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Susceptibility of the Human Pathogenic Fungi Cryptococcus neoformans and Histoplasma capsulatum to -Radiation Versus Radioimmunotherapy with - and ß-Emitting Radioisotopes

¹ Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, New York
² Department of Radiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey
³ Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
⁴ Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York

Fungal diseases are difficult to treat in immunosuppressed patients and, consequently, new approaches to therapy are urgently needed. One novel strategy is to use radioimmunotherapy (RIT) with fungal-binding monoclonal antibodies (mAbs) labeled with radionuclides. However, many fungi manifest extreme resistance to -radiation, such that the doses of several thousand gray are required for 90% cell killing, whereas for mammalian cells the lethal dose is only a few gray. We compared the susceptibility of human pathogenic fungi Cryptococcus neoformans (CN) and Histoplasma capsulatum (HC) to external -radiation and to the organism-specific mAbs 18B7 and 9C7, respectively, conjugated to ²¹³Bi and ¹⁸⁸Re radionuclides. Methods: CN and HC cells were irradiated with up to 8,000 Gy (¹³⁷Cs source, 30 Gy/min). RIT of CN with ²¹³Bi- and ¹⁸⁸Re-labeled specific mAb and of HC with ¹⁸⁸Re-labeled specific mAb used 0–1.2 MBq per 10⁵ microbial cells. After irradiation or RIT, the cells were plated for colony-forming units (CFUs). Cellular dosimetry calculations were performed, and the pathway of cell death after irradiation was evaluated by flow cytometry. Results: Both CN and HC proved to be extremely resistant to -radiation such that significant killing was observed only for doses of >4,000 Gy. In contrast, these cells were much more susceptible to killing by radiation delivered with a specific mAb, such that a 2-logarithm reduction in colony numbers was achieved by incubating them with ²¹³Bi- and ¹⁸⁸Re-labeled mAb 18B7 or with ¹⁸⁸Re-9C7 mAb. Dosimetry calculations showed that RIT was 1,000-fold more efficient in killing CN and 100-fold more efficient in killing HC than -radiation. Both -radiation and RIT caused cell death via an apoptotic-like pathway with a higher percentage of apoptosis observed in RIT-treated cells. Conclusion: Conjugating a radioactive isotope to a fungal-specific antibody converted an immunoglobulin with no antifungal activity into a microbicidal molecule. RIT of fungal cells using specific antibodies labeled with - and ß-emitting radioisotopes was significantly more efficient in killing CN and HC than -radiation when based on the mean absorbed dose to the cell. These results strongly support the concept of using RIT as an antimicrobial modality.

Key Words: radioimmunotherapy • infection • dosimetry • pathogenic fungi

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