CEACAM5-Targeted Therapy of Human Colonic and Pancreatic Cancer Xenografts with Potent Labetuzumab-SN-38 Immunoconjugates

Purpose: To improve the efficacy and reduce the gastrointestinal toxicity of the cancer prodrug, CPT-11, we have developed immunoconjugates of its active form, SN-38, and an anti-CEACAM5 antibody for targeted chemotherapy. Experimental Design: SN-38 conjugates of the anti-CEACAM5 monoclonal antibody, labetuzumab (hMN-14), varying in the nature of the cross-linker attachment at the drug9s 20-hydroxyl position, were evaluated in vitro , in metastatic and/or s.c. human colonic and pancreatic cancer xenografts in nude mice using appropriate controls, and in a CEACAM5-negative tumor model. Results: A pilot study in a s.c. LS174T model of human colonic carcinoma established the relative effectiveness of different conjugates. In the lung metastatic model of GW-39 human colonic carcinoma in nude mice, therapy with two specific labetuzumab-SN-38 conjugates, using 0.25 mg SN-38 equivalent/kg, q4d × 8, significantly extended median survival time versus controls ( P P Conclusions: The promising labetuzumab-SN-38 conjugates developed showed selective therapeutic efficacy in human tumor models at nontoxic doses that were a fraction of the CPT-11 doses used. (Clin Cancer Res 2009;15(19):6052–61)