4rgn

Publication Abstract from PubMed

Staphylococcal enterotoxin B (SEB) is a superantigen that cross-links the major histocompatibility complex class-II (MHC- II) and specific V-beta chains of the T-cell receptor (TCR) thus forming a ternary complex. Developing neutralizing monoclonal antibodies (mAb) to disrupt the ternary complex and abrogate the resulting toxicity is a major therapeutic challenge because SEB is effective at very low concentrations. We show that combining two SEB-specific mAbs enhances their efficacy even though one of the two mAbs by itself has no effect on neutralization. Crystallography was employed for fine- mapping of conformational epitopes in binary and ternary complexes between SEB and Fab fragments. NMR spectroscopy was used to validate and identify subtle allosteric changes induced by mAbs-binding to SEB. The mapping of epitopes established that combination of different mAbs can enhance efficacy of mAb-mediated protection from SEB induced lethal shock by two different mechanisms: one mAb cocktail promoted clearance of the toxin both in vitro and in vivo by FcR mediated crosslinking and clearance; whereas the other mAb cocktail induced subtle allosteric conformational changes in SEB that perturbed formation of the SEB:TCR:MHC-II trimer. Finally structural information accurately predicted mAb binding to other superantigens that share conformational epitopes with SEB. Fine mapping of conformational epitopes is a powerful tool to establish the mechanism and optimize the action of synergistic mAb combinations.

Mechanisms mediating enhanced neutralization efficacy of staphyloccoccal enterotoxin B by combinations of monoclonal antibodies.,Dutta K, Varshney AK, Franklin MC, Goger M, Wang X, Fries BC J Biol Chem. 2015 Jan 8. pii: jbc.M114.630715. PMID:25572397^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.