Staphylococcal enterotoxin B (SEB;Category B agent), a toxin that commonly causes classic food poisoning and can cause a non-menstrual toxic shock syndrome (TSS), has been studied as a potential biological warfare agent. Importantly, SEB is derived from common readily accessible bacteria, is relatively easily produced, and can be delivered in a stable aerosol form. SEB exhibits severe toxicity by the inhalation route;once inhaled it causes widespread systemic damage, multi- organ system failure, and even shock and death at microgram doses. Clearly, an SEB attack would be devastating to civilian populations as well as on the battlefield during times of war. Currently, there are no preventatives or therapeutics available against SEB. Monoclonal antibodies (mAbs) are a class of FDA-approved biologics that can potently neutralize toxins. Because of their stability, specificity, versatility, and low potential for immunogenicity, mAbs are ideal for biodefense-related countermeasures. As a result of successful completion of our Phase 1 efforts, we have identified a highly potent mAb that protects mice from systemic and aerosol challenge. Further, in this proposal we are combining forces with Integrated Biotherapeutics (Gaithersburg, MD) whose team has identified an additional anti-SEB mAb via separate NIAID funding. Together we will determine which of the two mAbs is the most appropriate for continued development, resulting in cost-savings for NIH. The Long Range Objective of this project is to develop a safe and effective immunoprotectant product for SEB. We expect the initial indication will be for pre- and post-exposure prophylaxis.
The Specific Aims and Milestones of this proposal are:
Aim 1. Produce the two candidate mAbs using a Nicotiana benthamiana based rapid antibody manufacturing platform (RAMP).
Aim 2. Evaluate the pre- and post-exposure efficacy of the two mAbs in non-human primates against aerosolized SEB. The most efficacious mAb, to be designated MB-SEB, will be chosen for continued development.
Aim 3. Complete Investigational New Drug (IND) enabling studies to prepare for clinical evaluation of MB-SEB in accordance with regulatory requirements. Using RAMP mAb produced under Good Manufacturing Practice (GMP), the studies necessary (pharmacology and toxicology;chemistry, manufacturing and control data) to submit an IND application will be performed to support a Phase 1 safety trial.
The efforts in this proposal will help in the development of a drug for preventing and treating exposure to SEB, a highly potent toxin that is a significant biological warfare threat to public and military safety.