Trends in Pharmacological Sciences
ReviewAntibody-Based Biologics and Their Promise to Combat Staphylococcus aureus 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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Tackling multidrug-resistant Staphylococcus aureus by natural products and their analogues acting as NorA efflux pump inhibitors
2023, Bioorganic and Medicinal ChemistryEngineering the supernatural: monoclonal antibodies for challenging infectious diseases
2022, Current Opinion in BiotechnologyCitation Excerpt :As a result, improved opsonophagocytic activity and reduced bacterial burden in a mouse model of sepsis have been observed [15]. However, the protection seen from highly opsonophagocytic mAbs in animal models is often not recapitulated in humans [16–18], suggesting that microbial uptake alone is insufficient to improve infection outcomes. Indeed, studies with Legionella show that bacteria can persist inside a host cell, and only in the presence of FcR signaling is bacteria directed into lysosomal compartments for degradation [19].
Host-acting antibacterial compounds combat cytosolic bacteria
2022, Trends in MicrobiologyCitation Excerpt :Moreover, several HACs obstruct bacterial internalization by blocking PAMPs. For instance, a monoclonal antibody (mAb AR-301) neutralizes the α-toxin of Staphylococcus aureus [42], ADAM10-bearing exosomes cause α-toxin oligomerization [43], and peptides that mimic mannose receptor C type 1 (MRC-1) act on pneumolysin, listeriolysin O, and streptolysin O of Streptococcus pneumoniae [44] to inhibit bacterial internalization (Table 1). Altogether, blocking the adhesion or internalization of pathogens is an energetically efficient strategy to develop new HACs and abolish bacterial infections.
Quantum leap of monoclonal antibody (mAb) discovery and development in the COVID-19 era
2020, Seminars in Immunology