 1 of beta2-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. ( 125)I-labeled LJP 993 was intravenously injected to mice, and levels of (125)I-labeled LJP 993 in plasma, tissues, urine and feces were determined at known intervals. Incubation of LJP 993 with mouse serum at 37 degrees 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 (125)I-LJP 993 (0.5 and 5 mg/kg) to mice, both C(max) 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 (125)I-LJP 993 was moderately distributed into organs and tissues with the exception that brain level of ( 125)I-LJP 993 was negligible. The major sites of (125)I-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, (125)I-LJP 993 was taken up mainly by kidney and then distributed extensively to tissues except brain. Both C(max) 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.
β2-糖蛋白 I 是抗磷脂自身抗体的最佳抗原靶标。我们合成了β2-糖蛋白 I 结构域 1 的四聚体缀合物（LJP 993），旨在将该缀合物开发为 Toleragen 以抑制抗磷脂综合征。本研究重点在于确定 LJP 993 在小鼠中的稳定性、组织分布、血浆浓度-时间曲线和排泄。使用强阳离子交换高效液相色谱法定量评估 LJP 993 在小鼠血浆中的稳定性。将（125）I 标记的 LJP 993 静脉注射到小鼠体内，并在已知时间间隔测定血浆、组织、尿液和粪便中的（125）I 标记的 LJP 993 水平。LJP 993 在 37°C 下与小鼠血清孵育 8 小时，导致 LJP 993 浓度降低 34%。在孵育过程中未观察到降解片段。单次静脉注射（125）I-LJP 993（0.5 和 5mg/kg）后，C（max）和 AUC 值均呈剂量依赖性增加，血液放射性以双指数方式消失，分布半衰期等于 1.7 分钟，消除半衰期分别为 188 和 281 分钟。（125）I-LJP 993 在器官和组织中分布适度，除脑内（125）I-LJP 993 水平可忽略不计外。（125）I-LJP 993 的主要摄取部位是肾脏（给药后 30 分钟），以及肾脏、肺、肝、心、脾、皮肤、肌肉和脂肪组织（给药后 4 小时）。给药后 0-48 小时内的累积尿液和粪便放射性分别占给药剂量的 44.7%和 4.2%，尿液排泄速度较快，发生在 8 小时内。总之，LJP 993 在小鼠血浆中相当稳定。给予小鼠后，（125）I-LJP 993 主要被肾脏摄取，然后广泛分布于除大脑以外的组织中。C（max）和 AUC 值均呈剂量依赖性增加。它主要通过尿液排泄，消除半衰期超过 3 小时。肾脏是排泄四聚体缀合物的主要途径。
