Monoclonal antibodies targeting the fungal cell surface: next generation antifungal therapeutics

Fungal pathogens of Candida and Aspergillus species cause life-threatening invasive fungal infections that can be recalcitrant to antifungal therapy. There is a clear clinical need for novel antifungal therapies. The fungal cell wall contains virulence factors and mediates interactions with the host. In a targeted approach we have engineered recombinant monoclonal antibodies that recognise cell wall proteins of fungal pathogens. These antibodies have huge potential to accurately diagnose and treat fungal infections. This PhD project will extensively characterise the binding interactions of our lead antibodies using heterologously expressed cell surface proteins, short peptide sequences, and fungal cells from different clinical isolates. At the University of Dundee, the Van Aalten lab has elucidated the structure of several fungal-specific cell surface proteins and will provide expertise in the expression of fungal glycoproteins that will be utilised for the characterisation of antibody binding using biochemical assays (ELISAs) and Surface Plasmon Resonance (SPR). In addition, they can provide expertise in protein crystallography to elicit antibody binding to the fungal targets and in silico construction of the 3D structure of these antibodies and target proteins to study the macromolecular interactions through interface predictions and molecular docking. The student will also receive advanced training in antibody engineering at the Scottish Biologics Facility, headed by Dr Soumya Palliyil. Using the latest tools in protein engineering and combining the expertise of recombinant antibody development, this project will also explore the feasibility of generating bispecific formats of the existing antibodies e.g. two different antigen binding arms on the same antibody molecule or potent antibody drug conjugates (ADCs) by biochemically coupling an antimicrobial agent to the selected lead antibody for enhanced pathogen killing.