Targeting Alpha Toxin To Mitigate Its Lethal Toxicity in Ferret and Rabbit Models of Staphylococcus aureus Necrotizing Pneumonia

Diep, Binh An; Hilliard, Jamese J.; Le, Vien T. M.; Tkaczyk, Christine; Le, Hoan N.; Tran, Vuvi G.; Rao, Renee; Dip, Etyene Castro; Pereira-Franchi, Eliane Patrícia Lino; Cha, Paulyn; Jacobson, Scott; Broome, Rosemary L.; Cheng, Lily; Weiss, Jason; Prókai, László; Nguyen, Vien; Stover, Charles K; Sellman, Bret R.

doi:10.1128/aac.02456-16

Cited by 39 publications

(31 citation statements)

References 41 publications

(45 reference statements)

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“…Although alpha-toxin is a key virulence determinant in S. aureus pneumonia and skin and soft-tissue infections (20,26), bloodstream infections are likely more complex, with a more complicated interplay of virulence determinants involved (27)(28)(29)(30)(31). Consistent with this hypothesis, prophylaxis with an anti-alpha-toxin IgG alone significantly reduced disease severity in S. aureus pneumonia and skin infection models in mice and rabbits (6,8,20,21,26,(32)(33)(34) but did not protect against challenge by all isolates tested in a lethal bacteremia model (Table 2) (9). However, passive immunization with MEDI4893* combined with anti-ClfA MAb 11H10 or SAR114 provided improved strain coverage, indicating that targeting multiple virulence factors may be necessary to protect against systemic S. aureus diseases such as bacteremia ( Table 2; Fig.…”

Section: Discussionmentioning

confidence: 81%

Multimechanistic Monoclonal Antibodies (MAbs) Targeting Staphylococcus aureus Alpha-Toxin and Clumping Factor A: Activity and Efficacy Comparisons of a MAb Combination and an Engineered Bispecific Antibody Approach

Tkaczyk¹,

Kasturirangan²,

Minola

et al. 2017

Antimicrob Agents Chemother

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Secreted alpha-toxin and surface-localized clumping factor A (ClfA) are key virulence determinants in Staphylococcus aureus bloodstream infections. We previously demonstrated that prophylaxis with a multimechanistic monoclonal antibody (MAb) combination against alpha-toxin (MEDI4893*) and ClfA (11H10) provided greater strain coverage and improved efficacy in an S. aureus lethal bacteremia model. Subsequently, 11H10 was found to exhibit reduced affinity and impaired inhibition of fibrinogen binding to ClfA002 expressed by members of a predominant hospital-associated methicillin-resistant S. aureus (MRSA) clone, ST5. Consequently, we identified another anti-ClfA MAb (SAR114) from human tonsillar B cells with >100-fold increased affinity for three prominent ClfA variants, including ClfA002, and potent inhibition of bacterial agglutination by 112 diverse clinical isolates. We next constructed bispecific Abs (BiSAbs) comprised of 11H10 or SAR114 as IgG scaffolds and grafted anti-alpha-toxin (MEDI4893*) single-chain variable fragment to the amino or carboxy terminus of the anti-ClfA heavy chains. Although the BiSAbs exhibited in vitro potencies similar to those of the parental MAbs, only 11H10-BiSAb, but not SAR114-BiSAb, showed protective activity in murine infection models comparable to the respective MAb combination. In vivo activity with SAR114-BiSAb was observed in infection models with S. aureus lacking ClfA. Our data suggest that high-affinity binding to ClfA sequesters the SAR114-BiSAb to the bacterial surface, thereby reducing both alpha-toxin neutralization and protection in vivo. These results indicate that a MAb combination targeting ClfA and alpha-toxin is more promising for future development than the corresponding BiSAb.

