High affinity mAbs against fungal glycans

Systemic candidiasis (SC) remains a leading infectious cause of morbidity and mortality in intensive care, post-surgical and cancer patients and accounts for substantial healthcare costs.  The eukaryotic nature of Candida will always make it a "tough nut to crack" and clinicians lack options when tackling systemic infection. Early diagnosis and initiation of an appropriate antifungal therapy is expected to deliver improved clinical outcomes; however timely diagnosis of SC is extremely challenging as a result of the nonspecific signs and symptoms associated with this disease.                 

Protective antibodies can confer passive immunity to patients and can be synergistic or additive when combined with conventional antimicrobial chemotherapy. This project specifically addresses this promising combination approach broadening the concept further to include passive immunisation therapy using a combination of antibodies specific for key carbohydrate antigens. Candida albicans cell wall glucans and mannans are very well established diagnostic and therapeutic targets as they represent the most abundant cell surface epitopes responsible for generation of unique antibodies against fungus.  

We have constructed a single chain antibody phage display library using the immune repertoire of a sheep hyperimmunised with C. albicans hyphal cell wall preparation. Analysis of polyclonal sera derived from immunised sheep confirm that the library contains a varied collection of antibodies with specificity to both fungal cell wall carbohydrates (mannans and glucans) as well as a number of important cell wall proteins. In vitro growth inhibition bioassays have demonstrated the neutralisation potential of polyclonal antibodies in the immune serum. This antibody library, one of the very first and largest against Candida cell wall antigens, has been successfully used to isolate high affinity and specificity binders to beta-glucans and alpha-mannans, which are otherwise poorly immunogenic glycans present on the fungal cell surface.

Project Team – Prof Andy Porter, Prof Al Brown, Dr Keith Charlton^*, Dr Soumya Palliyil, Abhishek Saxena

^{*Immunosolv Ltd}

Project Funding – European Commission Framework Programme 7