Selective and concentrated accretion of SN-38 with a CEACAM5-targeting antibody-drug conjugate (ADC), labetuzumab govitecan (IMMU-130)

Labetuzumab govitecan (IMMU-130), an antibody-drug conjugate (ADC) with an average of 7.6 SN-38/IgG, was evaluated for its potential to enhance delivery of SN-38 to human colonic tumor xenografts. Mice bearing LS174T or GW-39 human colonic tumor xenografts were injected with irinotecan or IMMU-130 (SN-38 equivalents ~500 µg or ~16 µg, respectively). Serum and homogenates of tumors, liver, and small intestine were extracted, and SN-38, SN-38G (glucuronidated SN-38), and irinotecan concentrations determined by reversed-phase HPLC. Irinotecan cleared quickly from serum, with only 1-2% injected dose/mL after 5 min; overall, ~20% was converted to SN-38 andSN-38G. At 1 h with IMMU-130, 45-63% injected dose/mL of the SN-38 was in the serum, with >90% bound to the ADC over 3 days, and with low levels of SN-38G. Total SN-38 levels decreased more quickly than the IgG, confirming a gradual SN-38 release from the ADC. Area under the curve analysis found SN-38 levels were ~11- and 16-fold higher in LS174T and GW-39 tumors, respectively, in IMMU-130-treated animals. This delivery advantage is amplified >30-fold when normalized to SN-38 equivalents injected for each product. Levels of SN-38 and SN-38G were appreciably lower in the liver and small intestinal contents in animals given IMMU-130. Based on the SN-38 equivalents administered, IMMU-130 potentially delivers >300-fold more SN-38 to CEA-producing tumors compared to irinotecan, while also reducing levels of SN-38 and SN-38G in normal tissues. These observations are consistent with preclinical and clinical data showing efficacy and improved safety.

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