Developing Bio-orthogonal Ynamine Reagents for the Preparation of Next-Generation Antibody-Drug Conjugates

Background

Biomolecule-based therapeutics – or biologics – have emerged as powerful modalities to treat diseases that are typically beyond the reach of conventional small molecules. However, to reach the full potential of biologics to deliver therapeutic payloads to the site of interest, synthetic methods are required to prepare these biologics (e.g., antibodies, therapeutic oligonucleotides). The current state-of-the-art in the preparation of antibody bioconjugates typically involve the formation of product mixtures where the site of functionalisation and the number of functional sites is not defined.

Previous work – Our collaborative team has recently identified the utility of aromatic ynamines as a superior reagent for the site-specific functionalisation of azides via a Cu-catalyzed alkyne-azide cycloaddition (CuAAC) reaction.[1-2] These alkyne surrogates require significantly less Cu catalyst are the only alkyne reagents reported to date which enable chemoselective control in a sequential two-step CuAAC process.[1,3]

Project Objective - The principal objective of this studentship is to develop aromatic ynamines as a powerful new bio-orthogonal reaction platform for the chemoselective tagging of antibodies and therapeutic oligonucleotides.

The specific aims of the project are to:

(i) gain a mechanistic understanding of the enhanced chemoselectivity of ynamines in CuAAC reactions, and potentially across other bio-orthogonal reaction classes.

(ii) establish conditions for chemoselective modification of antibodies and oligonucleotides.

(iii) prepare antibody-oligonucleotide conjugates and explore their biological activity in cell models.

Academic Environment - The student undertaking this project will receive unparalleled experience in all aspects of bioconjugate chemistry and chemical biology within the Strathclyde Centre for Molecular Bioscience (SCMB) – a new centre of excellence spanning chemistry and the biological sciences.  The Burley group (www.burleylabs.co.uk, University of Strathclyde) has extensive experience in small molecule synthesis, solid phase peptide/nucleic acid synthesis and the development of bioconjugation reagents.  In collaboration with the Watson group (University of St. Andrews, http://www.watsonresearchgroup.co.uk) we will explore the mechanistic aspects of these functional groups and apply this mechanistic insight to enhance their chemoselectivity. The analysis of these bioconjugates will also be explored using ion mobility mass spectrometry in collaboration with Dr Rebecca Beveridge.[4]