The Synthesis and Evaluation of Radioimmunoconjugates for Cancer Imaging and Therapy

Abstract

Positron emission tomography (PET) imaging is a powerful tool for detecting and characterising cancerous cells. By using radioimmunoconjugates (RICs) that selectively bind to cancer-specific cell surface antigens, PET imaging can provide quantitative information about the prevalence and distribution of these antigens, allowing multiple cancer types to be accurately diagnosed and staged in a non-invasive manner. RICs can also be used to develop antibody-drug conjugates and radioimmunotherapeutics, enabling the prediction and monitoring of therapeutic response in individual patients. This thesis describesthe development of novel antibody conjugates for cancer imaging and therapy. Following an introduction to molecular imaging, radiochemistry, therapeutic antibodies, and antibody conjugation chemistry, each chapter focuses on the development of a novel RIC for a specific application. These include dual-labelled RICs for both PET and fluorescence imaging of sarcoma, antibody-cell-penetrating peptide conjugates for enhanced cellular internalisation, and single-chain antibody conjugates for liver fibrosis imaging. Through a combination of chemical conjugation, radiolabelling, and in vitro and in vivo testing, the utility of these conjugates is demonstrated for improving the sensitivity and specificity of cancer imaging and the effectiveness of cancer therapies. An array of cargos, including fluorescent dyes, metal chelators, peptides, and click chemistry handles, were conjugated to antibodies through a range of bioorthogonal chemical reactions chosen based on specific requirements. The antibody conjugates were characterised using a variety of applicable analytical techniques and were radiolabelled with the positron-emitting radioisotope zirconium-89. Their stability was assessed in relevant sera, and various cell assays were performed to determine the immunoreactivity, binding affinity, and cellular internalisation rate of the RICs. Where necessary, mouse models were used to evaluate the specificity, tumour uptake, and biodistribution profile of the conjugates in vivo.