Pharmacokinetic and Pharmacodynamic Considerations for the Use of Monoclonal Antibodies in the Treatment of Bacterial Infections
Abstract
:1. Introduction
2. Pharmacokinetic Considerations
2.1. Target Mediated Drug Disposition
2.2. Distribution of mAbs in Infected Tissues
3. Pharmacodynamic Mechanisms of Action
3.1. Toxin Neutralization
3.2. Opsonophagocytosis
3.3. Complement-Dependent Cytotoxicity
3.4. Direct Bactericidal mAbs
3.5. Immunoconjugates
3.6. Immunomodulatory mAbs
4. Challenges in the Development of mAbs for the Treatment of Bacterial Infections
4.1. Difficulties in Selection of Bacterial Targets
4.2. Antibody-Dependent Enhancement of Infection
4.3. Countermeasures against Antibacterial mAbs
5. Currently Marketed mAbs for the Treatment of Bacterial Infections
5.1. Raxibacumab
5.2. Obiltoxaximab
5.3. Bezlotoxumab
6. Antibacterial mAbs in Clinical Trials
6.1. MEDI4893
6.2. ASN100
6.3. DSTA4637S
6.4. Salvecin
6.5. 514.G3
6.6. MEDI3902
6.7. Aerumab
6.8. Aerucin
6.9. Shigamab
7. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Antibody | Company | Format | Pathogen/Target | First Approved Indication | Reported Mechanism of Action | Approval Year |
---|---|---|---|---|---|---|
Raxibacumab | GlaxoSmith Kline | Human IgG1(λ) | Bacillus anthracis/Protective antigen | Treatment and prophylaxis of inhalational anthrax | Toxin neutralization | 2012 |
Obiltoxaximab | Elusys | Chimeric IgG1(κ) | Bacillus anthracis/Protective antigen | Treatment and prophylaxis of inhalational anthrax | Toxin neutralization | 2016 |
Bezlotoxumab | Merck & Co. | Human IgG1 | Clostridium difficile/Enterotoxin B | Prevention of Clostridium difficile infection recurrence | Toxin neutralization | 2016 |
Antibody | Sponsor | Format | Pathogen | Target | Reported Mechanism of Action | Current Status |
---|---|---|---|---|---|---|
MEDI4893 | MedImmune | Human IgG1(κ) | Staphylococcus aureus | Alpha toxin | Toxin neutralization | Phase 2 |
ASN100 | Arsanis | Human IgG1(κ) | Staphylococcus aureus | Alpha toxin and five leukocidins | Toxin neutralization | Phase 2 |
DSTA4637S | Genentech | Human IgG1 | Staphylococcus aureus | β-O-linked N-acetylglucosamine on wall teichoic acids | Antibody-antibiotic conjugate | Phase 1 |
Salvecin (AR-301) | Aridis | Human IgG1 | Staphylococcus aureus | Alpha toxin | Toxin neutralization | Phase 1/2a |
514G3 | XBiotech | Human IgG3 | Staphylococcus aureus | Protein A | Opsonophagocytosis | Phase 1/2 |
MEDI3902 | MedImmune | Human bispecific IgG1 | Pseudomonas aeruginosa | PsI and PcrV | Opsonophagocytosis; inhibition of cell attachment and cytotoxicity | Phase 2 |
Aerumab (AR-101) | Aridis | Human IgM(κ) | Pseudomonas aeruginosa | O-antigen (serotype O11) | Opsonophagocytosis; complement-mediated bacterial killing | Phase 2b |
Aerucin | Aridis | Human IgG1 | Pseudomonas aeruginosa | Alginate (surface polysaccharide) | Opsonophagocytosis; complement-mediated bacterial killing | Phase 2 |
Shigamab | Bellus Health | Chimeric IgG1(κ) | Escherichia coli | Shiga toxin 1 and 2 | Toxin neutralization | Phase 2 |
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Wang-Lin, S.X.; Balthasar, J.P. Pharmacokinetic and Pharmacodynamic Considerations for the Use of Monoclonal Antibodies in the Treatment of Bacterial Infections. Antibodies 2018, 7, 5. https://doi.org/10.3390/antib7010005
Wang-Lin SX, Balthasar JP. Pharmacokinetic and Pharmacodynamic Considerations for the Use of Monoclonal Antibodies in the Treatment of Bacterial Infections. Antibodies. 2018; 7(1):5. https://doi.org/10.3390/antib7010005
Chicago/Turabian StyleWang-Lin, Shun Xin, and Joseph P. Balthasar. 2018. "Pharmacokinetic and Pharmacodynamic Considerations for the Use of Monoclonal Antibodies in the Treatment of Bacterial Infections" Antibodies 7, no. 1: 5. https://doi.org/10.3390/antib7010005