Abstract
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.
Highlights
Antibody–drug conjugates (ADC) represent a new therapy class based on the proposition of their being able to deliver cytotoxic agents to their intended target with less collateral damage
We examine the advantage of delivering SN-38 with IMMU-132 compared with irinotecan in nude mice bearing 2 human tumor xenografts, as well as assess the concentrations of SN-38 and SN-38G in the serum, liver, and intestine
Of particular importance was the finding that the addition of the precipitating reagent to serum freshly spiked with IMMU132 recovered only about 7% of the expected amount of SN-38 associated with IMMU-132, indicating that the SN-38 bound to the IgG was not released effectively during the extraction process
Summary
Antibody–drug conjugates (ADC) represent a new therapy class based on the proposition of their being able to deliver cytotoxic agents to their intended target with less collateral damage. This technology has faced many challenges, but with 3 conjugates gaining FDA approval, each using drugs that are active at picomolar concentrations (so-called ultratoxic drugs), it appeared that the major hurdles facing this technology had been overcome and that a core platform on which similar agents could be developed was available [1,2,3,4,5]. Only a small portion of irinotecan is converted to SN-38, a process that occurs primarily in the liver, Immunomedics, Inc., Morris Plains, New Jersey
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