A multimodal approach for immunotherapy of Staphylococcus aureus bacteremia

Abvacc, Inc., Rockville MD

Investigators

Abstract

Staphylococcus aureus (S. aureus; SA) colonizes >50% of people and causes a wide range of diseases including bacteremia, pneumonia, and surgical site infections. No SA vaccines or immunotherapeutics are approved or in late-stage clinical development. Recent findings revealing the detrimental impact of prior exposure to SA on shaping the immune response to SA vaccine candidates highlight the importance of not only targeting bacterial growth, but also the immune evasion mechanisms of SA as treatment options. This proposed project seeks to develop an immunotherapeutic antibody cocktail for treatment of SA bacteremia (SAB) that targets multiple mechanisms of growth and immune evasion by SA through targeting three key factors. SA pore-forming toxins (PFTs) including leukocidins and hemolysins target the innate immune cells, as well as T cells that are required for protection against SA, and cells with barrier function required for containment of infection. These toxins also kill erythrocytes to extract iron for bacterial growth. SA protein A (SpA) binds to Fc and interferes with the complement mediated effector functions. SpA, through binding to VH3 Fabs, also acts as a B cell superantigen triggering polyclonal expansion followed by deletion of B cells bearing VH3 B cell receptors. SpA blunts the humoral responses to other SA antigens. SA autolysin (Atl) is a peptidoglycan- cleaving enzyme essential for productive division of SA cells. Clinical outcome in patients undergoing surgery after SA prosthetic joint infection correlates with antibodies to glucosaminidase (Gmd) domain of Atl. While humans have anti-Gmd IgG from SA infections and/or colonization, eliciting neutralizing antibodies is extremely rare. But in non-human primates (NHPs) we were able to induce high neutralizing titers upon vaccination with recombinant Gmd. We hypothesize that combined neutralization of PFTs, SpA, and Gmd during SAB and other invasive SA infections protects against SA invasive disease by antibacterial activity (anti-Gmd), protecting the immune cells (anti-PFT), helping with complement and macrophage mediated clearance of bacteria (anti-SpA and anti-Gmd), and by expanding immune responses to other SA antigens (anti-SpA). Using our mAb discovery platform we have already identified highly potent mAbs from macaques and humans against a wide range of SA toxins including a fully human mAb that cross-neutralizes five PFTs. This antibody combined with an anti- Gmd mAb protects in murine models of SAB and pneumonia. Furthermore, for the first time we have developed a novel nonhuman primate (NHP) model of SAB, that will be used in this project. In this project we will identify additional mAbs against these targets (Aim 1), determine the epitopes and crystal structures of at least one antigen-mAb complex in each group (Aim 2), evaluate the impact of neutralization of SpA on the outcome of immune response to SA infection in NHPs and evaluate the efficacy of a cocktail of three mAbs in guinea pig model of SAB (Aim 3). With this study, we expect to build the foundation for the development of an effective immunotherapy of SA invasive diseases.