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

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Trends

Community-onset invasive infections mediated by Staphylococcus aureus are a growing concern in global healthcare.

The paucity of novel antibiotics for the treatment of serious invasive diseases caused by S. aureus has spurred renewed interest in the discovery and development of alternate therapies, including antibody-based biologic agents.

Past failures in the clinical development of anti-staphylococcal antibodies for the treatment and prevention of S. aureus infections have focused on single antigens displayed at the bacterial cell surface.

Two antibody-based biologic agents currently under clinical evaluation target the secreted virulence factor, alpha-hemolysin.

A series of novel approaches is being explored towards the discovery and development of antibody-based biologic agents that target multiple S. aureus antigens, including host immune evasion factors and intracellular reservoirs of the bacterium.

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.

Section snippets

Staphylococcus aureus disease burden

Staphylococcus aureus is a human pathogen that greatly impacts individuals in both hospital and community settings and is capable of causing a wide spectrum of diseases, ranging from mild, and usually self-limiting conditions, such as impetigo, to severe, and potentially life-threatening diseases, such as pneumonia, endocarditis, and sepsis. In 2011, the Centers for Disease Control (CDC) identified 80 461 cases of diagnosed, severe infections mediated by MRSA in the USA, resulting in 11 285

Staphylococcus aureus Pathogenesis

Staphylococcus aureus is a commensal bacterium carried by 30% of the human population and, while colonization is associated with an increased risk for infection, natural carriers generally exhibit less severe infections than what is typically seen in noncarriers [2]. This observation demonstrates that pre-exposure to the bacterium provides an advantage in fighting off invasive infections. While it has not been conclusively shown what mediates this protection, it is known that persistent S.

Antibody Therapies Evaluated in Patients

The increasing prevalence of antibiotic-resistant S. aureus strains has bolstered the need for a dependable S. aureus immunization strategy. Unfortunately, all active and passive immunization (see Glossary) approaches to date have failed at the clinical trial stage. While this review primarily focuses on antibody-based passive immunization approaches, it should be recognized, and has been reviewed elsewhere, that both passive and active immunization strategies have implemented similar S. aureus

Why So Many Clinical Failures?

Antibody-based passive immunization agents that have thus far failed in clinical trials share several commonalities that might explain their lack of apparent efficacy. First, they have all targeted a single cell surface-associated antigen 7, 8, 9, 10, 11. Given the vast array of extracellular factors that S. aureus has, it is unlikely that focusing on a single antigen will cripple the bacterium. Another potential issue with targeting antibodies to surface proteins arose with the vaccine V710,

Next-Generation Biologics Target Immune Evasion Mechanisms

The failure of first-generation antibody-based biologic agents and the inadequacy of antibiotics in severe, invasive S. aureus disease may be accounted for in part by the array of different mechanisms used by the bacterium to circumvent components of the host immune system 5, 55, 56. Several such mechanisms being currently targeted by experimental antibody-based biologic agents are shown in Figure 1. These include: (i) surface-bound proteins that typically mediate adhesion to host tissues,

Clinical Utility of Antibody-Based Biologics Targeting Staphylococcus aureus: Potential Indications and Concerns

In the treatment of S. aureus infections, mAb-based biologics offer the promise to decrease unacceptably high levels of morbidity and mortality in severe, invasive disease states, such as pneumonia and bacteremia, as agents adjunctive to available antibiotics. Clinical benefit of such adjunctive therapy could arise directly through synergy at the mechanistic level and/or indirectly through effective boosting of antibiotic efficacy through enhanced assistance from host innate and adaptive immune

Concluding Remarks

The first successful therapeutic serum treatment of a child with a bacterial infection (diphtheria) caused by Corynebacterium diphtheriae, occurred in 1891 and, for this success and later accomplishments, Emil von Behring was recognized by the award of the first Nobel Prize for medicine in 1901. However, despite more than a century of research in understanding the pathophysiology of key human pathogens and developments in the synthesis and production of antibodies, approval of the first mAb

Glossary

Active immunity
immunity provided by antibodies that are generated in response to an antigen, such as a vaccine.
Bacteremia
bacteria in the bloodstream.
Opsonophagocytosis
phagocytosis of an opsonized pathogen.
Passive immunity
short-term immunity provided by exogenous antibodies.

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