title: Human monoclonal antibodies targeting carbonic anhydrase IX for the molecular imaging of hypoxic regions in solid tumours.
abstract: BACKGROUND
  Hypoxia, which is commonly observed in areas of primary tumours and of metastases, influences response to treatment. However, its characterisation has so far mainly been restricted to the ex vivo analysis of tumour sections using monoclonal antibodies specific to carbonic anhydrase IX (CA IX) or by pimonidazole staining, after the intravenous administration of this 2-nitroimidazole compound in experimental animal models.
  
  
  METHODS
  In this study, we describe the generation of high-affinity human monoclonal antibodies (A3 and CC7) specific to human CA IX, using phage technology.
  
  
  RESULTS
  These antibodies were able to stain CA IX ex vivo and to target the cognate antigen in vivo. In one of the two animal models of colorectal cancer studied (LS174T), CA IX imaging closely matched pimonidazole staining, with a preferential staining of tumour areas characterised by little vascularity and low perfusion. In contrast, in a second animal model (SW1222), distinct staining patterns were observed for pimonidazole and CA IX targeting. We observed a complementary pattern of tumour regions targeted in vivo by the clinical-stage vascular-targeting antibody L19 and the anti-CA IX antibody A3, indicating that a homogenous pattern of in vivo tumour targeting could be achieved by a combination of the two antibodies.
  
  
  CONCLUSIONS
  The new human anti-CA IX antibodies are expected to be non-immunogenic in patients with cancer and may serve as broadly applicable reagents for the non-invasive imaging of hypoxia and for pharmacodelivery applications.
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, Zurich CH-8093, Switzerland.
authors.forename: J K J
authors.initials: JK
authors.lastname: Ahlskog
authors.forename: C
authors.initials: C
authors.lastname: Schliemann
authors.forename: J
authors.initials: J
authors.lastname: Mårlind
authors.forename: U
authors.initials: U
authors.lastname: Qureshi
authors.forename: A
authors.initials: A
authors.lastname: Ammar
authors.forename: R B
authors.initials: RB
authors.lastname: Pedley
authors.forename: D
authors.initials: D
authors.lastname: Neri
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics; D000918:Antibody Specificity / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000276:immunology*; D003952:Diagnostic Imaging / Q000379:methods*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D013604:T-Phages; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases