title: Characterisation and radioimmunotherapy of L19-SIP, an anti-angiogenic antibody against the extra domain B of fibronectin, in colorectal tumour models.
abstract: Angiogenesis is a characteristic feature of tumours and other disorders. The human monoclonal antibody L19- SIP targets the extra domain B of fibronectin, a marker of angiogenesis expressed in a range of tumours. The aim of this study was to investigate whole body distribution, tumour localisation and the potential of radioimmunotherapy with the L19-small immunoprotein (SIP) in colorectal tumours. Two colorectal tumour models with highly different morphologies, the SW1222 and LS174T xenografts, were used in this study. Localisation and retention of the L19-SIP antibody at tumour vessels was demonstrated using immunohistochemistry and Cy3-labelled L19-SIP. Whole body biodistribution studies in both tumour models were carried out with (125)I-labelled L19-SIP. Finally, (131)I-labelled antibody was used to investigate the potential of radioimmunotherapy in SW1222 tumours. Using immunohistochemistry, we confirmed extra domain B expression in the tumour vasculature. Immunofluorescence demonstrated localisation and retention of injected Cy3-labelled L19-SIP at the abluminal side of tumour vessels. Biodistribution studies using a (125)I-labelled antibody showed selective tumour uptake in both models. Higher recorded values for localisation were found in the SW1222 tumours than in the LS174T (7.9 vs 6.6 %ID g(-1)), with comparable blood clearance for both models. Based on these results, a radioimmunotherapy study was performed in the SW1222 xenograft using (131)I-Labelled L19-SIP (55.5 MBq), which showed selective tumour uptake, tumour growth inhibition and improved survival. Radio- and fluorescence-labelled L19-SIP showed selective localisation and retention at vessels of two colorectal xenografts. Furthermore, (131)I-L19-SIP shows potential as a novel treatment of colorectal tumours, and provides the foundation to investigate combined therapies in the same tumour models.
authors.affiliation: 1Cancer Research UK Targeting and Imaging Group, Department of Oncology, Royal Free and University College Medical School (UCL), Hampstead Campus, Rowland Hill Street, London NW3 2PF, UK. e.el-emir@ucl.ac.uk
authors.forename: E
authors.initials: E
authors.lastname: El-Emir
authors.forename: J L J
authors.initials: JL
authors.lastname: Dearling
authors.forename: A
authors.initials: A
authors.lastname: Huhalov
authors.forename: M P
authors.initials: MP
authors.lastname: Robson
authors.forename: G
authors.initials: G
authors.lastname: Boxer
authors.forename: D
authors.initials: D
authors.lastname: Neri
authors.forename: G A M S
authors.initials: GA
authors.lastname: van Dongen
authors.forename: E
authors.initials: E
authors.lastname: Trachsel
authors.forename: R H J
authors.initials: RH
authors.lastname: Begent
authors.forename: R B
authors.initials: RB
authors.lastname: Pedley
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000532:radiotherapy*; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology / Q000532:radiotherapy*; D004195:Disease Models, Animal; D005260:Female; D005353:Fibronectins / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000276:immunology*; D016499:Radioimmunotherapy; D014183:Transplantation, Heterologous
chemical_list: D005353:Fibronectins