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Antimicrobial Monoclonal Antibodies For Toxins Neutralization

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Toxins are antigens secreted by microbes to act on the host tissue and can stimulate specific antibodies called antitoxins. Antimicrobial monoclonal antibodies (mAbs) synthesized by the host against microbial cell surface targets and soluble exotoxins. Its mode of action depends on the nature of the target, its role in the pathogenesis, isotype and structure. Anti-exotoxin mAbs attenuate microbial pathological effect by different modes including exotoxin neutralization, antibody-dependent phagocytosis, complement-mediated bactericidal activity and immune system-independent microbial killing.

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Antimicrobial mAbs act by neutralization of exotoxins by binding to soluble exotoxins which leads to the formation of antibody-toxin complexes, which are mainly cleared by the reticuloendothelial system. All the clinically used antimicrobial mAbs act via toxin neutralization. Neutralizing efficacy of mAbs directly correlated with mAb binding affinity. Raxibacumab is the leading biologic product that has an anti-protective antigen [PA] mAb, uesd for the management of anthrax in combination with antimicrobial agents. It binds free PA and inhibits engagement of PA to its receptors on macrophages. The antibody inhibits the entry of anthrax edema and lethal factor in to the host cell, which contribute substantially to the pathogenic effects of anthrax toxin. Obiltoxaximab is also another anti-PA mAb that was approved to prevent against anthrax toxin through inhibition of PA binding to cellular receptors on host cells. It is a chimeric agent, with 50-fold increase in affinity and neutralizing ability [Rodgers and Chou, 2016]. Bezlotoxumab is a human IgG1 used to reduce recurrence of Clostridium difficile infection [CDI] who are receiving antimicrobial agents for CDI and are at high risk for CDI recurrence. It binds with high affinity to toxin B, a vital virulence factor and inhibits toxin B binding to host cell. Hence it prevents toxin B-mediated inactivation of Rho GTPases and downstream signaling cascades in cells. In addition to the above agents, currently there are many mAbs are in clinical trials. Among these six mAbs are developed against S.aureus two are targeting Pseudomunosa aeruginosa and two is for E. coli.

The antibody also helps the uptake of antibiotic into phagolysosomes, where this antibody–antibiotic conjugate activated only when it is released in the proteolytic situation of the phagolysosome, allowing effective activity against intracellular bacteria. This strategy showed promising bactericidal activity against vancomycin-resistant S. aureus. Antibody-antibiotic conjugates proposed to be favorable pharmacokinetics decreases toxicity.

mAbs also may facilitate the removal of bacteria from the body by stimulating the host immune system. Studies showed the benefit of anti- Programmed death [PD]-1 mAb for the management of tuberculosis infection. PD-1 and its ligands decreased in CD4+ and CD8+ T cells in TB patients after standard-of-care therapy. Management with anti-PD-1 mAb restored cytokine secretion and antigen responsiveness of T cells isolated from TB patients ex vivo.

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