Characterization of Alpha-Toxin
            <i>hla</i>
            Gene Variants, Alpha-Toxin Expression Levels, and Levels of Antibody to Alpha-Toxin in Hemodialysis and Postsurgical Patients with Staphylococcus aureus Bacteremia

Sharma-Kuinkel, Batu K.; Wu, Yuling; Tabor, David E.; Mok, Hoyin; Sellman, Bret R.; Jenkins, Amy; Yu, Li; Jafri, Hasan S.; Rude, Thomas H.; Ruffin, Felicia; Schell, Wiley A.; Park, Lawrence P.; Yan, Qin; Thaden, Joshua T.; Messina, Julia A.; Fowler, Vance G.; Esser, Mark T.

doi:10.1128/jcm.02023-14

Cited by 45 publications

(72 citation statements)

References 62 publications

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“…The serum levels of anti-alpha-toxin-neutralizing antibody were sustained through 30 days postinfusion (day 31) and were 3-, 15-, 91-, and 92-fold higher than the median preinfusion baseline levels in the 225-, 750-, 2,250-, and 5,000-mg dose cohorts, respectively. The serum levels of anti-alpha-toxin-neutralizing antibody in the 750-, 2,250-, and 5,000-mg dose cohorts at day 31 were >3.2 IU/ml, a concentration that has been found to be associated with favorable clinical outcomes in epidemiology studies (20, 24). These data confirm the ex vivo alpha-toxin-neutralizing activity of MEDI4893 and show that high levels can be maintained through 30 days after intravenous (i.v.)…”

Section: Resultsmentioning

confidence: 85%

“…This monoclonal antibody recognizes a highly conserved region of alpha-toxin that has been identified in >97% of S. aureus clinical isolates sequenced to date around the world (17, 20) and exerts its neutralizing activity through a dual mechanism: (i) it sterically blocks binding of alpha-toxin to the toxin's cellular receptor, and (ii) it prevents alpha-toxin from adopting the pore-forming heptameric transmembrane conformation that is required for host cell lysis (19). MEDI4893 was derived from a previously described anti-alpha-toxin monoclonal antibody, LC10, and possesses a triple-amino-acid substitution (M252Y/S254T/T256E [YTE]) in the antibody Fc region that confers an extended serum half-life by increasing the affinity of antibody binding to the neonatal Fc receptor involved in lysosomal recycling of IgG molecules (21).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Safety, Tolerability, and Pharmacokinetics of MEDI4893, an Investigational, Extended-Half-Life, Anti-Staphylococcus aureus Alpha-Toxin Human Monoclonal Antibody, in Healthy Adults

Yu¹,

Robbie²,

Wu³

et al. 2017

Antimicrob Agents Chemother

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115

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MEDI4893 is an investigational immunoglobulin G1(κ) monoclonal antibody that specifically binds to and neutralizes alpha-toxin, a key Staphylococcus aureus virulence factor. A triple-amino-acid substitution, M252Y/S254T/T256E, was engineered into the MEDI4893 Fc region to extend its serum half-life. A phase 1, double-blind, dose escalation study was designed to evaluate the safety, tolerability, pharmacokinetics, anti-alpha-toxin-neutralizing activity, and antidrug antibody (ADA) response of MEDI4893 following a single intravenous infusion in healthy adults 18 to 65 years of age. Thirty-three subjects were randomly assigned to receive MEDI4893 at 225 mg (n = 3), 750 mg (n = 3), 2,250 mg (n = 8), or 5,000 mg (n = 12) or placebo (n = 7) and were followed for 360 days. Adverse events were mild or moderate in severity; none were serious. The MEDI4893 peak serum concentration increased dose proportionally from 77.2 μg/ml (225-mg dose) to 1,784 μg/ml (5,000-mg dose). The area under the concentration-time curve from 0 to 360 days also increased dose proportionally, from 4,840 μg · day/ml (225-mg dose) to 91,493 μg · day/ml (5,000-mg dose), indicating linear pharmacokinetics. MEDI4893's terminal half-life was estimated to be 80 to 112 days, which is approximately 4-fold longer than the half-lives of other human immunoglobulin G antibodies. The alpha-toxin-neutralizing activity in serum correlated highly with the MEDI4893 concentrations in serum. Three adults transiently tested positive for ADA on day 151, but this did not have an impact on MEDI4893 serum concentrations or the MEDI4893 safety profile; no subjects exhibited serum ADA at the study end. These data support the continued development of MEDI4893 for the prevention of S. aureus-mediated pneumonia. (This study has been registered at ClinicalTrials.gov under identifier NCT02296320.)

