Safety, tolerability, and pharmacokinetics of MEDI4893, an investigational, extended-half-life, anti-staphylococcus aureus alpha-toxin human monoclonal antibody, in healthy adults

Antimicrobial Agents and Chemotherapy

Volumn 61, Issue 1, 2017, Pages

  Yu, Xiang Qing ^a   Robbie, Gabriel J ^a   Wu, Yuling ^a   Esser, Mark T ^a   Jensen, Kathryn ^a   Schwartz, Howard I ^b   Bellamy, Terramika ^a   Hernandez Illas, Martha ^b   Jafri, Hasan S ^a  

^a MEDIMMUNE   (United States)

^b MIAMI RESEARCH ASSOCIATES   (United States)

Author keywords

Alpha Toxin; Anti infective monoclonal antibodies; Antimicrobial safety; Clinical pharmacokinetics; Efficacy; MEDI4893; Nosocomial pneumonia

Indexed keywords

HUMAN MONOCLONAL ANTIBODY; IMMUNOGLOBULIN G ANTIBODY; PLACEBO; STAPHYLOCOCCUS ALPHA TOXIN; SUVRATOXUMAB; MONOCLONAL ANTIBODY; NEUTRALIZING ANTIBODY;

ADULT; ADVERSE OUTCOME; AGED; ANAPHYLAXIS; ANTIBODY RESPONSE; AREA UNDER THE CURVE; ARTICLE; CLINICAL EVALUATION; CONTROLLED STUDY; DISEASE SEVERITY; DOUBLE BLIND PROCEDURE; DRUG BLOOD LEVEL; DRUG DOSE ESCALATION; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; EC90; EX VIVO STUDY; FEMALE; FOLLOW UP; GASTROESOPHAGEAL REFLUX; HEADACHE; HUMAN; HUMAN EXPERIMENT; HYPERSENSITIVITY; INJECTION SITE EXTRAVASATION; MALE; NORMAL HUMAN; PHASE 1 CLINICAL TRIAL; PLASMA CONCENTRATION-TIME CURVE; PNEUMONIA; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RASH; SINGLE DRUG DOSE; STAPHYLOCOCCUS AUREUS; UPPER RESPIRATORY TRACT INFECTION; URTICARIA; VOMITING; ADOLESCENT; BLOOD; CLINICAL TRIAL; DRUG EFFECTS; HALF LIFE TIME; MIDDLE AGED; STAPHYLOCOCCAL INFECTIONS; YOUNG ADULT;

ADOLESCENT; ADULT; AGED; ANTIBODIES, MONOCLONAL; ANTIBODIES, NEUTRALIZING; DOUBLE-BLIND METHOD; FEMALE; HALF-LIFE; HUMANS; MALE; MIDDLE AGED; STAPHYLOCOCCAL INFECTIONS; STAPHYLOCOCCUS AUREUS; YOUNG ADULT;

EID: 85009240311     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.01020-16     Document Type: Article

References (31)

