Antibody-Based Biologics and Their Promise to Combat Staphylococcus aureus Infections

Abstract

The growing incidence of serious infections mediated by methicillin-resistant Staphylococcus aureus (MRSA) strains poses a significant risk to public health. This risk is exacerbated by a prolonged void in the discovery and development of truly novel antibiotics and the absence of a vaccine. These gaps have created renewed interest in the use of biologics in the prevention and treatment of serious staphylococcal infections. In this review, we focus on efforts towards the discovery and development of antibody-based biologic agents and their potential as clinical agents in the management of serious S. aureus infections. Recent promising data for monoclonal antibodies (mAbs) targeting anthrax and Ebola highlight the potential of antibody-based biologics as therapeutic agents for serious infections.

Keywords: MRSA; antibody; biologics; immune evasion; infectious diseases.

Figure 1. S. aureus Immune Evasion Factors Targeted by Experimental Biologic Agents

S. aureus possesses an elaborate arsenal of extracellular virulence factors that serve as targets for the current class of anti-staphylococcal biologics being developed. These targets include: (1) surface bound adhesins that promote host colonization and disruption of complement pathways, (2) immunoglobulin binding proteins (Protein A, Sbi) that bind to IgGs and prevent engagement of host immune factors, (3) surface-associated and secreted proteases (GluV8) that digest IgG antibody components and diminish effector function, (4) a family of immune-stimulatory exotoxins called superantigens (SAgs), (5) potent leukocidal toxins that kill critical classes of immune cells, and (6) immunogenic cell wall autolysins that are important for bacterial uptake into non-professional phagocytes.

Figure 2. Extracellular and Intracellular killing mediated by S. aureus toxins

S. aureus implements a multi-pronged strategy to kill host immune cells from both outside of the cell and from within. Extracellular cytolysis: On the surface of the host cell, S. aureus delivers pore-forming toxins that target specific host receptors and destroy the phagocyte through cell lysis. Intracellular cytolysis: S. aureus is opsonized with immunglobulins and complement, which leads to phagocytosis of a subset of this population. Intracellular bacteria then promote their survival by releasing toxins that disrupt the integrity of the phagolysosome, promote bacterial escape into the cytoplasm, and destroy the phagocyte from within. Approaches to block extracellular and intracellular cytolysis: Current biologics under development attempt to account for all facets of this strategy using molecules that opsonize the bacterium and neutralize the toxins that are responsible for causing cell death, thus disarming the bacterium from the outside and from within. With this approach, the phagocyte is preserved and S. aureus is destroyed in the phagolysosome.