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Section: Resultsmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Safety, Tolerability, and Pharmacokinetics of MEDI4893, an Investigational, Extended-Half-Life, Anti-Staphylococcus aureus Alpha-Toxin Human Monoclonal Antibody, in Healthy Adults

Yu¹,

Robbie²,

Wu³

et al. 2017

Antimicrob Agents Chemother

Self Cite

115

View full text Add to dashboard Cite

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“…Although the antibody responses to staphylococcal antigens in infected individuals are generally greater than in non-infected individuals [49, 50], humoral immune responses between individuals with the same S. aureus disease can vary [51]. However, there is evidence that greater levels of anti-staphylococcal antibodies contribute to more favorable clinical outcomes [49, 52-55], which may be attributed to the potent toxin-neutralizing activities of the antibodies. These findings have galvanized efforts to explore the use of polyclonal and monoclonal antibodies (mAbs) as therapeutics to neutralize the cell-damaging properties of staphylococcal toxins and enhance recognition of S. aureus by interfering with its ability to evade the immune system (Tab.…”

Section: Alternatives To Conventional Antibioticsmentioning

confidence: 99%

Investigational drugs to treat methicillin-resistantStaphylococcus aureus

Vuong

Yeh

Cheung

et al. 2015

Expert Opinion on Investigational Drugs

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Introduction Staphylococcus aureus remains one of the leading causes of morbidity and mortality worldwide. This is to a large extent due to antibiotic-resistant strains, in particular methicillin-resistant S. aureus (MRSA). While the toll of invasive MRSA infections appears to decrease in U.S. hospitals, the rate of community-associated MRSA infections remains constant and there is a surge of MRSA in many other countries. This situation calls for continuing if not increased efforts to find novel strategies to combat MRSA infections. Areas covered This review will provide an overview of current investigational antibiotics in clinical development (up to phase II), and of therapeutic antibodies and alternative drugs against S. aureus in preclinical and clinical development, including a short description of the mechanism of action and a presentation of microbiological and clinical data. Expert opinion Increased recent antibiotic development efforts and results from pathogenesis research have led to several new antibiotics and alternative drugs, as well as a more informed selection of targets for vaccination efforts against MRSA. This developing portfolio of novel anti-staphylococcal drugs will hopefully provide us with additional and more efficient ways to combat MRSA infections in the near future and prevent us from running out of treatment options, even if new resistances arise.

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“…It is a major exoproduct of Staphylococcus aureus, secreted by most strains of this important pathogen [4] and is considered to play a central role in the pathogenesis of staphylococcal pneumonia and several other conditions [1,2]. Therefore, α-toxin is being discussed as a potential target for treatment or vaccination [5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Dissecting the role of ADAM10 as a mediator of Staphylococcus aureus α-toxin action

Hoven

Rivas

Neukirch

et al. 2016

Biochemical Journal

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Staphylococcus aureus is a leading cause of bacterial infections in humans, including life-threatening diseases such as pneumonia and sepsis. Its small membrane-pore-forming α-toxin is considered an important virulence factor. By destroying cell-cell contacts through cleavage of cadherins, the metalloproteinase ADAM10 (a disintegrin and metalloproteinase 10) critically contributes to α-toxin-dependent pathology of experimental S. aureus infections in mice. Moreover, ADAM10 was proposed to be a receptor for α-toxin. However, it is unclear whether the catalytic activity or specific domains of ADAM10 are involved in mediating binding and/or subsequent cytotoxicity of α-toxin. Also, it is not known how α-toxin triggers ADAM10's enzymatic activity, and whether ADAM10 is invariably required for all α-toxin action on cells. In the present study, we show that efficient cleavage of the ADAM10 substrate epithelial cadherin (E-cadherin) requires supra-cytotoxic concentrations of α-toxin, leading to significant increases in intracellular [Ca(2+)]; the fall in cellular ATP levels, typically following membrane perforation, became observable at far lower concentrations. Surprisingly, ADAM10 was dispensable for α-toxin-dependent xenophagic targeting of S. aureus, whereas a role for α-toxin attack on the plasma membrane was confirmed. The catalytic site of ADAM10, furin cleavage site, cysteine switch and intracellular domain of ADAM10 were not required for α-toxin binding and subsequent cytotoxicity. In contrast, an essential role for the disintegrin domain and the prodomain emerged. Thus, co-expression of the prodomain with prodomain-deficient ADAM10 reconstituted binding of α-toxin and susceptibility of ADAM10-deficient cells. The results of the present study may help to inform structural analyses of α-toxin-ADAM10 interactions and to design novel strategies to counteract S. aureus α-toxin action.

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Characterization of Alpha-Toxin hla Gene Variants, Alpha-Toxin Expression Levels, and Levels of Antibody to Alpha-Toxin in Hemodialysis and Postsurgical Patients with Staphylococcus aureus Bacteremia

Cited by 45 publications

References 62 publications

Safety, Tolerability, and Pharmacokinetics of MEDI4893, an Investigational, Extended-Half-Life, Anti-Staphylococcus aureus Alpha-Toxin Human Monoclonal Antibody, in Healthy Adults

Safety, Tolerability, and Pharmacokinetics of MEDI4893, an Investigational, Extended-Half-Life, Anti-Staphylococcus aureus Alpha-Toxin Human Monoclonal Antibody, in Healthy Adults

Investigational drugs to treat methicillin-resistantStaphylococcus aureus

Dissecting the role of ADAM10 as a mediator of Staphylococcus aureus α-toxin action

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