title: Generation and characterization of the first inhibitory antibody targeting tumour-associated carbonic anhydrase XII.
abstract: 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.
authors.affiliation: Department of Gene Vectors, Helmholtz-Center, Marchioninistrasse 25, Munich, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Battke
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Josef
authors.initials: J
authors.lastname: Mysliwietz
authors.forename: Gabor
authors.initials: G
authors.lastname: Gondi
authors.forename: Claudia
authors.initials: C
authors.lastname: Dumitru
authors.forename: Sven
authors.initials: S
authors.lastname: Brandau
authors.forename: Stephan
authors.initials: S
authors.lastname: Lang
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Claudiu
authors.initials: C
authors.lastname: Supuran
authors.forename: Reinhard
authors.initials: R
authors.lastname: Zeidler
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006863:Hydrogen-Ion Concentration; D008565:Membrane Proteins / Q000276:immunology; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology*; D051381:Rats
chemical_list: D000911:Antibodies, Monoclonal; D002257:Carbonic Anhydrase Inhibitors; D008565:Membrane Proteins; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII