Monoclonal Antibodies Targeting Surface-Exposed Epitopes of Candida albicans Cell Wall Proteins Confer In Vivo Protection in an Infection Model.
Soumya PalliyilMark MawerSami A AlawfiLily FoggTyng H TanGiuseppe Buda De CesareLouise A WalkerDonna M MacCallumAndrew J PorterCarol A MunroPublished in: Antimicrobial agents and chemotherapy (2022)
Monoclonal antibody (mAb)-based immunotherapies targeting systemic and deep-seated fungal infections are still in their early stages of development, with no licensed antifungal mAbs currently being available for patients at risk. The cell wall glycoproteins of Candida albicans are of particular interest as potential targets for therapeutic antibody generation due to their extracellular location and key involvement in fungal pathogenesis. Here, we describe the generation of recombinant human antibodies specifically targeting two key cell wall proteins (CWPs) in C. albicans: Utr2 and Pga31. These antibodies were isolated from a phage display antibody library using peptide antigens representing the surface-exposed regions of CWPs expressed at elevated levels during in vivo infection. Reformatted human-mouse chimeric mAbs preferentially recognized C. albicans hyphal forms compared to yeast cells, and increased binding was observed when the cells were grown in the presence of the antifungal agent caspofungin. In J774.1 macrophage interaction assays, mAb pretreatment resulted in the faster engulfment of C. albicans cells, suggesting a role of the CWP antibodies as opsonizing agents during phagocyte recruitment. Finally, in a series of clinically predictive mouse models of systemic candidiasis, our lead mAb achieved improved survival (83%) and a several-log reduction of the fungal burden in the kidneys, similar to the levels achieved for the fungicidal drug caspofungin and superior to the therapeutic efficacy of any anti- Candida mAb reported to date.
Keyphrases
- candida albicans
- cell wall
- monoclonal antibody
- biofilm formation
- induced apoptosis
- cell cycle arrest
- cancer therapy
- newly diagnosed
- end stage renal disease
- ejection fraction
- recombinant human
- endothelial cells
- mouse model
- signaling pathway
- risk factors
- endoplasmic reticulum stress
- adipose tissue
- mesenchymal stem cells
- staphylococcus aureus
- single cell
- peritoneal dialysis
- patient reported outcomes
- immune response