An Overview of Bacterial Superantigen Toxins, CD28, and Drug Development

Acute toxic shock is induced by superantigen toxins, a diverse set of proteins secreted by Grampositive
staphylococcal and streptococcal bacterial strains that overstimulate the inflammatory
response by orders of magnitude. The need to protect from superantigen toxins led to our discovery
that in addition to the well-known MHC class II and T cell receptors, the principal costimulatory
receptor, CD28, and its constitutively expressed coligand, B7-2 (CD86), previously thought to have
only costimulatory function, are actually critical superantigen receptors. Binding of the superantigen
into the homodimer interfaces of these costimulatory receptors greatly enhances B7-2/CD28
engagement, leading to excessive pro-inflammatory signaling. This finding led to the design of short
receptor dimer interface mimetic peptides that block the binding of superantigen and thus protect from
death. One such CD28 mimetic peptide is advancing in a Phase 3 clinical trial to protect from lethal
wound infections by flesh-eating bacteria. These host-oriented therapeutics target the human immune
system itself, rendering pathogens less likely to become resistant.