Generation and characterization of the first inhibitory antibody targeting tumour-associated carbonic anhydrase XII

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2011-05, Vol.60 (5), p.649-658
• Main Authors: Battke, Christina, Kremmer, Elisabeth, Mysliwietz, Josef, Gondi, Gabor, Dumitru, Claudia, Brandau, Sven, Lang, Stephan, Vullo, Daniela, Supuran, Claudiu, Zeidler, Reinhard
• Format: Article
• Language: English
• Subjects: Acidosis; Animals; Antibodies, Monoclonal - metabolism; Antineoplastic agents; Biological and medical sciences; Cancer Research; Carbon dioxide; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrases - genetics; Carbonic Anhydrases - immunology; Cell Line, Tumor; Cell Proliferation - drug effects; Cells; Enzymes; Flow Cytometry; Fluorescent Antibody Technique; Gene Expression; Glaucoma; Hydrogen-Ion Concentration; Hypoxia; Immunology; Immunotherapy; Kidney cancer; Localization; Medical sciences; Medicine; Medicine & Public Health; Membrane Proteins - immunology; Monoclonal antibodies; Neoplasms - enzymology; Neoplasms - immunology; Oncology; Original; Original Article; Pharmacology. Drug treatments; Rats; Tumors
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-011-0980-z

The carbonic anhydrases (CAs) constitute a family of almost ubiquitous enzymes of significant importance for many physiological and pathological processes. CAs reversely catalyse the conversion of CO 2  + H 2 O to HCO 3 − and H + , thereby contributing to the regulation of intracellular pH. Above all, CAs are of key importance for cells that perform glycolysis that inevitably leads to the intracellular accumulation of lactate. CA XII is a plasma membrane-associated isoform of the enzyme, which is induced by hypoxia and oestrogen and, consequently, expressed at high levels on various types of cancer and, intriguingly, on cancer stem cells. The enzyme is directly involved in tumour progression, and its inhibition has an anti-tumour effect. Apart from its role in carcinogenesis, the enzyme contributes to various other diseases like glaucoma and arteriosclerotic plaques, among others. CA XII is therefore regarded as promising target for specific therapies. We have now generated the first monoclonal antibody (6A10) that binds to the catalytic domain of CA XII on vital tumour cells and inhibits CA XII enzyme activity at nanomolar concentrations and thus much more effective than acetazolamide. In vitro results demonstrate that inhibition of CA XII by 6A10 inhibits the growth of tumour cells in 3-dimensional structures. In conclusion, we generated the first specific and efficient biological inhibitor of tumour-associated CA XII. This antibody may serve as a valuable tool for in vivo diagnosis and adjuvant treatment of different types of cancer.