Toward Developing a Universal Treatment for Fungal Disease Using Radioimmunotherapy Targeting Common Fungal Antigens

R. A. Bryan, A. J. Guimaraes, S. Hopcraft, Z. Jiang, K. Bonilla, A. Morgenstern, F. Bruchertseifer, M. Del Poeta, A. Torosantucci, A. Cassone, Joshua D. Nosanchuk, A. Casadevall, E. Dadachova

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Background: 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 IgG2b 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 22% 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. Conclusion: Our results suggest that it is feasible to develop RIT against fungal pathogens by targeting common antigens and such an approach could be developed against fungal diseases for which existing therapy is unsatisfactory.

Original languageEnglish (US)
Pages (from-to)463-471
Number of pages9
JournalMycopathologia
Volume173
Issue number5-6
DOIs
StatePublished - Jun 2012

Fingerprint

fungal antigens
Fungal Antigens
Radioimmunotherapy
Mycoses
Cryptococcus neoformans
bismuth
monoclonal antibodies
Chaperonin 60
Monoclonal Antibodies
Bismuth
ceramides
Ceramides
Melanins
melanin
beta-glucans
heat shock proteins
Fungi
Candida albicans
Cell Wall
fungi

Keywords

  • C. albicans
  • C. neoformans
  • Ceramide
  • Glucan
  • Hsp60
  • Melanin
  • Radioimmunotherapy

ASJC Scopus subject areas

  • Plant Science
  • Agronomy and Crop Science
  • Applied Microbiology and Biotechnology
  • Microbiology
  • veterinary (miscalleneous)

Cite this

Bryan, R. A., Guimaraes, A. J., Hopcraft, S., Jiang, Z., Bonilla, K., Morgenstern, A., ... Dadachova, E. (2012). Toward Developing a Universal Treatment for Fungal Disease Using Radioimmunotherapy Targeting Common Fungal Antigens. Mycopathologia, 173(5-6), 463-471. https://doi.org/10.1007/s11046-011-9476-9

Toward Developing a Universal Treatment for Fungal Disease Using Radioimmunotherapy Targeting Common Fungal Antigens. / Bryan, R. A.; Guimaraes, A. J.; Hopcraft, S.; Jiang, Z.; Bonilla, K.; Morgenstern, A.; Bruchertseifer, F.; Del Poeta, M.; Torosantucci, A.; Cassone, A.; Nosanchuk, Joshua D.; Casadevall, A.; Dadachova, E.

In: Mycopathologia, Vol. 173, No. 5-6, 06.2012, p. 463-471.

Research output: Contribution to journalArticle

Bryan, RA, Guimaraes, AJ, Hopcraft, S, Jiang, Z, Bonilla, K, Morgenstern, A, Bruchertseifer, F, Del Poeta, M, Torosantucci, A, Cassone, A, Nosanchuk, JD, Casadevall, A & Dadachova, E 2012, 'Toward Developing a Universal Treatment for Fungal Disease Using Radioimmunotherapy Targeting Common Fungal Antigens', Mycopathologia, vol. 173, no. 5-6, pp. 463-471. https://doi.org/10.1007/s11046-011-9476-9
Bryan, R. A. ; Guimaraes, A. J. ; Hopcraft, S. ; Jiang, Z. ; Bonilla, K. ; Morgenstern, A. ; Bruchertseifer, F. ; Del Poeta, M. ; Torosantucci, A. ; Cassone, A. ; Nosanchuk, Joshua D. ; Casadevall, A. ; Dadachova, E. / Toward Developing a Universal Treatment for Fungal Disease Using Radioimmunotherapy Targeting Common Fungal Antigens. In: Mycopathologia. 2012 ; Vol. 173, No. 5-6. pp. 463-471.
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abstract = "Background: 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 IgG2b 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 22{\%} 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. Conclusion: Our results suggest that it is feasible to develop RIT against fungal pathogens by targeting common antigens and such an approach could be developed against fungal diseases for which existing therapy is unsatisfactory.",
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