Overview of clinical trials employing antibody-targeted superantigens

Two Phase I clinical trials have been conducted using PNU-214565, a recombinant fusion protein of C242Fab and staphylococcal enterotoxin A (SEA). The initial escalating single dose trial was performed to determine safety and define toxicities. Cumulative doses determined to be safe as single doses were incorporated in an escalating, repeated dose regimen. Twenty-one patients were treated in the single dose and 27 in the repeated dose trials. Patient demographics were equivalent in both, as were the toxicities encountered - primarily fever and hypotension. Three patients in the single dose regimen treated at 0.5 ng/kg experienced grade 3 fever and/or hypotension, and one patient in the repeated dose trial had a dose-limiting grade 4 hypotension (2.75 ng/kg). TNFalpha and IL-2 induction in circulating blood preceded the development of clinical symptoms. One partial response was observed in the repeated dose trial. Pre-existing anti-SEA plasma antibodies protect patients against toxicity at a given drug dose. Based on these findings, a pharmacodynamically-based dosing scheme is currently being tested in a new repeated dose trial.