BACKGROUND: IMMU-130 is an antibody-drug conjugate (ADC) undergoing clinical investigation in patients with metastatic colorectal cancer (, NCT01605318). It is composed of a humanized anti-CEACAM5 IgG conjugated via a cleavable linker to SN-38, a topoisomerase-I inhibitor and active form of irinotecan. We investigated the potential advantage of IMMU-130 versus irinotecan for SN-38 delivery in nude mice bearing CEA-expressing human colonic tumor xenografts (LS174T or GW-39).

METHODS: Mice were injected with irinotecan (~ 900 µg; SN-38 equivalents = ~500 µg) or 1.0 mg of IMMU-130 (16 µg SN-38 equivalents). Irinotecan-treated animals were necropsied 5 min, 1, 2, 6-8 h post-injection, while IMMU-130-treated animals were evaluated at 1, 6, 24, 48-72 h. Serum and homogenates of tumors, liver, and small intestinal contents were extracted, and SN-38, SN-38G, and irinotecan concentrations were determined by reversed-phase HPLC. For IMMU-130-treated specimens, SN-38 concentrations were assessed in the extracted samples (Free SN-38), as well as in acid-hydrolyzed samples to determine Total SN-38 (Free + bound). IgG was measured by ELISA.

RESULTS: Irinotecan cleared quickly from serum, with [SN-38]averaging ~900 ng/mL to 200 ng/mL from 5 min to 6 h. SN-38G and SN-38 levels were similar. With IMMU-130, Free SN-38 was detected in serum over the entire monitoring period, but levels were only a small fraction of the Total SN-38 (~10%). Importantly, Free SN-38G was very low, being detected only within the first 6 h. Total SN-38 levels dropped more quickly than the IgG, confirming in vitro studies showing gradual SN-38 release from the ADC. In tumors, for irinotecan-treated animals, SN-38 peaked at 5 min, representing ≤0.2%/g of the SN-38 equivalent given. In IMMU-130-treated animals, no Free SN-38 was detected in tumors, but levels of Total SN-38 peaked at 6 h, with ~5%/g of the injected SN-38 dose present at that time, and were sustained longer than SN-38 delivered by irinotecan. Area under the curve analysis found SN-38 levels were ~10- and 17-fold higher in LS174T and GW-39 tumors, respectively, from IMMU-130-dosed versus irinotecan-dosed animals. This delivery advantage is amplified > 30-fold when normalized to SN-38 equivalents injected for each product, illustrating the improved bioavailability with IMMU-130-targeted SN-38. Levels of SN-38 and SN-38G were appreciably lower in the liver and small intestinal contents, which likely explains the lower incidence of severe diarrhea reported in patients given IMMU-130.

CONCLUSION: IMMU-130 delivers >300-fold more SN-38 to CEA-producing tumors compared to irinotecan, while also reducing levels of potentially harmful SN-38 and SN-38G in normal tissues. These observations are consistent with preclinical data showing improved efficacy and safety.

Citation Format: Thomas M. Cardillo, Robert M. Sharkey, Serengulam V. Govindan, Jennifer Donnel, Maria Zalath, David M. Goldenberg. Superior SN-38 pharmacodynamic and tumor-accretion profiles of labetuzumab govitecan (IMMU-130) versus irinotecan in experimental human colonic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4081. doi:10.1158/1538-7445.AM2017-4081