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Section: Discussionmentioning

confidence: 81%

Multimechanistic Monoclonal Antibodies (MAbs) Targeting Staphylococcus aureus Alpha-Toxin and Clumping Factor A: Activity and Efficacy Comparisons of a MAb Combination and an Engineered Bispecific Antibody Approach

Tkaczyk¹,

Kasturirangan²,

Minola

et al. 2017

Antimicrob Agents Chemother

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“…Of the Hu-mAbs being clinically evaluated, the products from AstraZeneca PLC (formerly MedImmune) have been extensively evaluated in a number of preclinical models. MEDI4893 was developed for S. aureus and has been shown to be protective in multiple models of pneumonia including ferret, rabbit and mouse [50,51]. The antibody targets the secreted alpha-toxin and prevents the bacterium's ability to cause apoptosis in cells, which, in turn, prevents lysis and tissue necrosis caused by S. aureus infection.…”

Section: Previous Failures Lead To Current Successmentioning

confidence: 99%

Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens

2020

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In the beginning of the 21st century, the frequency of antimicrobial resistance (AMR) has reached an apex, where even 4th and 5th generation antibiotics are becoming useless in clinical settings. In turn, patients are suffering from once-curable infections, with increases in morbidity and mortality. The root cause of many of these infections are the ESKAPEE pathogens (Enterococcus species, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli), which thrive in the nosocomial environment and are the bacterial species that have seen the largest rise in the acquisition of antibiotic resistance genes. While traditional small-molecule development still dominates the antibacterial landscape for solutions to AMR, some researchers are now turning to biological approaches as potential game changers. Monoclonal antibodies (mAbs)—more specifically, human monoclonal antibodies (Hu-mAbs)—have been highly pursued in the anti-cancer, autoimmune, and antiviral fields with many success stories, but antibody development for bacterial infection is still just scratching the surface. The untapped potential for Hu-mAbs to be used as a prophylactic or therapeutic treatment for bacterial infection is exciting, as these biologics do not have the same toxicity hurdles of small molecules, could have less resistance as they often target virulence proteins rather than proteins required for survival, and are narrow spectrum (targeting just one pathogenic species), therefore avoiding the disruption of the microbiome. This mini-review will highlight the current antibacterial mAbs approved for patient use, the success stories for mAb development, and new Hu-mAb products in the antibacterial pipeline.

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“…S. aureus ␣-toxin has been shown to inhibit not only membrane binding through receptor blockade but also the heptameric oligomer association needed for pore formation, providing a dual mechanism and potent neutralizing activity (53,54).…”

Section: Tcdb Neutralization By Pa41mentioning

confidence: 99%

A neutralizing antibody that blocks delivery of the enzymatic cargo of Clostridium difficile toxin TcdB into host cells

Kroh

Chandrasekaran

Zhang

et al. 2018

Journal of Biological Chemistry

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infection is the leading cause of hospital-acquired diarrhea and is mediated by the actions of two toxins, TcdA and TcdB. The toxins perturb host cell function through a multistep process of receptor binding, endocytosis, low pH-induced pore formation, and the translocation and delivery of an N-terminal glucosyltransferase domain that inactivates host GTPases. Infection studies with isogenic strains having defined toxin deletions have established TcdB as an important target for therapeutic development. Monoclonal antibodies that neutralize TcdB function have been shown to protect against infection in animal models and reduce recurrence in humans. Here, we report the mechanism of TcdB neutralization by PA41, a humanized monoclonal antibody capable of neutralizing TcdB from a diverse array of strains. Through a combination of structural, biochemical, and cell functional studies, involving X-ray crystallography and EM, we show that PA41 recognizes a single, highly conserved epitope on the TcdB glucosyltransferase domain and blocks productive translocation and delivery of the enzymatic cargo into the host cell. Our study reveals a unique mechanism of toxin neutralization by a monoclonal antibody, which involves targeting a process that is conserved across the large clostridial glucosylating toxins. The PA41 antibody described here provides a valuable tool for dissecting the mechanism of toxin pore formation and translocation across the endosomal membrane.

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Targeting Alpha Toxin To Mitigate Its Lethal Toxicity in Ferret and Rabbit Models of Staphylococcus aureus Necrotizing Pneumonia

Cited by 39 publications

References 41 publications

Multimechanistic Monoclonal Antibodies (MAbs) Targeting Staphylococcus aureus Alpha-Toxin and Clumping Factor A: Activity and Efficacy Comparisons of a MAb Combination and an Engineered Bispecific Antibody Approach

Multimechanistic Monoclonal Antibodies (MAbs) Targeting Staphylococcus aureus Alpha-Toxin and Clumping Factor A: Activity and Efficacy Comparisons of a MAb Combination and an Engineered Bispecific Antibody Approach

Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens

A neutralizing antibody that blocks delivery of the enzymatic cargo of Clostridium difficile toxin TcdB into host cells

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