The development of next-generation nanoparticle delivery systems using variable new antigen receptors for the treatment of cancer

Abstract

With a growing knowledge of the biology of cancer, a range of potential new drug targets have been identified, many of which are intracellular or difficult to target. Monoclonal antibodies and their derivatives have transformed the field of oncology, with monoclonal antibodies a current gold standard treatment both as single agents and  in combination with other therapeutic approaches. However, their use is often limited, with targeting only successful for those antigens/receptors expressed on the cell surface. Consequently, those targets which are expressed intracellularly lack a viable targeting option. Thus, novel approaches to target cancer oncogenes, both intracellular and extracellular, are required. This thesis, in collaboration with Elasmogen Ltd, pioneers of vNAR technology, aims to outline the potential of vNARs as novel therapeutic agents to bind to and inhibit both intracellular oncogenes, in addition to exploring extracellular proteins as targets. Possessing remarkable stability, far superior to that of antibodies or fragments and an ability to bind cryptic/hidden epitopes with high affinity, it is hypothesised that vNARs may be ideally suited not only to inhibiting the activity of these intracellular antigens, but as promising alternatives to monoclonal antibodies in targeting cell surface proteins.
 
One of the most pertinent challenges affecting drug development, is the ability to control the biological fate of the active pharmaceutical ingredient (API) following administration. Therefore, this thesis illustrates the isolation and evaluation of novel vNAR binders towards a panel of both intracellular and extracellular targets for application in the treatment of cancer. Isolated vNARs were evaluated for development into a novel vNAR-conjugated, nanoparticle-based delivery systems for superior delivery of cytotoxic payloads. Alongside this, a cationic nanoparticle delivery system was developed to facilitate enhanced cellular uptake and intracellular cargo delivery.

Thesis embargoed until 31 July 2027.

Date of Award	Jul 2022
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy, Biotechnology & Biological Sciences Research Council & Elasmogen Ltd
Supervisor	Daniel Longley (Supervisor) & Christopher Scott (Supervisor)