Serum and Lung Pharmacokinetics of ASN100, a Monoclonal Antibody Combination for the Prevention and Treatment of Staphylococcus aureus Pneumonia

Abstract

BackgroundMonoclonal 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. Aureus 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.MethodsThe 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.ResultsNo 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.ConclusionASN100 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. Aureus 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.

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

“…Prophylaxis with mAbs directed against this toxin or use of the mAbs as an adjunctive therapy combined with antibiotics should improve survival rates. [372] One conserved epitope is able to bind five toxins alone.I ti sc urrently under investigation in phase II studies. It is currently being studied in phase II as an adjunctive therapy to standard-of-care antibiotics in patients diagnosed with severe hospital-acquired bacterial pneumonia.…”

“…[371] ASN-100 from Arsanis is ac ombination of two mAbs that target at otal of six different S. aureus toxins,w hich are involved in killing various immune system components,s uch as macrophages and neutrophils. [372] One conserved epitope is able to bind five toxins alone.I ti sc urrently under investigation in phase II studies.…”

Disarming Staphylococcus aureus from destroying human cells by simultaneously neutralizing six cytotoxins with two human monoclonal antibodies

“…Based on the pharmacokinetic analysis from a healthy volunteer study, this ASN100 dose is expected to result in approximately 450 µg/mL initial and >150 µg/mL plasma levels of ASN-1 and ASN-2 for at least 2 weeks following intravenous administration. 58 …”

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

“…Bei der Antivirulenz-Strategie werden mAbs mit dem Ziel entwickelt, bakterielle Toxine zu binden. [372] Ein konserviertes einzelnes Epitop ist dabei in der Lage,f ünf Toxine zu binden. Die prophylaktische Therapie mit mAbs,d ie gegen dieses Toxin gerichtet sind, oder die Anwendung dieser mAbs als Begleittherapie zusammen mit Antibiotika sollten demnach die Überlebensrate verbessern.…”

“…[371] Bei ASN-100 von der Firma Arsanis handelt es sich um eine Kombination zweier verschiedener mAbs,d ie insgesamt sechs verschiedene S.-aureus-Toxine binden kçnnen, welche bei der Abtçtung verschiedener Komponenten des Immunsystems,w ie Makrophagen und Neutrophile,m itwirken. [372] Ein konserviertes einzelnes Epitop ist dabei in der Lage,f ünf Toxine zu binden. Derzeit befindet sich der Wirkstoffkandidat in der klinischen Phase II.…”