Invasive fungal infections (IFI) cause devastating morbidity and mortality, with the number of IFIs more than tripling since 1979. Our laboratories were the first to demonstrate that radiolabeled microorganism-specific monoclonal antibodies are highly effective for treatment of experimental fungal, bacterial and viral infections. Later we proposed to utilize surface expressed pan-antigens shared by major IFI-causing pathogens such as beta-glucans as RIT targets. Here we evaluated in vivo RIT targeting beta-glucan in Blastomyces dermatitidis which causes serious infections in immunocompromised and immunocompetent individuals and in companion dogs. B. dermatitidis cells were treated with the 400-2 antibody to (1→3)-β-glucans radiolabeled with the beta-emitter 177Lutetium (177Lu) and alpha-emitter 213Bismuth (213Bi) and the efficacy of cell kill was determined by colony forming units (CFUs). To determine the antigen-specific localization of the 400-2 antibody in vivo, C57BL6 mice were infected intratracheally with 2 × 105 B. dermatitidis cells and given 111In-400-2 antibody 24 h later. To evaluate the killing of B. dermatitidis cells with RIT, intratracheally infected mice were treated with 150 μCi 213Bi-400-2 and their lungs analyzed for CFUs 96 h post-infection. 213Bi-400-2 proved to be more effective in killing B. dermatitidis cells in vitro than 177Lu-400-2. Three times more 111In-400-2 accumulated in the lungs of infected mice, than in the non-infected ones. 213Bi-400-2 lowered the fungal burden in the lungs of infected mice more than 2 logs in comparison with non-treated infected controls. In conclusion, our results demonstrate the ability of an anti-(1-3)-beta-D-glucan antibody armed with an alpha-emitter 213Bi to selectively kill B. dermatitidis cells in vitro and in vivo. These first in vivo results of the effectiveness of RIT targeting pan-antigens on fungal pathogens warrant further investigation.
Keywords: (1→3)-β-glucan; 213Bismuth; Blastomyces dermatitidis; mouse model; radioimmunotherapy.
Copyright © 2020 Helal, Allen, van Dijk, Nosanchuk, Snead and Dadachova.