CEACAM5-Targeted Therapy of Human Colonic and Pancreatic Cancer Xenografts with Potent Labetuzumab-SN-38 Immunoconjugates
| Autor: | Hans J. Hansen, Serengulam V. Govindan, Sung-Ju Moon, David M. Goldenberg, Thomas M. Cardillo |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty Immunoconjugates Colorectal cancer medicine.medical_treatment Mice Nude Antineoplastic Agents Antibodies Monoclonal Humanized GPI-Linked Proteins Irinotecan Models Biological Article Labetuzumab Targeted therapy Mice Drug Delivery Systems Pancreatic cancer Tumor Cells Cultured medicine Animals Humans Chemotherapy business.industry Carcinoma Antibodies Monoclonal Cancer medicine.disease Xenograft Model Antitumor Assays Carcinoembryonic Antigen Pancreatic Neoplasms Transplantation Oncology Colonic Neoplasms Sacituzumab govitecan Cancer research Camptothecin Female business medicine.drug |
| Zdroj: | Clinical Cancer Research. 15:6052-6061 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-09-0586 |
| Popis: | 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 drug's 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 < 0.002). In an expanded evaluation in the s.c. LS174T xenograft model, specific SN-38 conjugates produced significant tumor growth control and increases in median survival time versus other controls, including CPT-11 at a 33-fold greater cumulative dose (P < 0.01). An improvement was also observed in the therapy of a s.c. human pancreatic tumor xenograft. In a CEACAM5-negative systemic lymphoma xenograft, one labetuzumab-SN-38 conjugate examined was ineffective, whereas the conjugate specific for the tumor model produced 100% survival. 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) |
| Databáze: | OpenAIRE |
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