TSG101 Based Antibody Therapeutic for Ebola and Related Viruses
Final progress rept. 15 Apr 2004-14 Oct 2006
FUNCTIONAL GENETICS INC ROCKVILLE MD
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Functional Genetics received a contract from DARPA, No. W911NF04-C-0039, from April 2004 to October 2006, to study TSG101 Based Antibody Therapeutic for Ebola and Related Viruses . We had set an overall goal for this contract to discover anti-TSG101 antibody therapeutics that would inhibit the budding of Ebola and related viruses which rely on TSG101 to exit infected cells. TSG101 is normally an intracellular protein and belongs to the endosomal ESCRT-I protein sorting complex. TSG101 is hijacked by Ebola, HIV, and other viruses for budding out of the infected cells to produce new viral particles. Because TSG101 binds directly to Ebola VP40 protein and HIV p6 though the same protein motif, PTAP, on these viral proteins, we have proposed to use HIV as a surrogate of Ebola due to the similarity in budding mechanisms and the difficulty in performing Ebola experiments. After extensive screening of mouse monoclonal antibodies by traditional immunological assays, unlike the results from the polyclonal antibodies, we have not found monoclonal antibodies that directly inhibited viral budding and the consequent infection. Although we have not obtained antibody therapeutics for Ebola based on direct inhibition of budding through TSG101, we did make major progress in demonstrating that TSG101 was exposed extracellularly in virus infected cells but not in uninfected cells. Previous literature has demonstrated the general movement of intracellular TSG101 to the cytoplasmic membrane location but has not demonstrated the extracellular exposure of TSG101. We have therefore devised a new approach to use TSG101 to specifically mark viral infected cells for antibody-mediated killing or clearance , instead of finding antibodies that directly inhibit budding as a result of binding to TSG101.
- Medicine and Medical Research