Passive Immunotherapeutics for Select Agents

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Post exposure prophylaxis and treatment are aitical challenges in the management of emerging viral diseases. Vaccines may be helpful in post exposure prophylaxis where agents replicate s10wty or are initially sequestered in the periphery. However, in most instances, active immunity does not occur in a lime frame wherein disease can be prevented or ameliorated. Passive immunotherapy has an established track record in management of infections with rabies. respiratory syncytial, and variola viruses. Except in rare instances where antibodies cross react with host tissues to cause disease or enhance virus uptake to accelerate progression of infection, the effects of passive immunotherapy are specific. Anlivirals have been used with success in many infections, and the repertoire of effective compounds will undoubtedly improve; nonetheless. passive immunotherapy will continue to be a significant primary or complementary line of defense. Reagents for passive immunotherapy include both convalescent serum and monoclonal antibodies (MAbs). MAbs have the advantages of defined reactivity and specificity. and enhanced safety profiles. Through previous work in pathogen detection in context of the WHO laboratory network we have access to peripheral blood lymphocytes (PBL) from victims recovered from infection with high.risk pathogens. We have established that PBL can be stored frozen and used for fusion several months after ootlection with only insignificant loss of Ig production. This Trans-RCE project will exploit human PBL and direct fusion with an effICient human hybridoma fusion partner cell line (MFP¿2), as well as immortalization of B cells using EBV and CpG followed by e1eeuofusion with a HMMA2.5 fusion partner cell line to produce fully human MAbs (fhMAB) SpecifIC for three select agents: Junin virus, Nipah virus, and Rift. VaHey fever virus. The choice of targets is based on data indicating a potential therapeutic role for passive immunotherapy and the avaHability well-characterized clinical materials. A limited evaluation of MFP-2 has been oonducted in the context of ding an INO with the FDA. Furthennore, a commercial relationship has been established with the goal of producing GMP grade fhMAbs for treatment of non-Hodgkin lymphomas. These factors will enable transition of fhMAbs with antiviral activity from animal models to clinical use. Specific aims include: 1. Establish serologic assays for screening of convalescent donor sera and human hybridoma supernatants; 2. Characterize donor sera and PBl, and generate human hybridoma lines; and 3. Test neutraliZing fhMAbs for protective activity in animal models.