The occurrence of certain AIDS-associated opportunistic infectious diseases for which there is no cure combined with the emergence of multidrug-resistant strains of bacteria and fungi has produced an urgent need for new approaches to antimicrobial therapy. We have recently suggested the use of radioimmunotherapy (RIT) as a novel modality for treatment of opportunistic infections whereby radiolabeled specific antibodies are used to deliver microbicidal radiation to pathogens. A proof of principle for this strategy was achieved by demonstrating that radiolabeled antibodies can be used in the therapy of experimental Cryptococcus neoformans infection. This application proposes to investigate the interaction betweenAIDS-associated opportunistic microorganisms and particulate radiation delivered to the microbial cells by specific antibodies during radioimmunotherapy. Our goal is to carry out basic research studies that will explore fundamental questions related to antimicrobial radioimmunotherapy to further the development of this promising experimental treatment. C. neoformans has several advantages as a model system for radioimmunotherapy of fungal AIDS-associatedopportunistic infections which include the existenceof excellent animal models and the availability of several well characterized immunological reagents. Furthermore, monoclonal antibody (mAb) therapy is already in clinical testing for C. neoformans using the mAb 18B7. We hypothesize that radiolabeled antibodies will be efficient delivery vehicles for targeting radiation to microbial cells. We anticipate that targeted microbes will be killed by RIT through """"""""direct hit"""""""", """"""""cross-fire"""""""" or """"""""bystander"""""""" effects. We also hypothesize that it is possible to eradicate C. neoformans infection in vivo without clinically significant radiation injury to the surrounding tissue and major organs and without damage to the components of immune system.
Three aims are proposed: 1) To investigate the radiobiological mechanisms of interaction between radiolabeled antibodies and fungal cells; 2) To establish correlation between pharmacology, efficacy and toxicity of radioimmunotherapy in animal models of fungal infection; 3) To define the mechanisms of interaction of radiolabeled antibodies with the host immune system. The research proposed here will elucidate the fundamentals of the interactions between microorganisms, antibodies, particulate-emitting radioisotopes and the host immune system. Such knowledge will contribute to development of a novel therapeutic modality based on radioimmunotherapy for treatment of currently incurable or multidrug-resistant AIDS-associated opportunistic infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI060507-03S1
Application #
7439794
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Lambros, Chris
Project Start
2005-02-15
Project End
2010-01-31
Budget Start
2007-07-01
Budget End
2008-01-31
Support Year
3
Fiscal Year
2007
Total Cost
$56,385
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Dadachova, Ekaterina; Casadevall, Arturo (2014) Radiolabeled Antibodies for Therapy of Infectious Diseases. Microbiol Spectr 2:
Rivera, Johanna; Morgenstern, Alfred; Bruchertseifer, Frank et al. (2014) Microbicidal power of alpha radiation in sterilizing germinating Bacillus anthracis spores. Antimicrob Agents Chemother 58:1813-5
Bryan, Ruth A; Jiang, Zewei; Morgenstern, Alfred et al. (2013) Radioimmunotherapy of Cryptococcus neoformans spares bystander mammalian cells. Future Microbiol 8:1081-9
Jandl, Thomas; Revskaya, Ekaterina; Jiang, Zewei et al. (2013) Melanoma stem cells in experimental melanoma are killed by radioimmunotherapy. Nucl Med Biol 40:177-81
Jiang, Zewei; Bryan, Ruth A; Morgenstern, Alfred et al. (2012) Treatment of early and established Cryptococcus neoformans infection with radiolabeled antibodies in immunocompetent mice. Antimicrob Agents Chemother 56:552-4
Dufresne, Simon F; Datta, Kausik; Li, Xinming et al. (2012) Detection of urinary excreted fungal galactomannan-like antigens for diagnosis of invasive aspergillosis. PLoS One 7:e42736
Harris, Matthew; Wang, Xing Guo; Jiang, Zewei et al. (2011) Radioimmunotherapy of experimental head and neck squamous cell carcinoma (HNSCC) with E6-specific antibody using a novel HPV-16 positive HNSCC cell line. Head Neck Oncol 3:9
Phaeton, Rebecca; Harris, Matthew; Jiang, Zewei et al. (2010) Radioimmunotherapy with an antibody to the HPV16 E6 oncoprotein is effective in an experimental cervical tumor expressing low levels of E6. Cancer Biol Ther 10:1041-7
Dadachova, Ekaterina (2010) Cancer therapy with alpha-emitters labeled peptides. Semin Nucl Med 40:204-8
Phaeton, Rébécca; Wang, Xing Guo; Einstein, Mark H et al. (2010) The influence of proteasome inhibitor MG132, external radiation, and unlabeled antibody on the tumor uptake and biodistribution of (188)re-labeled anti-E6 C1P5 antibody in cervical cancer in mice. Cancer 116:1067-74

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