625 Background: IMMU-130 is a CEACAM5-targeted ADC, labetuzumab-SN-38, with the drug being the active form of the topoisomerase I inhibitor, CPT-11, and substituted at 7-8 moles/mole of IgG. This agent is in phase I/II clinical trials in patients with relapsed mCRC (NCT01270698; NCT01605318). Methods: Therapy experiments were conducted in female athymic nude mice (n=5-10 per group), 4-6 weeks of age, bearing s.c. LS174T human colon carcinoma xenografts of ~0.2 cm3 size, or 2 weeks after lung metastases were generated by i.v. injection of GW-39 human colon carcinoma cells. Untreated controls, including a non-targeting ADC, were included. Biodistribution was examined in the s.c model using a single 12.5-mg/kg dose of the ADC or unconjugated labetuzumab, each spiked with 111In-labeled substrate. Tolerability studies were conducted in white New Zealand rabbits. Results: In the metastatic model, fractionated dosing of a total of 50 mg/kg of ADC showed that 2 × the schedules of twice-weekly × 2 weeks with 1 week off and once-weekly × 2 weeks with 1 week off doubled the median survival vs. untreated mice, and were better than a 25-mg/kg dose given on days 1 and 15 (p < 0.0474; log-rank). Pre-dosing with as much as twice the dose of labetuzumab as the ADC dose in the metastatic model did not affect median survival (p > 0.15). Therapy experiments in the s.c. model revealed that IMMU-130, with 50% of drug released in ~20 h, was superior to the conjugate with an ultrastable linker, that the ADC was better than an MTD of 5FU/leucovorin chemotherapy (p < 0.0001), and that the ADC could be combined with bevacizumab for improved efficacy (p < 0.031). Significantly better efficacy for the specific ADC vs. nonspecific ADC was observed. Pharmacokinetics in mice indicated ~25% longer half-life for the unconjugated MAb vs. ADC, but with minimal impact on tumor uptake. A tolerability study in rabbits showed the NOAEL to be the human equivalent dose of 40-60 mg/kg, given as two doses. Conclusions: Preclinical data show an excellent therapeutic window for IMMU-130, which appears to be translated into the clinical experience thus far. The potential for combination therapy is also indicated.
Identification and Characterization of a Deletion Mutant of DNA Topoisomerase I mRNA in a Camptothecin-resistant Subline of Human Colon Carcinoma