Serum and Lung Pharmacokinetics of ASN100, a Monoclonal Antibody Combination for the Prevention and Treatment of Staphylococcus aureus Pneumonia. (4th October 2017)

• Record Type: Journal Article
• Authors: Magyarics, Zoltan; Leslie, Fraser; Luperchio, Steven A; Bartko, Johann; Schörgenhofer, Christian; Schwameis, Michael; Derhaschnig, Ulla; Lagler, Heimo; Stiebellehner, Leopold; Jilma, Bernd; Stevens, Christopher; Nagy, Eszter
• Is Part Of: Open forum infectious diseases. Volume 4(2017)Supplement 1
• Page Start: S310
• Page End: S310
• Publication Date: 2017-10-04
• Subjects: Communicable diseases -- Periodicals; Medical microbiology -- Periodicals; Infection -- Periodicals; 616.9
• DOI: 10.1093/ofid/ofx163.722
• Languages: English
• ISSNs: 2328-8957

Abstract

Abstract: Background: Monoclonal antibodies (mAbs) are well-suited for the prevention and treatment of acute bacterial infections. ASN100 is a combination of two fully human IgG1 mAbs, ASN-1 and ASN-2 that together neutralize six Staphylococcus aureus cytotoxins, alpha-hemolysin (Hla) and five leukocidins (HlgAB, HlgCB, LukED, LukSF [PVL] and LukGH) that are important in the pathogenesis of S . A ureus pneumonia. We aimed to characterize the pharmacokinetics (PK) of ASN100 in both serum and lung epithelial lining fluid (ELF) in male and female healthy volunteers. Methods: The safety, tolerability, and serum and lung PK of single intravenous infusion of ASN100 was evaluated in a Phase 1 study. Eight subjects (3:1 randomization) in two double-blind cohorts received ASN100 (doses of 3600 mg or 8000 mg) or placebo. ASN-1 and ASN-2 were administered in a fixed dose 1:1 ratio. Twelve subjects received ASN100 open-label at doses of 3600 mg or 8000 mg and each underwent two bronchoalveolar lavage (BAL) fluid collections either on days 1 and 30 or on days 2 and 8 post-dosing. ASN-1 and ASN-2 concentrations were determined by ELISA. The ELF concentrations were normalized based on urea concentrations in serum and BAL fluid. Results: No dose limiting toxicity was observed. Adverse events (AEs) showed no association of increased incidence with higher dose. All AEs were mild or moderate in severity, with 83.3% of subjects receiving ASN100 reporting at least one AE vs. 100% of placebo subjects. A dose proportional increase in serum peak and exposure (AUC) of ASN-1 and ASN-2 was observed and the serum PK of ASN-1 and ASN-2 were comparable (approximate half-life of each antibody was 3 weeks). Penetration of ASN-1 and ASN-2 into the ELF of the lung was observed at the first post-dose time point of 24 hours, peak concentrations were observed after day 2 and the mAbs remained detectable at day 30. Conclusion: ASN100 was safe and well tolerated at doses up to 8000 mg (4000 mg ASN-1 and 4000 mg ASN-2). The PK profiles of ASN-1 and ASN-2 were comparable following simultaneous administration. Significant lung concentrations of each mAb were demonstrated between day 1 and 30 post-dosing. These data support continued clinical development of ASN100 for the prevention and treatment of S . A ureus pneumonia. Disclosures: Z. Magyarics, Arsanis Biosciences GmbH: Employee, Salary. Arsanis, Inc.: Shareholder, Share options. F. Leslie, Arsanis., Inc.: Employee and Shareholder, Salary. S. A. Luperchio, Arsanis Inc.: Employee and Shareholder, Salary. B. Jilma, Arsanis Biosciences GmbH: Investigator, Investigator fee. C. Stevens, Arsanis Inc.: Employee and Shareholder, Salary.E. Nagy, Arsanis: Employee and Shareholder, Salary.