Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study of the Penetration of a Monoclonal Antibody Combination (ASN100) Targeting Staphylococcus aureus Cytotoxins in the Lung Epithelial Lining Fluid of Healthy Volunteers

Abstract

ASN100 is a novel antibody combination of two fully human IgG1(κ) monoclonal antibodies (MAbs), ASN-1 and ASN-2, which neutralize six Staphylococcus aureus cytotoxins, alpha-hemolysin (Hla) and five bicomponent leukocidins. We assessed the safety, tolerability, and serum and lung pharmacokinetics of ASN100 in a randomized, double-blind, placebo-controlled single-dose-escalation first-in-human study. Fifty-two healthy volunteers were enrolled and randomized to receive either ASN-1, ASN-2, a combination of both MAbs (ASN100), or a corresponding placebo. Thirty-two subjects in the double-blind dose escalation portion of the study received ASN-1 or ASN-2 at a 200-, 600-, 1,800-, or 4,000-mg dose, or placebo. Eight subjects received both MAbs simultaneously in a 1:1 ratio (ASN100) at 3,600 or 8,000 mg, or they received placebos. Twelve additional subjects received open-label ASN100 at 3,600 or 8,000 mg to assess the pharmacokinetics of ASN-1 and ASN-2 in epithelial lining fluid (ELF) by bronchoalveolar lavage fluid sampling. Subjects were monitored for 98 days (double-blind cohorts) or 30 days (open-label cohorts) for safety assessment. No dose-limiting toxicities were observed, and all adverse events were mild and transient, with only two adverse events considered possibly related to the investigational product. ASN100 exhibited linear serum pharmacokinetics with a half-life of approximately 3 weeks and showed detectable penetration into the ELF. No treatment-emergent anti-drug antibody responses were detected. The toxin neutralizing potency of ASN100 in human serum was confirmed up to 58 days postdosing. The favorable safety profile, ELF penetration, and maintained functional activity in serum supported the further clinical development of ASN100.

Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

“…No dose-limiting toxicities or treatment-emergent anti-drug antibody responses were detected [239]. All adverse events resolved without treatment and the frequency of these events was not dependent on dosages [239].…”

“…ASN100 demonstrated linear serum pharmacokinetics with a half-life of approximately three weeks and measurable levels of ASN-1 and ASN-2 were detected in ELF from as early as day one to day 30 post-dosing [239]. No dose-limiting toxicities or treatment-emergent anti-drug antibody responses were detected [239]. All adverse events resolved without treatment and the frequency of these events was not dependent on dosages [239].…”

“…The safety, tolerability and serum and lung pharmacokinetics of ASN-100 was investigated in a single-dose escalation, first-in-human study with 52 healthy volunteers [239]. ASN100 was administered intravenously as a 1:1 ratio of ASN-1 and ASN-2 simultaneously through separate intravenous lines at 3600 or 8000 mg [239].…”

“…The safety, tolerability and serum and lung pharmacokinetics of ASN-100 was investigated in a single-dose escalation, first-in-human study with 52 healthy volunteers [239]. ASN100 was administered intravenously as a 1:1 ratio of ASN-1 and ASN-2 simultaneously through separate intravenous lines at 3600 or 8000 mg [239]. ASN100 demonstrated linear serum pharmacokinetics with a half-life of approximately three weeks and measurable levels of ASN-1 and ASN-2 were detected in ELF from as early as day one to day 30 post-dosing [239].…”

“…ASN100 was administered intravenously as a 1:1 ratio of ASN-1 and ASN-2 simultaneously through separate intravenous lines at 3600 or 8000 mg [239]. ASN100 demonstrated linear serum pharmacokinetics with a half-life of approximately three weeks and measurable levels of ASN-1 and ASN-2 were detected in ELF from as early as day one to day 30 post-dosing [239]. No dose-limiting toxicities or treatment-emergent anti-drug antibody responses were detected [239].…”