Ionizing radiation delivered by specific antibody is therapeutic against a fungal infection

Abstract

There is an urgent need for new antimicrobial therapies to combat drug resistance, new pathogens, and the relative inefficacy of current therapy in compromised hosts. Ionizing radiation can kill microorganisms quickly and efficiently, but this modality has not been exploited as a therapeutic antimicrobial strategy. We have developed methods to target ionizing radiation to a fungal cell by labeling a specific mAb with the therapeutic radioisotopes Rhenium-188 and Bismuth-213. Radiolabeled antibody killed cells of human pathogenic fungus Cryptococcus neoformans in vitro, thus converting an antibody with no inherent antifungal activity into a microbicidal molecule. Administration of radiolabeled antibody to mice with C. neoformans infection delivered 213Bi and 188Re to the sites of infection, reduced their organ fungal burden, and significantly prolonged their survival without apparent toxicity. This study establishes the principle that targeted radiation can be used for the therapy of an infectious disease, and suggests that it may have wide applicability as an antimicrobial strategy.

Fig. 1.

Immunoscintigraphic image (48 h) of infected A/JCr mouse, imaged with ¹⁸⁸Re-18B7 mAb. The lungs and the brain are marked with arrows. On a color scale, red represents the highest radioactivity uptake.

Fig. 2.

The dose dependence of CN killing by radiolabeled mAbs. (a) ¹⁸⁸Re-labeled mAbs. (b) ²¹³Bi-labeled mAbs.

Fig. 3.

Kaplan–Meier survival curves for A/JCr mice i.v. infected with 10⁵ CN cells 24 h before treatment with 50–200 μCi of ¹⁸⁸Re-labeled mAbs (a) and 50–200 μCi of ²¹³Bi-labeled mAbs (b). Mice injected with PBS or 50 μg of nonradioactive 18B7 served as controls.