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|Title:||Towards developing a universal treatment for fungal disease using radioimmunotherapy targeting common fungal antigens|
|Authors:||BRYAN R. A.; GUIMARAES A.j.; HOPCRAFT S.; JIANG Z.; MORGENSTERN Alfred; BRUCHERTSEIFER Frank; DEL POETA M.; TOTOSANTUCCI A.; CASSONE A.; NOSANCHUK J.d.; CASADEVALL A.; DADACHOVA E.|
|Citation:||MYCOPATHOLOGIA vol. 173 p. 463 - 471|
|Type:||Articles in periodicals and books|
|Abstract:||Previously we demonstrated the ability of radiolabeled antibodies recognizing the cryptococcal polysaccharide capsule to kill Cryptococcus neoformans both in vitro and in infected mice. This approach, known as radioimmunotherapy (RIT), uses the exquisite ability of antibodies to bind antigens to deliver microbicidal radiation. To create RIT reagents which would be efficacious against all major medically important fungi, we have selected monoclonal antibodies (mAbs) to common surface fungal antigens such as heat shock protein 60 (HSP60), which is found on the surface of diverse fungi; beta (1,3)-glucan, which is a major constituent of fungal cell walls; ceramide which is found at the cell surface, and melanin, a polymer present in the fungal cell wall. Methods: MAbs 4E12, an IgG2a to fungal HSP60; 2G8, an IgG 2b to beta-(1,3)-glucan; and 6D2, an IgM to melanin, were labeled with the alpha-particle emitting radionuclide 213-Bismuth (213Bi) using the chelator CHXA". B11, an IgM antibody to glucosylceramide, was labeled with the beta emitter 188-Rhenium (188Re). Model organisms Cryptococcus neoformans and Candida albicans were used to assess the cytotoxicity of these compounds after exposure to either radiolabeled mAbs or controls.. Results: 213Bi-mAbs to HSP60 and to the beta-(1,3)-glucan each reduced the viability of both fungi by 80-100%. The 213Bi-6D2 mAb to melanin killed 50% of C. neoformans, but did not kill C. albicans. B11 mAb against fungal ceramide was effective against wild type C. neoformans, but was unable to kill a mutant lacking the ceramide target. Unlabeled mAbs and radiolabeled irrelevant control mAbs caused no killing.|
|JRC Directorate:||Nuclear Safety and Security|
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