Toxins are protein, secreted by the viable bacterial to act on the host cells. Understanding the interaction of toxins with the host tissue has been a vital tool to prepare inhibition strategies. Toxins are antigens that elicit specific antibodies called antitoxins. Antibacterial mAbs have been produced against bacterial cell surface targets (i.e., polysaccharides and proteins) and soluble exotoxins. The mode of antibacterial mAbs depends on the nature of the target, its role in the pathogenesis, isotype and structure (i.e., IgG fragments, immunoconjugates, etc.). Anti-exotoxin mAbs attenuate bacterial pathological activity by different mode including neutralization of exotoxin, antibody-dependent phagocytosis, complement-mediated bactericidal activity and immune system-independent bacterial killing.
Antibacterial mAbs act by neutralization of exotoxins. mAb bind soluble exotoxins which leads to the formation of antibody-toxin complexes, which are primarily cleared by the reticuloendothelial system. All the currently marketed antibacterial mAbs act via toxin neutralization. The efficacy of neutralizing mAbs directly correlated with mAb binding affinity. Immunoconjugates
The antibody mediates uptake into phagolysosomes, where a potent antibiotic payload is released, allowing efficient killing of intracellular bacteria. This strategy showed promising bactericidal activity against vancomycin-resistant S. aureus. Antibody-antibiotic conjugates considered to be favorable pharmacokinetics (i.e., long half-lives) and decreases toxicity. For example, the Antibody-antibiotic conjugates may decrease antibiotic caused disruption of normal flora, and may decrease selective pressure that enhances the appearance of cross resistance, due to the specificity provided by the antibody carrier.
The advantages provided by antibody conjugation may allow for antimicrobials agent that failed in clinical trials due to unfavorable pharmacokinetics or toxicities. Radioimmunoconjuates, which conjugate radionuclides to mAbs, may allow targeted delivery of bactericidal radiation to microorganism. Example Bismuth-213 linked to mAb (D11) targeting the pneumococcal capsular polysaccharide which showed dose-dependent bacterial killing in vitro. There is a clinical trial in phase 1 (DSTA-4637S) ,the IgG monoclonal antibody bound to a rifamycin analogue and this Antibody binds to surface proteins of S. aureus and releases the drug to kill intracellular S. aureus.
Immunomodulatory mAbs may facilitate the clearance 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. Treatment with anti-PD-1 mAb restored cytokine secretion and antigen responsiveness of T cells isolated from TB patients ex vivo.
Currently Marketed antibacterial mAbs agent
Raxibacumab is the first biologic product that has an anti-protective antigen (PA) mAb, approved for the management of anthrax in combination with antimicrobial agents. It binds free PA and inhibits engagement of PA to its cellular receptors on macrophages. The antibody impedes intracellular entry of anthrax lethal factor and edema factor, which contribute substantially to the pathogenic effects of anthrax toxin.
Obiltoxaximab is also annother anti-PA mAb that was approved to protect against anthrax toxin through inhibition of PA binding to cellular receptors on host cells. It is a chimeric agent, consisting of enhanced 14B7VH and VL genes connected to human ν1 and K constants, which was derived from the murine monoclonal antibody 14B7, with mutations resulting in a 50-fold increase in affinity and corresponding neutralizing capability.
Bezlotoxumab is a human IgG1 was approved to reduce recurrence of Clostridium difficile infection (CDI) who are receiving antibacterial drugs 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 pathways in cells. Thus bezlotoxumab is indicated only for prevention of recurrence of CDI, but not for treatment. In addition to the above mAb products, there are many mAbs are currently in clinical trials. Among these six mAbs are developed against S.aureus (514G3, MEDI4893, Salvecin (AR-301), DSTA-46375, Suvratoxumab, ASN-100) two are targeting Pseudomunosa aeruginosa (MEDI-3902A , Aerubumab) and two is for E. coli(PolyCab, MM-529 .