The use of closo-dodecaborate-containing linker improves targeting of HNSCC xenografts with radioiodinated chimeric monoclonal antibody U36

Abstract

Abstract. radionuclide imaging of head and neck squamous cell carcinoma (HnScc) using monoclonal antibodies (Mabs) has the potential to contribute to improved diagnosis and staging, thereby making more effective treatment possible. chimeric monoclonal antibody U36 (cMAb U36), specific to CD44v6 antigen, is a candidate for the targeting of HnScc. The aim of this study was to compare the influence of indirect iodination via closo-dodecaborate-based linker (DABI) with the influence of direct radioiodination on the biodistribution of the chimeric anti-CD44v6 antibody U36. The study was performed using nude mice bearing uT-Scc7 HnScc xenografts using the paired-label method. The biodistribution of cMab u36 labelled directly with 131 i and using daBi with 125 i was compared in the same animals. The influence of DABI on the tumour-to-organ ratio was evaluated. For both conjugates, radioactivity uptake in blood and organs decreased with time, except in tumours and the thyroid. daBi-labelled cMab u36 was characterised by fast blood clearance and an elevated uptake in the liver and spleen. The use of daBi enabled a 1.5 to 2-fold improvement in the tumour-to-blood and tumour-to-organ ratios in comparison with direct radioiodination, with the exception of the liver and spleen. These results indicate that daBi is a promising linker for the coupling of radioiodine to HnScc-targeting antibodies. IntroductionSquamous cell carcinoma, the predominant histological type among cancer of the head and neck (HnScc), remains the sixth most common neoplasm, accounting for approximately 5% of all malignant tumours worldwide (1,2). The prognosis for patients with HNSCC has not improved significantly over the past 25 years (3,4). Locoregional recurrence following conventional therapy occurs in approximately 50% of patients with advanced-stage HnScc, and distant metastases develop in nearly 25% of patients (5,6). Treatment with (neo)adjuvant chemotherapy has not led to improvements in the survival of these groups (7). Progress in therapy may be achieved in part by improvements in diagnostics, which would allow for the determination of optimal treatment strategy, and by accurate staging, which would enable the avoidance of over-and undertreatment (8,9).The introduction of new diagnostic radionuclide-based modalities, such as FdG-PeT, appears to be promising for improving the accuracy of staging (10). From a clinical point of view, improved imaging of HnScc in patients is important for pre-operative evaluation. nonetheless, a decisive breakthrough in comparison with other diagnostic methods, such as ultrasound, cT or Mri, has yet to be achieved (11,12). in order to improve staging, the radioimmunoscintigraphy of lymph node metastases has been proposed (13). The authors concluded that radioimmunoscintigraphy was not superior to cT or Mri for the detection of lymph node metastases due to its lack of sensitivity; the use of radioimmuno-PeT was suggested as a method for improving detection (13).Iodine-124 (T 1/2 =100 h) is among the long-lived pos...