伊立替康
序号38
结合
体内
间隙
抗体
药代动力学
体外
化学
药理学
葡萄糖醛酸化
高效液相色谱法
免疫学
医学
癌症
内科学
生物
生物化学
色谱法
泌尿科
微粒体
结直肠癌
数学
生物技术
数学分析
作者
Robert M. Sharkey,William J. McBride,Thomas M. Cardillo,Serengulam V. Govindan,Yan Wang,Edmund A. Rossi,Chien-Hsing Chang,David M. Goldenberg
标识
DOI:10.1158/1078-0432.ccr-15-0670
摘要
This study examined the delivery of SN-38 to Trop-2-expressing tumors and assessed the constitutive products in the serum, liver, and small intestine in nude mice bearing human tumor xenografts (Capan-1 or NCI-N87) given a single injection of irinotecan (40 mg/kg; ∼ 0.8 mg/mouse, containing ∼ 460 μg SN-38 equivalents) or sacituzumab govitecan (IMMU-132), an antibody-drug conjugate composed of a humanized anti-Trop-2 IgG coupled site specifically with an average of 7.6 molecules of SN-38.At select times, tissues were extracted and concentrations of the products measured by reversed-phase high-performance liquid chromatography (HPLC).In serum, >98% irinotecan cleared within 5 minutes; peak levels of SN-38 and SN-38G (glucuronidated SN-38) were detected in equal amounts at this time, and no longer detected after 6 to 8 hours. IMMU-132 was detected in the serum over 3 days, and at each interval, ≥ 95% of total SN-38 was bound to the antibody. Intact IMMU-132 cleared with a half-life of 14 hours, which closely reflected the in vitro rate of SN-38 released from the conjugate in mouse serum (i.e., 17.5 hours), whereas the IgG portion of the conjugate cleared with a half-life of 67.1 hours. In vitro and in vivo studies disclosed IgG-bound SN-38 was protected from glucuronidation. Area under the curve (AUC) analysis indicated that IMMU-132 delivers 20-fold to as much as 136-fold more SN-38 to tumors than irinotecan, with tumor:blood ratios favoring IMMU-132 by 20- to 40-fold. Intestinal concentrations of SN-38/SN-38G also were 9-fold lower with IMMU-132.These studies confirm a superior SN-38 tumor delivery by IMMU-132 compared with irinotecan.
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