Antitumor Efficacy of a Monoclonal Antibody That Inhibits the Activity of Cancer-Associated Carbonic Anhydrase XII
| Autor: | Pawel Swietach, Elisabeth Kremmer, Jian Ping Jen, Alzbeta Hulikova, Gabor Gondi, Josef Mysliwietz, Reinhard Zeidler |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Immunoprecipitation medicine.drug_class Intracellular pH Blotting Western Fluorescent Antibody Technique Apoptosis Mice SCID Monoclonal antibody Catalysis Mice Mice Inbred NOD Neoplasms Spheroids Cellular Carbonic anhydrase Tumor Cells Cultured medicine Animals Humans Carbonic Anhydrase Inhibitors Carbonic Anhydrases Cell Proliferation chemistry.chemical_classification biology Cell Membrane Interleukin-2 Receptor alpha Subunit Antibodies Monoclonal Hydrogen-Ion Concentration Molecular biology In vitro Enzyme Oncology chemistry Biochemistry Cancer cell biology.protein Antibody circulatory and respiratory physiology |
| Zdroj: | Cancer Res. 73, 6494-6503 (2013) |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-13-1110 |
| Popis: | Carbonic anhydrase XII (CA XII) is a membrane-tethered cell surface enzyme that is highly expressed on many human tumor cells. Carbonic anhydrase members in this class of exofacial molecules facilitate tumor metabolism by facilitating CO2 venting and intracellular pH regulation. Accordingly, inhibition of exofacial CAs has been proposed as a general therapeutic strategy to target cancer. The recent characterization of 6A10, the first CA XII-specific inhibitory monoclonal antibody, offered an opportunity to evaluate this strategy with regard to CA XII-mediated catalysis. Using functional assays, we showed that 6A10 inhibited exofacial CA activity in CA XII-expressing cancer cells. 6A10 reduced spheroid growth in vitro under culture conditions where CA XII was active (i.e., alkaline pH) and where its catalytic activity was likely rate-limiting (i.e., restricted extracellular HCO3− supply). These in vitro results argued that the antibody exerted its growth-retarding effect by acting on the catalytic process, rather than on antigen binding per se. Notably, when administered in a mouse xenograft model of human cancer, 6A10 exerted a significant delay on tumor outgrowth. These results corroborate the notion that exofacial CA is critical for cancer cell physiology and they establish the immunotherapeutic efficacy of targeting CA XII using an inhibitory antibody. Cancer Res; 73(21); 6494–503. ©2013 AACR. |
| Databáze: | OpenAIRE |
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