1. Lowy FD. 1998. Staphylococcus aureus infections. N Engl J Med 339:1-9. https://doi.org/10.1056/NEJM199808203390806.
2. Jones RN. 2010. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Clin Infect Dis 51(Suppl 1):S81-S87. https://doi.org/10.1086/653053.
3. Kyaw MH, Kern DM, Zhou S, Tunceli O, Jafri HS, Falloon J. 2015. Healthcare utilization and costs associated with S. aureus and P. aeruginosa pneumonia in the intensive care unit: a retrospective observational cohort study in a US claims database. BMC Health Serv Res 15:241. https://doi.org/10.1186/s12913-015-0917-x.
4. File TM, Jr. 2010. Recommendations for treatment of hospital-acquired and ventilator-associated pneumonia: review of recent international guidelines. Clin Infect Dis 51(Suppl 1):S42-S47. https://doi.org/10.1086/653048.
5. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM, Jr, Musher DM, Niederman MS, Torres A, Whitney CG. 2007. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44(Suppl 2):S27-S72. https://doi.org/10.1086/511159.
6. Hampton T. 2013. Report reveals scope of US antibiotic resistance threat. JAMA 310:1661-1663. https://doi.org/10.1001/jama.2013.280695.
7. Di Giandomenico A, Sellman BR. 2015. Antibacterial monoclonal antibodies: the next generation? Curr Opin Microbiol 27:78-85. https://doi.org/10.1016/j.mib.2015.07.014.
8. Hua L, Hilliard JJ, Shi Y, Tkaczyk C, Cheng LI, Yu X, Datta V, Ren S, Feng H, Zinsou R, Keller A, O'Day T, Du Q, Cheng L, Damschroder M, Robbie G, Suzich J, Stover CK, Sellman BR. 2014. Assessment of an anti-alphatoxin monoclonal antibody for prevention and treatment of Staphylococcus aureus-induced pneumonia. Antimicrob Agents Chemother 58: 1108-1117. https://doi.org/10.1128/AAC.02190-13.
9. Lorenz U, Lorenz B, Schmitter T, Streker K, Erck C, Wehland J, Nickel J, Zimmermann B, Ohlsen K. 2011. Functional antibodies targeting Isa A of Staphylococcus aureus augment host immune response and open new perspectives for antibacterial therapy. Antimicrob Agents Chemother 55:165-173. https://doi.org/10.1128/AAC.01144-10.
10. Oleksiewicz MB, Nagy G, Nagy E. 2012. Anti-bacterial monoclonal antibodies: back to the future? Arch Biochem Biophys 526:124-131. https://doi.org/10.1016Zj.abb.2012.06.001.
11. Ragle BE, Bubeck Wardenburg J. 2009. Anti-alpha-hemolysin monoclonal antibodies mediate protection against Staphylococcus aureus pneumonia. Infect Immun 77:2712-2718. https://doi.org/10.1128/IAI.00115-09.
12. Tkaczyk C, Hua L, Varkey R, Shi Y, Dettinger L, Woods R, Barnes A, Mac Gill RS, Wilson S, Chowdhury P, Stover CK, Sellman BR. 2012. Identification of anti-alpha toxin monoclonal antibodies that reduce the severity of Staphylococcus aureus dermonecrosis and exhibit a correlation between affinity and potency. Clin Vaccine Immunol 19:377-385. https://doi.org/10.1128/CVI.05589-11.
13. Berube BJ, Bubeck Wardenburg J. 2013. Staphylococcus aureus alpha-toxin: nearly a century of intrigue. Toxins (Basel) 5:1140-1166. https://doi.org/10.3390/toxins5061140.
14. Prince LR, Graham KJ, Connolly J, Anwar S, Ridley R, Sabroe I, Foster SJ, Whyte MK. 2012. Staphylococcus aureus induces eosinophil cell death mediated by alpha-hemolysin. PLoS One 7:e31506. https://doi.org/10.1371/journal.pone.0031506.
15. Menzies BE, Kourteva I. 2000. Staphylococcus aureus alpha-toxin induces apoptosis in endothelial cells. FEMS Immunol Med Microbiol 29:39-45. https://doi.org/10.1111/j.1574-695X.2000.tb01503.x.
16. Nygaard TK, Pallister KB, Du Mont AL, De Wald M, Watkins RL, Pallister EQ, Malone C, Griffith S, Horswill AR, Torres VJ, Voyich JM. 2012. Alpha-toxin induces programmed cell death of human T cells, B cells, and monocytes during USA300 infection. PLoS One 7:e36532. https://doi.org/10.1371/journal.pone.0036532.
17. Tabor DE, Yu L, Mok H, Tkaczyk C, Sellman BR, Wu Y, Oganesyan V, Slidel T, Jafri H, Mc Carthy M, Bradford P, Esser MT. 2016. Staphylococcus aureus alpha-toxin is conserved amongst diverse hospital respiratory isolates collected from a global surveillance study and is neutralized by monoclonal antibody MEDI4893. Antimicrob Agents Chemother 60: 5312-5321. https://doi.org/10.1128/AAC.00357-16/AAC.00357-16.
