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

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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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References

  1. Caston-Osorio JJ, Rivero A, Torre-Cisneros J. Epidemiology of invasive fungal infection. Int J Antimicrob Agents. 2008;32(Suppl 2):S103–9.

    Article  PubMed  CAS  Google Scholar 

  2. Dadachova E, Nakouzi A, Bryan RA, Casadevall A. Ionizing radiation delivered by specific antibody is therapeutic against a fungal infection. Proc Natl Acad Sci USA. 2003;100(19):10942–7.

    Article  PubMed  CAS  Google Scholar 

  3. Dadachova E, Bryan RA, Apostolidis C, Morgenstern A, Zhang T, Moadel T, et al. Interaction of radiolabeled antibodies with fungal cells and components of the immune system in vitro and during radioimmunotherapy for experimental fungal infection. J Infect Dis. 2006;193(10):1427–36.

    Article  PubMed  CAS  Google Scholar 

  4. Dadachova E, Bryan RA, Frenkel A, Zhang T, Apostolidis C, Nosanchuk JS, et al. Evaluation of acute hematologic and long-term pulmonary toxicities of radioimmunotherapy of Cryptococcus neoformans infection in murine models. Antimicrob Agents Chemother. 2004;48(3):1004–6.

    Article  PubMed  CAS  Google Scholar 

  5. Bryan RA, Jiang Z, Howell RC, Morgenstern A, Bruchertseifer F, Casadevall A, et al. Radioimmunotherapy is more effective than antifungal treatment in experimental cryptococcal infection. J Infect Dis. 2010;202(4):633–7.

    Article  PubMed  CAS  Google Scholar 

  6. Bowman SM, Free SJ. The structure and synthesis of the fungal cell wall. Bioessays. 2006;28(8):799–808.

    Article  PubMed  Google Scholar 

  7. Rachini A, Pietrella D, Lupo P, Torosantucci A, Chiani P, Bromuro C, et al. An anti-beta-glucan monoclonal antibody inhibits growth and capsule formation of Cryptococcus neoformans in vitro and exerts therapeutic, anticryptococcal activity in vivo. Infect Immun. 2007;75(11):5085–94.

    Article  PubMed  CAS  Google Scholar 

  8. Torosantucci A, Chiani P, Bromuro C, De Bernardis F, Palma AS, Liu Y, et al. Protection by anti-beta-glucan antibodies is associated with restricted beta-1, 3 glucan binding specificity and inhibition of fungal growth and adherence. PLoS One. 2009;4(4):e5392.

    Article  PubMed  Google Scholar 

  9. Guimaraes AJ, Frases S, Gomez FJ, Zancope-Oliveira RM, Nosanchuk JD. Monoclonal antibodies to heat shock protein 60 alter the pathogenesis of Histoplasma capsulatum. Infect Immun. 2009;77(4):1357–67.

    Article  PubMed  CAS  Google Scholar 

  10. Gomez BL, Nosanchuk JD. Melanin and fungi. Curr Opin Infect Dis. 2003;16(2):91–6.

    Article  PubMed  CAS  Google Scholar 

  11. Langfelder K, Streibel M, Jahn B, Haase G, Brakhage AA. Biosynthesis of fungal melanins and their importance for human pathogenic fungi. Fungal Genet Biol. 2003;38(2):143–58.

    Article  PubMed  CAS  Google Scholar 

  12. Nosanchuk JD, Rosas AL, Casadevall A. The antibody response to fungal melanin in mice. J Immunol. 1998;160(12):6026–31.

    PubMed  CAS  Google Scholar 

  13. Rosas AL, Nosanchuk JD, Gomez BL, Edens WA, Henson JM, Casadevall A. Isolation and serological analyses of fungal melanins. J Immunol Methods. 2000;244(1–2):69–80.

    Article  PubMed  CAS  Google Scholar 

  14. Revskaya E, Jongco AM, Sellers RS, Howell RC, Koba W, Guimaraes AJ, et al. Radioimmuno-therapy of experimental human metastatic melanoma with melanin-binding antibodies and in combination with dacarbazine. Clin Cancer Res. 2009;15(7):2373–9.

