Tosatoxumab (AR-301, Salvecin®) is a fully human IgG1 monoclonal antibody (mAb) that specifically targets Staphylococcus aureus (S. aureus) alpha-toxin, an important virulence factor that is secreted by both methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA). Top-line data was recently reported from a double-blinded, placebo-controlled Phase 2a clinical trial conducted across 31 intensive care units in four European countries and the U.S. evaluating the safety, pharmacokinetics, and efficacy of ascending doses of tosatoxumab. Tosatoxumab was tested as an adjunctive therapy to standard of care antibiotics in patients diagnosed with severe hospital-acquired pneumonia (HAP) and ventilator associated pneumonia (VAP) patients caused by S. aureus. Patients treated with tosatoxumab consistently demonstrated less time spent under mechanical ventilation and higher rates of S. aureus eradication as compared to those treated with antibiotics alone. Tosatoxumab was deemed to be safe and well tolerated, as no serious adverse events were reported in patients receiving tosatoxumab at all dose levels, and there was no difference in adverse events reported among the groups. In March 2012, orphan designation was granted to tosatoxumab by the European Commission for the treatment of pneumonia caused by S. aureus. In September 2015, tosatoxumab received Fast Track designation from the U.S. Food and Drug Administration (FDA) for the treatment of acute pneumonia caused by S. aureus. Tosatoxumab is currently being evaluated in a global Phase 3 clinical study. Interim clinical data from this study is expected in late 2019.
Research on alpha-toxin’s mechanism of action indicates that the toxin binds to the metalloproteinase ADAM 10 and enters the cytoplasmic membrane before moving laterally until seven subunits unite into a circular arrangement forming a pore through the cytoplasmic membrane. The pore allows small molecules to exit the cell and calcium to enter causing a cellular dysregulation. Alpha-toxin lyses neutrophils, platelets, monocytes, T cells, pneumocytes, keratinocytes, and endothelial cells. Alpha-toxin binding activates its receptor protease, ADAM 10, which then cleaves the E-cadherin molecules involved in attaching cells to a membrane, as happens to the corneal epithelium when subjected to alpha-toxin. The production and secretion of active alpha-toxin is maximally regulated by the Agr regulator system that triggers a 50-fold increase in alpha-toxin production starting late in the log phase. Other regulators also affect the production of alpha-toxin, including Sar, Sae and SarH1 such that the toxin production depends on the interaction of multiple regulators. In the early phase of growth, before the Agr system is activated, alpha-toxin production has been linked to the production of phenol-soluble-modulin peptides, which are important to virulence. Tosatoxumab protects against alpha-toxin mediated destruction of host cells, preserving the human immune cells. Tosatoxumab’s mode of action is independent of the antibiotic resistance profile of S. aureus and it is active against infections caused by both MRSA and MSSA.
Fig.1 Mechanism of action of Tosatoxumab