18. De Leo FR, Kennedy AD, Chen L, Bubeck Wardenburg J, Kobayashi SD, Mathema B, Braughton KR, Whitney AR, Villaruz AE, Martens CA, Porcella SF, Mc Gavin MJ, Otto M, Musser JM, Kreiswirth BN. 2011. Molecular differentiation of historic phage-type 80/81 and contemporary epidemic Staphylococcus aureus. Proc Natl Acad Sci USA 108:18091-18096. https://doi.org/10.1073/pnas.1111084108.
19. Oganesyan V, Peng L, Damschroder MM, Cheng L, Sadowska A, Tkaczyk C, Sellman BR, Wu H, Dall'Acqua WF. 2014. Mechanisms of neutralization of a human anti-alpha-toxin antibody. J Biol Chem 289:29874-29880. https://doi.org/10.1074/jbc.M114.601328.
20. Sharma-Kuinkel BK, Wu Y, Tabor DE, Mok H, Sellman BR, Jenkins A, Yu L, Jafri HS, Rude TH, Ruffin F, Schell WA, Park LP, Yan Q, Thaden JT, Messina JA, Fowler VG, Jr, Esser MT. 2015. 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. J Clin Microbiol 53:227-236. https://doi.org/10.1128/JCM.02023-14.
21. Dall'Acqua WF, Kiener PA, Wu H. 2006. Properties of human Ig G1s engineered for enhanced binding to the neonatal Fc receptor (Fc Rn). J Biol Chem 281:23514-23524. https://doi.org/10.1074/jbc.M604292200.
22. U.S. Department of Health and Human Services, Food and Drug Admin-istration, Center for Drug Evaluation and Research. 2005. Guidance for industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Rockville, MD. http://www.fda.gov/downloads/Drugs/Guidance Compliance Regulatory Information/Guidances/ucm078932.pdf.
23. Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S. 2011. Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: what have we learned? MAbs 3:61-66. https://doi.org/10.4161/mabs.3.1.13799.
24. Ruotsalainen E, Karden-Lilja M, Kuusela P, Vuopio-Varkila J, Virolainen-Julkunen A, Sarna S, Valtonen V, Jarvinen A. 2008. Methicillin-sensitive Staphylococcus aureus bacteraemia and endocarditis among injection drug users and nonaddicts: host factors, mi-crobiological and serological characteristics. J Infect 56:249-256. https://doi.org/10.1016/j.jinf.2008.01.009.
25. Deng R, Jin F, Prabhu S, Iyer S. 2012. Monoclonal antibodies: what are the pharmacokinetic and pharmacodynamic considerations for drug development? Expert Opin Drug Metab Toxicol 8:141-160. https://doi.org/10.1517/17425255.2012.643868.
26. Hinton PR, Johlfs MG, Xiong JM, Hanestad K, Ong KC, Bullock C, Keller S, Tang MT, Tso JY, Vasquez M, Tsurushita N. 2004. Engineered human Ig G antibodies with longer serum half-lives in primates. J Biol Chem 279: 6213-6216.
27. Hinton PR, Xiong JM, Johlfs MG, Tang MT, Keller S, Tsurushita N. 2006. An engineered human Ig G1 antibody with longer serum half-life. J Immunol 176:346-356. https://doi.org/10.4049/jimmunol.176.1346.
28. Yeung YA, Leabman MK, Marvin JS, Qiu J, Adams CW, Lien S, Starovasnik MA, Lowman HB. 2009. Engineering human Ig G1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates. J Immunol 182:7663-7671. https://doi.org/10.4049/jimmunol.0804182.
29. Robbie GJ, Criste R, Dall'acqua WF, Jensen K, Patel NK, Losonsky GA, Griffin MP. 2013. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob Agents Chemother 57:6147-6153. https://doi.org/10.1128/AAC.01285-13.
30. Yu X, Iciek L, Criste R, Sellman B, Strover C, Jafri H, Esser M, Roskos L, Robbie G. 2013. Modeling of pharmacokinetics (PK) of a YTE-monoclonal antibody targeting Staphylococcus aureus alpha toxin in cynomolgus monkeys: human PK prediction, abstr T2123. Abstr Am Assoc Pharm Sci Natl Biotechnol Conf, San Diego, CA.
31. National Institute for Biological Standards and Control. 2010. The 3rd international standard for Staphylococcus alpha antitoxin, equine. World Health Organization International Laboratory for Biological Standards, Potters Bar, Hertfordshire, United Kingdom. https://www.nibsc.org/documents/ifu/STA.pdf.