    Article  PubMed  CAS  Google Scholar 

  15. Rhome R, Singh A, Kechichian T, Drago M, Morace G, Luberto C, et al. Surface localization of glucosylceramide during Cryptococcus neoformans infection allows targeting as a potential antifungal. PLoS One. 2011;6(1):e15572.

    Article  PubMed  CAS  Google Scholar 

  16. Rittershaus PC, Kechichian TB, Allegood JC, Merrill AH Jr, Hennig M, Luberto C, Del Poeta M. Glucosylceramide synthase is an essential regulator of pathogenicity of Cryptococcus neoformans. J Clin Invest. 2006;116(6):1651–9.

    Article  PubMed  CAS  Google Scholar 

  17. Walker CA, Gomez BL, Mora-Montes HM, Mackenzie KS, Munro CA, Brown AJ, et al. Melanin externalization in Candida albicans depends on cell wall chitin structures. Eukaryot Cell. 2010;9(9):1329–42.

    Article  PubMed  CAS  Google Scholar 

  18. Suzuki CK, Kutejová E, Suda K. Analysis and purification of ATP-dependent mitochondrial lon protease of Saccharomyces cerevisiae. Methods Enzymol. 1995;260:486–94.

    Article  PubMed  CAS  Google Scholar 

  19. Batista WL, Matsuo AL, Ganiko L, Barros TF, Veiga TR, Freymüller E, Puccia R. The PbMDJ1 gene belongs to a conserved MDJ1/LON locus in thermodimorphic pathogenic fungi and encodes a heat shock protein that localizes to both the mitochondria and cell wall of Paracoccidioides brasiliensis. Eukaryot Cell. 2006;5(2):379–90.

    Article  PubMed  CAS  Google Scholar 

  20. Gomez FJ, Gomez AM, Deepe GS Jr. Protective efficacy of a 62-kilodalton antigen, HIS-62, from the cell wall and cell membrane of Histoplasma capsulatum yeast cells. Infect Immun. 1991;59(12):4459–64.

    PubMed  CAS  Google Scholar 

  21. Apostolidis C, Molinet R, Rasmussen G, Morgenstern A. Production of Ac-225 from Th-229 for targeted alpha therapy. Anal Chem. 2005;77(19):6288–91.

    Article  PubMed  CAS  Google Scholar 

  22. Rakesh V, Schweitzer AD, Zaragoza O, Bryan R, Wong K, Datta A, et al. Finite-element model of interaction between fungal polysaccharide and monoclonal antibody in the capsule of Cryptococcus neoformans. J Phys Chem B. 2008;112(29):8514–22.

    Article  PubMed  CAS  Google Scholar 

  23. Dadachova E, Howell RW, Bryan RA, Frenkel A, Nosanchuk JD, Casadevall A. Susceptibility of the human pathogenic fungi Cryptococcus neoformans and Histoplasma capsulatum to gamma-radiation versus radioimmunotherapy with alpha- and beta-emitting radioisotopes. J Nucl Med. 2004;45(2):313–20.

    PubMed  CAS  Google Scholar 

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Acknowledgments

E. Dadachova is a Sylvia and Robert S. Olnick Faculty Scholar in Cancer Research and is supported by the NIH grant R56 AI060507-06. A. Morgenstern and F. Bruchertseifer are supported by European Commission. Part of the results was presented at the 111th ASM General Meeting, May 2011, New Orleans, LA.

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Correspondence to E. Dadachova.

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Bryan, R.A., Guimaraes, A.J., Hopcraft, S. et al. Toward Developing a Universal Treatment for Fungal Disease Using Radioimmunotherapy Targeting Common Fungal Antigens. Mycopathologia 173, 463–471 (2012). https://doi.org/10.1007/s11046-011-9476-9

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  • DOI: https://doi.org/10.1007/s11046-011-9476-9

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