HUMAN ANTIBODIES FOR THERAPEUTIC INTERVENTION OF SEB EXPOSURE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This research plan relates to the preclinical development of antibodies capable of neutralizing staphylococcal enterotoxin B (SEB) in vivo. The ultimate objective of this proposal is the development of Human Anti-SEB MAbs (HASMs). Thus far, we have completed a full pharmacokinetics study with MORAb-048 (the candidate therapeutic antibody) in rhesus macaques. We have also performed a preliminary therapeutics evaluation against SEB toxin in rhesus macaques. The experimental therapeutic (MORAb-048) was administered either intravenously or intramuscularly and blood was drawn at 12 preselected time points. Results of the study show a rapid increase in plasma levels in IV-administered MORAb-048, whereas peak levels for IM administration are 48 hours postexposure. Using these data, we administered the therapeutic to rhesus macaques (n=14) either 48 hours (IM) or immediately before (-30 min) aerosol exposure to SEB toxin. Results of the aerosol exposure showed that, although the exposure concentration provided was congruent with a lethal dose (1 LD50), the challenge failed to effect the majority of the untreated controls (n=4, 3/4; 75% survival). Further analysis of the challenge material indicated that the loss of critical amino acid chains during the enterotoxin purification process limited the toxic potential of the reagent. As a result, the aerosol challenge with SEB was not adequate to test the protective capacity of the therapeutic under testing (MORAb-048). This study is being repeated with challenge material that has been assurance-purified using Western blot analysis to confirm the complete structural integrity of the SEB reagent.