DEVELOPMENT AND PRECLINICAL VALIDATION OF AN ANTI-EDNRB IMMUNOPET PROBE FOR MELANOMA IMAGING

Abstract

Melanoma comprises only 1-2% of skin cancer cases, but it is responsible for 90% of mortality from this disease. Global incidence has also been drastically increasing for the last century, with cases doubling every 10-20 years. Melanoma’s high propensity to metastasize is the major cause of mortality, as primary melanoma is relatively manageable, with 5-year survival rates >98%. [18F]-fluorodeoxyglucose positron emission tomography is the current state of the art for detecting metastases, disease staging, recurrence, and monitoring response to treatment. However, the general specificity this probe has for glucose metabolism and not melanoma itself results in off-target uptake in other glucose avid processes, like inflammation (false positives), and low/indeterminate uptake in small or metabolically inactive metastases (false negatives). To address this issue, a melanoma-specific immunoPET probe, [89Zr]Zr-DFO-3H5, was developed in collaboration with the National Research Council of Canada. The following work describes the development and preclinical validation of [89Zr]Zr-DFO-3H5. The antibody, 3H5, targets endothelin receptor type B, which is overexpressed in metastatic melanoma in comparison to both healthy tissues and other cancers. Zirconium-89, linked to the antibody via the bifunctional chelator DFO (deferoxamine), can then be delivered to metastatic sites, where it can emit positrons used in PET imaging. In preclinical in vivo PET imaging and biodistribution studies, the probe successfully and specifically delineated implanted tumours, demonstrating high tumour uptake (24.88 %ID/g), favourable biodistribution (<8 %ID/g in off-target tissues), and promising tumour-to-muscle (89.3), tumour-to-heart (7.2), and tumour-to-liver ratios (3.3). Specificity was shown by a decrease in uptake in a blocked control cohort (13.40 %ID/g) and in another control cohort that received a probe analog comprising a non-specific antibody (4.40 %ID/g). These promising early data warrant the continued investigation and validation of this probe as a radiopharmaceutical with the potential to improve upon metastatic melanoma imaging.