Dectin-2-Targeted Antifungal Liposomes Exhibit Enhanced Efficacy

Abstract

Invasive fungal diseases caused by Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus have mortality rates ranging from 10 to 95%. Individual patient costs may exceed $100,000 in the United States. All antifungals in current use have serious limitations due to host toxicity and/or insufficient fungal cell killing that results in recurrent infections. Few new antifungal drugs have been introduced in the last 2 decades. Hence, there is a critical need for improved antifungal therapeutics. By targeting antifungal-loaded liposomes to α-mannans in the extracellular matrices secreted by these fungi, we dramatically reduced the effective dose of drug. Dectin-2-coated liposomes loaded with amphotericin B bound 50- to 150-fold more strongly to C. albicans, C. neoformans, and A. fumigatus than untargeted liposomes and killed these fungi more than an order of magnitude more efficiently. Targeting drug-loaded liposomes specifically to fungal cells has the potential to greatly enhance the efficacy of most antifungal drugs.

Aiming for a bull’s-eye: Targeting antifungals to fungi with dectin-decorated liposomes

“…A strong indication that DectiSomes are more effective than untargeted drugs came first from in vitro fungal cell binding and killing studies (Table 1). DEC1-AmB-LLs and DEC2-AmB-LLs bind to the cell walls and more efficiently to the exopolysaccharide matrices of in vitro grown Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans 50-to 200-fold more strongly than untargeted AmB-LLs [9,10]. Binding is oligoglycan cognate specific, such that the oligoglucan laminarin specifically inhibits DEC1-AmB-LL binding [10], and yeast applied for a patent (62/913,489, WO/2020/ 146514) on this technology.…”

“…Current antifungal therapies rely on free antifungal drugs or untargeted liposomal or micellar drugs, which distribute randomly to fungal and mammalian cells alike. By contrast, DectiSomes are drugloaded liposomes coated with a protein(s) that targets them to fungal cell walls and their exopolysaccharide matrices (Fig 1A) [9,10]. DectiSomes bring antifungal drugs in close proximity to fungal cells to increase their local concentrations and to lower their concentration in host cells, thereby lowering the mg/kg effective dose of drug needed to control the pathogen [9][10][11], reducing host toxicity, and allowing temporally extended treatment regimens.…”

“…By contrast, DectiSomes are drugloaded liposomes coated with a protein(s) that targets them to fungal cell walls and their exopolysaccharide matrices (Fig 1A) [9,10]. DectiSomes bring antifungal drugs in close proximity to fungal cells to increase their local concentrations and to lower their concentration in host cells, thereby lowering the mg/kg effective dose of drug needed to control the pathogen [9][10][11], reducing host toxicity, and allowing temporally extended treatment regimens. All these effects should lead to better fungal clearance and better patient outcomes.…”

“…We've made 2 types of DectiSomes so far (Fig 1B), based on Dectin-1 [10][11][12] and Dectin-2 [9], the mammalian immune receptors for oligoglucans and oligomannans, respectively. We first prepared AmB-loaded liposomes, AmB-LLs [10].…”

“…AmB-LLs are pegylated analogs of the widely used commercial drug AmBisome. We then coated the AmB-LLs with the carbohydrate recognition domains of Dectin-1 [10,12] and Dectin-2 [9] to make DEC1-AmB-LLs and DEC2-AmB-LLs, respectively. Two Dectin monomers float together and form dimers that bind specifically to oligoglucans and oligomannans found in the cell walls, exopolysaccharide matrices, and biofilms of fungal pathogens [13].…”