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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 to prepare for submission of an IND to the FDA for the clinical development of Human Anti-SEB MAbs (HASMs). Morphotek has identified at least two HASMs that can block SEB activity in vivo. The aims of this proposal address all the requirements for an IND submission including but not limited to: 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 reversing SEB toxicity. The humanized monoclonal antibody MORAb-048 has shown in vitro and in vivo (rodent models) to be specific to and neutralize SEB. This antibody was further evaluated in a nonhuman primate aerosol model of SEB intoxication. An initial pharmacokinetic profile of MORAb-048 indicated plasma levels peaked at approximately 48 hours after injection. Thereafter, MORAb-048 was administered prophylactically and animals were then exposed to either three or nine times the 50% lethal dose of purified SEB by small particle aerosol. Results indicated that MORAb-048 completely protected (100% survival) animals from SEB-induced lethality at the lower challenge dose (3x LD^50) and partially protected (83% survival) at the higher challenge dose (9x LD^50). Groups administered MORAb-048 appeared to experience a lower rate of clinical/enteric effects than unprotected animals. Collectively, these results show that MORAb-048 protects rhesus macaques from SEB-induced intoxication and there is a dose-limiting effect based upon an escalating challenge used in the study.