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 relates to the preclinical development of antibodies capable of neutralizing staphylococcal enterotoxin B (SEB) in vivo; the ultimate objective of this project is to development Human Anti-SEB MAbs (HASMs). At least two HASMs have been identified that can block SEB activity in vivo. The aims of this project are justification and rationale of the proposed therapeutic approach; efficacy in animal models; toxicology and safety parameters of our antibodies(s); chemistry, manufacturing and controls (CMC) section; design of clinical protocol. There is considerable need to develop vaccines and therapeutic strategies capable of preventing or reverse SEB toxicity. In this work plan, one objective is to further improve the potency of the current HASMs by increasing their affinities using Morphotek's antibody optimization technology named morphogenics, and to find HASMs combinations and ratios that would allow lowering the HASMs dose (e.g. 1,000 human LD50). One major objective is to demonstrate survival of rhesus monkeys challenged with aerosol SEB and treated with HASMs. A nonhuman primate study at the TNPRC will 1) determine the biological half life of HASMs in vivo in nonhuman primates and correlate to molar ratios determined to be efficacious in mice, and 2) determine the therapeutic efficacy of HASMs in rhesus nonhuman primates challenged with aerosolized SEB. This study will begin in March 2009.