Characterisation and radioimmunotherapy of L19-SIP, an anti-angiogenic antibody against the extra domain B of fibronectin, in colorectal tumour models

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 125I-labelled L19-SIP. Finally, 131I-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 125I-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 131I-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, 131I-L19-SIP shows potential as a novel treatment of colorectal tumours, and provides the foundation to investigate combined therapies in the same tumour models

The Cost of Missed EU Integration

The 2016 referendum held in the UK about the possibility to quit EU membership as well as a wave of populistic movements sweeping all over European Countries seem to suggest that less integration could be an outcome for the European Union. This paper has the aim to measure the cost of a missed integration, by highlighting what GDP growth would be in case of a missed integration. It does so by building a scenario of missed integration and compares it with a reference scenario. Scenarios are based on the Macroeconomics, Social, Sectoral, Territorial (MASST) model that has recently been updated to its fourth generation, whereby regional economic relations are tested econometrically. The estimated cause–effect chains are then the basis to build new scenarios simulated under complex sets of internally coherent assumptions in a simulation stage. The reference scenario presented is not a simple extrapolation of past trends; the post-crisis period registered structural changes to be taken into account for the future. In the integration scenario, we assume further integration within the EU to take place through the following changes: (1) higher trade flows among EU countries (“production integration effect”); (2) higher decrease in non-tariffs barriers (“proximity effect to larger markets”); (3) higher trust within and among countries (“social effect”); (4) higher quality of government (“institutional effect”); (5) stronger cooperation networks among cities (“cooperation effect”); and (6) higher exports (“market integration effect”). Results show that a more integrated scenario leads to faster economic growth across all EU countries. Territorial disparities are also initially lower in the case of more integration, although this difference abates over time. Lastly, the gains from integration are not spatially even and some regions gain more than others