Next generation aptamers for faster safer more sensitive in vivo PET imaging

Abstract Significance ImmuoPET is a powerful in vivo imaging technique with unique advantages over standard of care ex vivo methods to improve cancer diagnosis monitoring and treatment selection Despite ImmunoPET s potential standard antibody based targeting methods result in long multi day procedures insufficient specificity and contrast for early detection and risk of adverse immunological response with repeated use While solutions such as minibodies or affibodies can resolve some of these issues no complete solution to all three of these challenges is available Aptamers single stranded nucleic acid ligands can yield high binding affinity and specificity to a target favorable pharmacokinetics and a highly non immunogenic composition However aptamers have been stymied in clinical imaging due to rapid nuclease mediated degradation and difficulty retaining affinity in vivo within biological environments preventing them from accumulating in target tissue in sufficient quantities Hypothesis Next gen aptamer targeting agents designed with increased longevity and performance within in vivo environments offer a non immunogenic alternative to antibody based targeting agents with the possibility of increased imaging quality and favorable pharmacokinetics Preliminary Data Aptitude has developed Chemically Augmented Particle Display CAPD a novel platform that yields next gen aptamers with unprecedented affinity specificity and in vivo stability via a novel non SELEX approach of ultra high throughput quantitative screening Aims In this proposal we aim to utilize CAPD to develop and validate an initial suite of next gen aptamer based immunoPET imaging agents and then compare to established antibody based methods in an animal model First we will use CAPD to create next gen aptamers to an angiogenesis marker VEGF and a checkpoint marker PD L We will synthetize and conjugate aptamers for radiolabeling and characterize their affinity specificity and stability in human serum We will validate our Ga labeled anti VEGF aptamer in vivo and with an ovarian cancer xenograft model assess image development time sensitivity and biodistribution We will compare to Zr labeled bevacizumab the radiolabeled form of Avastin an FDA approved anti VEGF therapy previously validated in immunoPET imaging If successful this study will support both the validation of our aptamer imaging agents and the applicability of our aptamer generation platform which we plan to use to create a broad suite of safer faster and more sensitive in vivo imaging agents for PET Narrative ImmunoPET is a powerful imaging technique used to detect and monitor malignant tumors yet existing antibody based agents suffer from long procedure times and the risk of adverse immunogenic side effects Aptamers are nucleic acid ligands that have the potential to overcome the limitations of antibodies as the targeting agent but they have shown low specificity in biological environments and are easily degraded in the body This study aims to develop and validate next generation aptamers which yield unprecedented stability and the capability to bind targets with high specificity in the body and if successful will enable faster safer and more sensitive PET imaging