Enhanced Delivery of SN-38 to Human Tumor Xenografts with an Anti-Trop-2–SN-38 Antibody Conjugate (Sacituzumab Govitecan)

Purpose: 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. Experimental Design: At select times, tissues were extracted and concentrations of the products measured by reversed-phase high-performance liquid chromatography (HPLC). Results: 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. Conclusions: These studies confirm a superior SN-38 tumor delivery by IMMU-132 compared with irinotecan. Clin Cancer Res; 21(22); 5131–8. ©2015 AACR .