1st supervisor: Ran Yan, King’s College London
2nd supervisor: Philip Miller, King’s College London
Integrin-αvβ6 is an epithelial-specific cell surface receptor. It is absent in healthy adult epithelia, but significantly upregulated in many carcinomas including ovarian, breast, and lung cancer. Furthermore, increased expression of the integrin-αvβ6 is positively correlated with tumour cell invasion and metastatic potential. Currently, the combination of early diagnosis and complete surgical removal represents the most effective therapeutic modality for many malignant tumours. So far, all the integrin-αvβ6 targeting PET/SPECT probes are still in the preclinical stage. They are mainly peptide based. Example include the [18F]FBA-A20FMDV2, 64Cu-AcD10, and 99mTc-SAAC-S02. However, all of them exhibit limited tumour uptake and retention due to non-specific binding to normal tissue or metabolic instability. Thus, there are unmet clinical needs to develop molecular probes for the early diagnosis and treatment of integrin-αvβ6 over-expressing carcinomas.
Several integrin-αvβ6 inhibiting antibodies have shown great promise for αvβ6 over-expressing carcinoma therapy. The commercially available humanised monoclonal antibodies 6.3G9 and 264RAD selectively bind to integrin-αvβ6 with high affinity (Kd=15.6 pM and 10.0 pM, respectively). Both antibodies significantly inhibited the integrin-αvβ6 over-expressing human cancer xenograft growth. Despite these attractive characteristics, their potential as cancer imaging reagents have never been exploited. We envisage that an integrin αvβ6-specific antibody dual labelled with a PET and a fluorescent reporter could enable the diagnosis, detection, and surgical treatment of integrin-αvβ6 over-expressing carcinomas to adopt a highly integrated approach. PET/CT imaging would enable more sensitive staging and allow accurate pre-operative surgical planning. During surgery, the tumour deposits, could then be rapidly localised with a handheld radiation detector and at the same time fluorescence imaging would ‘light up’ these tumours for real-time assessment and more accurate resection.
Recently, a dual PET and fluorescent labelling reagent, 124I-Green was developed in Yan’s group for bioconjugation with antibodies for theranostic applications. 124I-Green was coupled with a carcinoembryonic antigen (CEA)-specific antibody A5B7. The 124I-Green-A5B7 provided excellent tumour-to-background contrast in both PET/CT and ex vivo fluorescence imaging in a CEA-expressing xenograft model (Fig. 1A). To further minimise the background fluorescence, a second-generation dual labelling reagent, 124I-ICG with a near-infrared fluorophore, indocyanine green (ICG) was prepared (Fig. 1B). In this project, we will develop multifunctional theranostic reagents for integrin-αvβ6 expressing carcinomas PET imaging and fluorescence-guided surgery by systematically screening the 124I-ICG-6.3G9 and 124I-ICG-264RAD antibody conjugates.
Figure 1. A) PET/CT and ex vivo fluorescence imaging of the 124I-Green-A5B7 in a CEA-expressing xenograft model; B) the dual PET and fluorescent labelling reagent, 124I-ICG.