Staphylococcal enterotoxin B (SEB) is a prototype enterotoxin produced by many isolates of Staphylococcus aureus. SEB causes polyclonal activation of T lymphocytes resulting in massive release of pro-inflammatory mediators and culminating in severe toxic shock. SEB is considered by the Centers for Disease Control and Prevention (CDC) as a category B select agent. SEB is also a major cause of food poisoning and toxic shock syndrome. Currently, there are no therapeutics available against SEB for human use. This proposal is aimed at preclinical development of fully human therapeutic anti-SEB monoclonal antibodies (hMabs). By using a human combinatorial antibody library and a phage display approach, a cohort of fully human antibodies against SEB were identified. Preliminary characterization has led to the selection of eight clones for pre-clinical testing and evaluation. Several of these hMabs displayed neutralizing activity towards SEB. The research plan is designed in 4 Specific Aims.
In Aim 1, lead hMabs with neutralizing activity against SEB intoxication and other related superantigens will be identified based upon extensive studies using in vitro proliferation assays and an in vivo mouse model of SEB intoxication. Therapeutic efficacy of the lead hMabs will be determined within Aim 2 in a mouse model of SEB-induced toxic shock to identify a short list of lead therapeutics.
In Aim 3, the lead therapeutic antibodies will be subjected to affinity maturation, if necessary, by using a proprietary mutagenesis technology that will result in a second generation of optimized anti-SEB hMabs. Therapeutic candidates will be biophysically characterized. The optimized hMabs will be tested within Aim 4 via a humanized transgenic mouse model and rhesus aerosol challenge model for toxic shock to identify the final preclinical therapeutic candidate against SEB intoxication. The envisioned clinical applications of the developed antibody will be both prophylactic to provide passive immunity to individuals at high risk via an imminent bioterror attack, and as a therapeutic antidote for treatment of individuals already exposed to SEB. This proposal brings together expertise from Integrated Biotherapeutics Inc, the US Army Medical Research Institute of Infectious Diseases (USAMRIID), Biocon, Inc., as well as MorphoSys AG and its subsidiary AbD-Serotec, in anti-toxin therapeutic development, animal studies with biothreat agents, and a novel proprietary technology for development of fully human antibodies.
| Karauzum, Hatice; Chen, Gang; Abaandou, Laura et al. (2012) Synthetic human monoclonal antibodies toward staphylococcal enterotoxin B (SEB) protective against toxic shock syndrome. J Biol Chem 287:25203-15 |
